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Item 1. Business

2023-03-28 compared with 2022-03-29 · 469 added, 421 removed, 564 unchanged (61% of the section changed)

HCW Biologics Inc.

("HCW Biologics", "HCW", the "Company, or "we") is a biopharmaceutical company focused on discovering and developing novel immunotherapies to lengthen health span by disrupting the link between chronic, low-grade inflammation and age-related diseases.

is a clinical-stage biopharmaceutical company focused on discovering and developing novel immunotherapies to lengthen health span by disrupting the link between chronic, low-grade inflammation and age-related diseases.

We believe age-related, chronic, low-grade inflammation, or “inflammaging,”

is a significant contributing factor to several diseases and conditions, such as cancer, cardiovascular disease, diabetes, neurodegenerative diseases, and autoimmune diseases.

The induction and retention of low-grade inflammation in an aging human body is mainly the result of the accumulation of non-proliferative senescent cells and persistent activation of protein complexes, known as inflammasomes, in innate immune cells.

These two elements share common mechanisms in promoting secretion of proinflammatory proteins and in many cases interact to drive inflammaging.

Our novel approach is to treat both of these elements.

The induction and retention of low-grade inflammation in an aging human body is mainly the result of the accumulation of non-proliferative but metabolically active senescent cells, which can also be caused by persistent activation of protein complexes, known as inflammasomes, in innate immune cells.

These two elements share common mechanisms in promoting secretion of pro-inflammatory proteins and in many cases interact to drive senescence, and thus, inflammaging.

Our novel approach is to reduce senescent cells and eliminate the pro-inflammatory factors they secrete systemically through multiple pathways.

We believe our approach has the potential to fundamentally change the treatment of age-related diseases.

We have combined our deep understanding of disease-related immunology with our expertise in advanced protein engineering to develop our TOBI TM (Tissue factOr-Based fusIon) discovery platform for the design of category-defining immunotherapeutic drugs.

This modular and tunable technology has allowed us to generate a novel pipeline of internally-developed product candidates capable of activating and targeting desired immune responses and blocking unwanted immunosuppressive activities.

Using our TOBI TM platform, we have successfully developed over 30 molecules that can be administered by subcutaneous injection as well as used in adoptive cell therapy approaches.

Our focus is to develop immunotherapeutic therapies administered by subcutaneous injection, and we intend to out-license cell therapy based approaches.

Senescence is a physiologic process important in promoting wound healing, tissue homeostasis, regeneration, embryogenesis, fibrosis regulation, and tumorigenesis suppression.

However, accumulation of senescent cells with Senescence-Associated Phenotype (“SASP”) pro-inflammatory factors has been implicated as a major source of chronic sterile inflammation leading to many aging-related pathologies.

SASP factors, including pro-inflammatory cytokines, chemokines, and proteinases, drive an inflammation cycle.

Senescence is considered a stress response and can be induced by a wide range of intrinsic and extrinsic insults.

Over time, these insults cause normal tissue cells to enter a senescent state of irreversible growth arrest accompanied by the release of SASP factors.

The inflammation cycle promoted by SASP factors also activates inflammasomes.

As the first line of defense to infections or tissue injuries, the innate immune system activates inflammasomes to initiate protective immune responses.

Similar to senescent cells, prolonged activation of inflammasomes promote the release of highly pro-inflammatory cytokines.

Unresolved activation of inflammasomes due to chronic infection or persistent tissue injury leads to chronic low-grade inflammation, which perpetuates this cycle.

We have combined our deep understanding of disease-related immunology with our expertise in advanced protein engineering to develop our TOBI TM discovery platform, or Tissue factOr-Based fusIon discovery platform, for the design of category-defining immunotherapeutic drugs.

Our focus is to develop protein-based immunotherapies that are administered by subcutaneous injection.

We have selected two molecules as our lead product candidates:

HCW9218 and HCW9302.

HCW9218 is a bifunctional immunotherapeutic designed with the capabilities to neutralize transforming growth factor-β

and stimulate immune cells, targeting senescent cells and the SASP factors they secrete.

HCW9302 is designed to activate and expand regulatory T cells, which deactivate inflammasomes.

We have chosen these product candidates because we believe they have the potential to become transformative immunotherapeutics for the treatment of a broad range of age-related diseases, and both can be administered to patients by subcutaneous injection.

In response to physiological or environmental stress, normal tissue cells enter a senescent state of irreversible growth arrest accompanied by the release of Senescence-Associated Secretory Phenotype (“SASP”) factors.

SASP factors, including proinflammatory cytokines, chemokines, and proteinases, drive the inflammation cycle, including activation of inflammasomes.

As our body ages, senescent cells accumulate and increase the release of SASP factors leading to chronic, low-grade inflammation, and organ/tissue damage.

Studies have shown that strategies to reduce or eliminate senescent cells can delay, prevent, and improve age-related dysfunctions, including cancer.

The bifunctionality of HCW9218 allows it to function as both a senolytic and senomorphic immunotherapeutic.

HCW9218 is designed to treat the impact of accumulated senescent cells and the SASP factors which they secrete by eliminating senescent cells (i.e., senolytic effect) and reducing SASP factors (i.e., senomorphic effect).

This molecule is a heterodimeric, bifunctional fusion protein complex comprising extracellular domains of the human transforming growth factor-β

Unfortunately, to date, there has been limited clinical success in targeting senescent cell accumulation or aberrant inflammasome activity using small molecule-based approaches.

Preclinical research and preliminary results from first-in-human clinical trials indicate that our immunotherapeutic approach may achieve success for cancer indications, and many other age-related diseases and conditions.

We believe our lead product candidates represent a novel immunotherapeutic approach and clinically promising new class of senotherapeutic drugs for the treatment of age-related diseases.

Novel Bifunctional Immunotherapeutic with TGF-β

HCW9218 is designed to treat the impact of accumulated senescent cells and the SASP factors which they secrete by eliminating senescent cells ( i.e.

, senescent cell reducing effect) and reducing SASP factors ( i.e.

, senomorphic effect).

This molecule is a heterodimeric, bifunctional fusion protein complex comprised of extracellular domains of the human transforming growth factor-β

(“TGF-β”) receptor II, as a TGF-β

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Together, the activities of these domains drive senescent cell clearance and SASP factor neutralization.

The Company published a paper authored by our scientific research team in the peer-reviewed journal, Molecular Therapy, entitled, “Bifunctional TGF-β

The Company published a paper in October 2021 authored by our scientific research team in the peer-reviewed journal, Molecular Therapy , entitled “Bifunctional TGF-β

trap/IL-15 Protein Complex Elicits Potent NK Cell and CD8 + T Cell Immunity Against Solid Tumors.”

The paper highlights preclinical data from in vivo studies demonstrating the potential of HCW9218 as a novel immunostimulant with the ability to simultaneously lessen immunosuppression in patients with cancer.

As the first line of defense to infections or tissue injuries, the innate immune system activates inflammasomes to initiate protective immune responses.

Similar to senescent cells, activated inflammasomes promote the release of proinflammatory factors.

Unresolved activation of inflammasomes due to chronic infection or persistent tissue injury leads to chronic low-grade inflammation which perpetuates this cycle.

HCW9302 is designed to activate and expand regulatory T (“T reg ”) cells to suppress the activity of inflammasome-bearing cells and the inflammatory factors which they secrete.

This molecule is a single-chain, IL-2-based fusion protein.

Inflammasomes are expressed in innate immune cells.

When these cells are stimulated by various signals, the inflammasomes become active and the cells release inflammatory factors.

In certain conditions, these signaling pathways persist leading to chronic inflammatory responses and associated tissue destruction.

Preclinical studies in mouse models have demonstrated the ability of HCW9302 to activate T reg cells and reduce inflammation-related diseases, supporting the potential of HCW9302 to treat a wide variety of autoimmune and age-related diseases.

To date, there has been limited clinical success in targeting senescent cell accumulation or aberrant inflammasome activity using small molecule-based approaches.

Studies have found the immune cell activity in young individuals is capable of limiting these processes, which we believe indicates that immunotherapeutic approaches that combine relevant stimulatory and inhibitory components may provide a means of treating age-related diseases by addressing chronic inflammation.

Novel Senolytic and Senomorphic Immunotherapeutic

We have selected cancer as the initial indication for our clinical development.

In cancer patients, chemotherapy treatments cause therapy-induced senescence, or TIS, which drives tumor cells to senescence, resulting in increased drug-resistance, immune evasion, disease relapse, and tumor metastasis.

We believe the bifunctionality of HCW9218 will allow it to be effective against solid tumor cancers because it simultaneously provides immunostimulation of natural killer (“NK”) cells and effector T cells to enhance the cytotoxicity of immune cells against tumor targets, while reducing immunosuppression associated with solid tumors by capturing and neutralizing TGF-β.

The paper highlights preclinical data from in vitro and in vivo studies demonstrating the potential of HCW9218 as a novel immunostimulant with the ability to simultaneously lessen immunosuppression in patients with cancer.

Chemotherapy is the current standard of care for treating most forms of cancer.

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The persistence of viable and metabolically active senescent tumor cells after chemotherapy has been attributed to worse overall survival in patients.

Tumor cells can undergo senescence and secrete proinflammatory factors, or SASP factors, in response to chemotherapy.

Tumor cells can undergo senescence and secrete pro-inflammatory factors, or SASP factors, in response to chemotherapy, a process referred to a therapy-induced senescence (“TIS”).

SASP factors promote TIS cancer cells to re-enter the growth cycle with stem-like characteristics which can result in disease relapse and metastasis.

One of the key SASP factors is TGF-ß, well known for its immunosuppressive role in cancer progression.

In healthy tissue, TGF-ß

One of the key SASP factors is TGF-β, well known for its immunosuppressive role in cancer progression.

In healthy tissue, TGF-β

is transiently activated in response to tissue injury, resulting in collagen production and, ultimately, healing of the tissue.

However, when TFG-ß

However, when TGF-β

becomes continuously active, studies have shown that it induces pathological effects associated with inflammation.

Food and Drug Administration (“FDA”) has permitted two clinical trials to proceed to evaluate HCW9218 in difficult-to-treat cancer indications.

A Company-sponsored clinical trial will evaluate HCW9218 in advanced pancreatic cancer, and an Investigator-sponsored trial with the Masonic Cancer Center at University of Minnesota as the sponsor will evaluate HCW9218 in other solid tumors.

Company-sponsored clinical trial.

In October 2021, the FDA permitted a Company-sponsored first-in-human Phase 1b clinical trial to proceed with a multi-site trial to evaluate our lead drug candidate, HCW9218, in patients with advanced pancreatic cancer.

The Company has identified several potential clinical sites that are National Cancer Institute (“NCI”) designated Comprehensive Cancer Centers.

These Comprehensive Cancer Centers are completing their internal review processes for study start-up.

We expect to initiate this trial in the first half of 2022.

The Phase 1b portion is planned to be a dose escalation study of HCW9218 as a monotherapy in refractory patients with advanced pancreatic cancer.

If the initial phase of the trial is completed successfully, the Company plans to have the primary aim of the later phases of the study to evaluate HCW9218 as an adjunct therapy to chemotherapy.

We expect that the Phase 2 portion of this pancreatic trial will include a cohort of patients receiving HCW9218 as monotherapy and a cohort of patients receiving HCW9218 as an adjunct to chemotherapy.

Investigator-sponsored clinical trial.

In January 2022, the FDA permitted the Masonic Cancer Center at University of Minnesota to proceed with a Phase 1 clinical trial, which is a single-center, Investigator-sponsored clinical trial to evaluate HCW9218 in patients with advanced solid tumors with progressive disease after prior chemotherapies.

We expect to initiate this trial in the first half of 2022.

The Masonic Cancer Center is the Twin Cities’

only NCI-designated Comprehensive Cancer Center, and they are designated ‘Outstanding’

by the National Cancer Institute.

This trial is planned to be a dose-escalation study and is designed as a “basket trial”

and may include patients with breast, ovarian, prostate, and colorectal cancers.

The Principal Investigator of the clinical trial is Melissa A.

Geller, M.D., M.S., Professor and Division Director of Gynecologic Oncology in the Department of Obstetrics, Gynecology and Women’s Health at the University of Minnesota.

The Co-Principal Investigator is Jeffrey A.

Miller, M.D., Deputy Director of the Masonic Cancer Center.

If the initial phase of the trial is completed successfully, the Principal Investigators may design later phases of clinical trials in solid tumors with the end goal of estimating the response in select solid tumors in combination with disease-appropriate anti-cancer treatment.

The timing of the initiation of the Company-sponsored clinical trial depends upon completion of an internal review and approval process required for each site in order to participate in a clinical study.

If any of the clinical sites we have selected does not receive approval to participate, then we will need to identify other potential clinical sites which may cause a delay.

The duration of both the Company-sponsored trial and the Investigator-sponsored trial is expected to be approximately 12 months once patient enrollment begins;

however, the timing depends on site preparation, how quickly patients can be enrolled in the studies, and the number of dose escalations that will be required to meet the primary objective of the studies.

If all of the currently available lot of HCW9218 is used in the initial phase of the trial, continuing to the next phase of clinical trials is contingent upon obtaining FDA

approval of additional lots of cGMP material.

Since we plan to have product release of additional cGMP material that meets FDA requirements by the end of 2022, we do not anticipate any delay in advancing our clinical trial to the next phase due to supply issues.

However, we cannot assure you that supply will be available if and when it is needed owing to, among other things, the ongoing macro supply chain issues arising from the impact of the COVID-19 pandemic, which are beyond our control.

See “Risk Factors -- Supply sources could be interrupted from time to time and, if interrupted, there is no guarantee that supplies could be resumed within a reasonable time frame and at an acceptable cost or at all.”

We have selected difficult-to-treat, chemo-resistant cancer indications for our initial clinical trials.

We believe a well- designed clinical trial in such challenging indications will demonstrate that HCW9218 can improve the efficacy of chemotherapy and minimize its side effects by eliminating TIS, that is chemotherapy-induced senescent cells in tumors and normal tissues.

We are leveraging the extensive clinical expertise of our team to structure clinical trials with clear, objective, and measurable endpoints.

We intend to manage initial clinical trials internally and will not use a clinical research organization to assist us.

In preclinical animal tumor models, HCW9218 treatment reduced the immunosuppressive tumor microenvironment and enhanced immune cell infiltration and cytotoxicity in the tumors to eliminate TIS cancer cells, thus improving the efficacy of chemotherapy.

Additionally, HCW9218 treatment following chemotherapy further enhanced anti-tumor activity of tumor antigen-specific and anti-programmed death-ligand 1 (“PD-L1”) antibodies in tumor-bearing mice.

The results of these studies have been published by our scientific research team in April 2022 in the peer-reviewed journal, Molecular Therapy , entitled “Immunotherapeutic HCW9218 Augments Anti-Tumor Activity of Chemotherapy via NK Cell-Mediated Reduction of Therapy-Induced Senescent Cells.”

We believe these findings support the clinical development of HCW9218 in combination with standard-of-care anti-cancer therapies, including chemotherapies, therapeutic antibodies and immune checkpoint inhibitors, for patients with cancer.

Novel Immunotherapeutic for T reg Expansion

Our internally developed, lead product candidate, HCW9302, is an IL-2-based fusion molecule that expands T reg cells in vivo and ex vivo as an injectable or cell-based strategy to reduce inflammation through deactivation of inflammasomes.

Preclinical studies have demonstrated the ability of HCW9302 to reduce inflammation, allowing for the potential to treat a wide variety of autoimmune and age-related diseases.

We expect to complete activities required for submission of an Investigational New Drug Application (“IND”) to evaluate HCW9302 in an autoimmune disorder by the end of 2022.

Upon completion of IND-enabling activities, we intend to submit an IND for a Phase 1b clinical trial to evaluate HCW9302 in alopecia areata.

We have not submitted the IND for the planned trial, and we cannot provide any assurance that the FDA will allow us to initiate our planned clinical trials on a timely basis, or at all.

In the event that the FDA does not accept our IND, we may also be required to seek feedback, and the feedback may be unfavorable.

In the event we do not receive feedback on a timely basis, or we are required to change the design of our clinical protocol or address other feedback, clinical development of our products would be delayed and our costs may increase.

Moreover, if the FDA does not allow our initial clinical trial to proceed, we may be required to conduct additional preclinical testing or other IND-enabling activities, which would result in further delay and additional costs.

If we successfully complete a Phase 1b study, we plan to build on the safety data established with alopecia areata and expand indications in Phase 2 clinical trials to evaluate HCW9302 in other autoimmune indications or pro-inflammatory diseases, such as atherosclerosis.

Out-Licensing:

Strategy for Monetizing Non-Core Assets

We have internally-developed over 30 molecules using our TOBI TM platform.

In preclinlical studies, several of these molecules show pharmacological activity when administered as an injectable as well as a cell-based therapy.

Our core focus will be the development of our lead product candidates, HCW9218 and HCW9302, as transformative immunotherapeutics, administered by subcutaneous injection.

We intend to out-license certain rights for other internally-developed molecules with commercial potential that are outside of our focus area.

We signed our first out-license agreement at the end of 2020, when we entered into an exclusive worldwide license with Wugen, Inc.

HCW9302 is designed to activate and expand regulatory T (“T reg ”) cells to suppress the activity of inflammasome-bearing cells and the inflammatory factors which they secrete.

This molecule is a single-chain, IL-2-based fusion protein.

Inflammasomes are expressed in innate immune cells.

When these cells are stimulated by various signals, the inflammasomes become active and the cells release inflammatory factors.

In certain conditions, these signaling pathways persist leading to chronic inflammatory responses and associated tissue destruction.

The Company published a paper in January 2023 that was authored by our scientific research team in the peer-reviewed journal, Frontiers in Immunology , entitled, “A Novel Interleukin-2-Based Fusion Molecule, HCW9302, Differentially Promotes Regulatory T Cell Expansion to Treat Atherosclerosis in Mice.”

The paper highlights preclinical data from in vitro and in vivo studies demonstrating the potential of HCW9302 as a novel immunotherapeutic with the ability to suppress the progression of atherosclerosis.

IL-2 signaling is essential for homeostasis of T reg cells.

Since recombinant IL-2 has an unfavorable pharmacokinetic profile limiting its therapeutic use, our challenge was to create an immunotherapeutic with the therapeutic advantages of IL-2 but was well tolerated.

HCW9302 addresses this challenge.

As described in our Frontiers in Immunology paper, we found that HCW9302 exhibited a longer serum half-life with an approximately 1,000-fold higher affinity for the IL2Rα

In addition, preclinical studies have shown HCW9302 can be administered at a dosing range that expanded and activated T reg cells but not CD4 + effector T cells.

We believe that these studies support the clinical development of HCW9302 as a potential therapeutic agent for treatment of autoimmune and pro-inflammatory diseases.

Other Compounds under Development

Using our TOBI platform, we have successfully developed over 30 molecules that can be administered by subcutaneous injection as well as used in adoptive cell therapy approaches.

We have a library of fusion molecules with cytokines, chemokines, ligands, receptors, and internally-developed single-chain antibodies.

Clinical Development Strategy

HCW Biologics has a two-pronged clinical development strategy based on its two lead product candidates.

Currently, we are managing our clinical trials internally.

The fusion protein compounds we created have demonstrated the ability to activate the immune system in vivo and ex vivo as an injectable or cell-based strategy;

however, we have chosen to focus clinical development on immunotherapeutics administered by subcutaneous injection.

We believe that our chosen method of administration will align with growing concerns about the costs associated with health care treatments.

Our vision is to simplify administration by developing injectable treatments that can be administered in a physician’s office or, in some instances, self-administered at home.

HCW9218 is currently being evaluated in two clinical trials.

The Company has selected difficult-to-treat cancer indications as the gateway indication.

A Company-sponsored, multi-center Phase 1b/2 clinical trial is being conducted to evaluate HCW9218 in advanced pancreatic cancer.

An Investigator-sponsored Phase 1 clinical study to evaluate HCW9218 in chemo-refractory/chemo-resistant solid tumors is being conducted by the Masonic Cancer Center, University of Minnesota.

There have been no dose-limiting toxicities reported for either trial.

For Phase 2 studies, we expect to evaluate HCW9218 in patients as a second line treatment and/or as an adjuvant therapy with standard-of-care treatments.

From the solid tumor trial, we intend to narrow the indication to one type of cancer, such as ovarian cancer.

Advancing HCW9218 to Phase 2 clinical trials depends on successfully completing the Phase 1 trial, identifying the Recommended Phase 2 Dose (“RP2D”), securing clinical sites for the Phase 2 study, and receiving authorization from the FDA to proceed.

Extensive, rigorous preclinical testing and research is being conducted to identify expanded indications for future clinical development.

We believe that HCW9218 represents a new class of safe and effective senescent cell reducing and senomorphic drugs for the treatment of a broad range of inflammaging indications, including cancer, metabolic dysfunctions, fibrosis-related pathologies, as well as neuro-inflammation and neurodegenerative diseases, such as Parkinson’s and Alzheimer’s Diseases.

HCW9302 is a preclinical molecule which is a fusion protein that contains two IL-2 domains linked by an extracellular tissue factor domain.

Recombinant IL-2 has an unfavorable pharmacokinetic profile limiting its therapeutic use.

HCW9302 is designed to overcome the most restrictive issue of its dose-limiting toxicities.

Preclinical studies demonstrated the HCW9302 exhibited longer serum half-life and was well tolerated, offering support for the potential of HCW9302 to treat a wide variety of autoimmune and pro-inflammatory, age-related disease.

For our lead molecule HCW9302, the Company plans to use an autoimmune disease as the gateway indication for clinical development.

If we are successful in advancing the clinical development of HCW9302, we intend to expand to other pro-inflammatory indications.

The Company expects to complete the activities required to prepare an Investigational New Drug (“IND”) application in the first half of 2023.

We expect to submit an IND application for a Phase 1b/2 clinical study to evaluate HCW9302 in an autoimmune disease to the FDA in the second half of 2023.

Our ability to initiate a clinical trial to evaluate HCW9302 in an autoimmune disease depends on completion of our toxicology studies, preparation and submission of an IND, and obtaining clearance to proceed from the FDA.

Out-Licensing, Cooperative Agreements and Strategic Collaborations

We continue to pursue our strategy of out-licensing certain rights outside of our focus area for our existing molecules and discovery programs created with our TOBI discovery platform, as further discussed under “—Out-License Programs.”

We plan to expand our out-licensing discussions to include marketing rights to those regions outside of our focus area.

We believe the potential for cooperative agreements and collaborations is growing for HCW Biologics, since we are now a clinical-stage company with human data, peer-reviewed research publications, CMC manufacturing and issued patents on fundamental intellectual property.

We signed our first out-license agreement at the end of 2020, when we entered into an exclusive worldwide license (the “Wugen License”) with Wugen, Inc.

(“Wugen”), a company that specializes in cell-based therapies for cancer.

Wugen licensed limited rights to develop, manufacture, and commercialize cell therapy treatments for cancer based on two of our internally-developed multi-cytokine fusion protein molecules.

Our clinical-stage molecule, HCW9201, is currently being evaluated for generation of memory-like NK (“ML-NK”) cell products in two Phase 2 studies with patients with relapsed/refractory Acute Myeloid Leukemia ("r/r AML").

The studies were initiated by the School of Medicine at Washington University in St.

Louis and are supported financially by Wugen.

HCW Biologics is currently assessing opportunities to out-license rights to HCW9302, our molecule for T reg activation and expansion, under terms that may include an upfront licensing fee, milestone payments based on performance, and a royalty based on sales of commercial products.

Wugen licensed limited rights to develop, manufacture, and commercialize cell-based therapy treatments for cancer based on two of our internally-developed, multi-cytokine fusion protein molecules, HCW9201 and HCW9206.

On December 3, 2022, under a Cooperative Research and Development Agreement (“CRADA”), the National Cancer Institute (“NCI”) and HCW Biologics are collaborating to perform a Phase 1b/2 clinical study to evaluate the safety and tolerability of HCW Biologics’

lead product candidate, HCW9218, in patients with advanced/metastatic and chemo-refractory/chemo-resistant pancreatic cancer.

The CRADA is entitled, “A Phase 1b/2 Study of HCW9218, a Bifunctional TGF- β

Antagonist/IL-15 Protein Complex, for Advanced Pancreatic Cancer.”

The Principal Investigator at NCI is Christine Alewine, M.D., Ph.D.

Alewine is a Lasker Clinical Research Scholar at the National Institutes of Health in the Laboratory of Molecular Biology.

Her research focuses on identifying new treatments for pancreatic cancer including pancreatic adenocarcinoma, adenosquamous carcinoma, and acinar cell carcinoma.

Alewine is board certified in internal medicine and medical oncology.

We are exploring potential cooperative agreements with pharmaceutical companies for joint clinical trials relating to Phase 2 clinical trials to evaluate HCW9218 in cancer indications when used as an adjuvant therapy to a standard-of-care treatment.

This type of arrangement would allow us to evaluate HCW9218 in combination with other cancer treatments with some assistance in offsetting the costs of a Phase 2 randomized trial.

The indications we would target for study in these trials are ovarian and pancreatic cancer, although the targeted indication(s) may change as discussions continue.

While we are encouraged by the interest shown by these pharma companies, there are no assurances that we will enter into cooperative arrangements for Phase 2 clinical trials to evaluate HCW9218 in combination with cancer therapies.

Clinical Development Update

The Company's lead immunotherapeutic programs are summarized in the table below:

There is an ongoing Company-sponsored Phase 1b/2 clinical trial to evaluate HCW9218 in patients with advanced chemo-refractory/chemo-resistant pancreatic cancer.

There is an ongoing Investigator-sponsored Phase 1 clinical trial to evaluate HCW9218 in patients with chemo-refractory/chemo-resistant solid tumors, including ovarian, prostate, breast and colorectal cancers.

Wugen’s lead clinical program, WU-NK-101, is based on HCWB licensed molecules.

Wugen holds an exclusive worldwide license for two of our molecules, HCW9201 and HCW9206.

The Wugen License conveys limited rights to develop cell-based therapy treatments for cancer using the licensed molecules.

HCW Biologics has retained all other rights to HCW9201 and HCW9206, including, but not limited to, manufacturing rights and injectable rights.

Phase 1b/2 Clinical Trial to Evaluate HCW9218 in Pancreatic Cancer

This multi-center Company-sponsored Phase 1b/2 clinical trial was initiated in October 2022.

There are currently four clinical sites participating in this trial, including the NCI Center for Cancer Research, Medical University of South Carolina (an NCI-designated Comprehensive Cancer Center), Washington University in St.

Louis (an NCI-designated Comprehensive Cancer Center), and HonorHealth Research Institute.

A preliminary human data readout is expected in the first half of 2023.

We expect to complete the Phase 1b portion of this study in 2023.

Phase 1 Clinical Trial to Evaluate HCW9218 in Solid Tumors

HCW9218 reached the clinical stage of its development in the first half of 2022, with the initiation of a Phase 1 clinical trial by the Masonic Cancer Center, University of Minnesota (“UMN”) to evaluate HCW9218 in the treatment of solid tumor cancers that progressed after at the least of two lines of standard-of-care treatment.

UMN presented preliminary human data from the solid tumor trial in a poster presentation at the 2022 Society for Immunotherapy of Cancer annual conference in November 2022.

Analysis of blood samples and biopsies taken from participants in the Phase 1 study shows encouraging preliminary results for the level of immune system responses after HCW9218 administration, as well as no incidence of mucosal bleeding caused by the HCW9218 TGF-β

Based on the results of the Phase 1 study, we expect to complete selection of the recommended Phase 2 dose in the first half of 2023.

IND-Enabling Activities for HCW9302

For HCW9302, IND-enabling activities are expected to be completed in the first half of 2023.

We plan to submit an IND to the FDA for a Phase 1b/2 clinical trial to evaluate HCW9302 in an autoimmune disorder in the second half of 2023.

Our ability to evaluate HCW9302 in a clinical trial depends on completion of our toxicology studies, preparation and submission of an IND, and obtaining clearance to proceed from the FDA.

We believe we have an innovative strategy to treat age-related diseases.

Our unique approach is to utilize our internally-developed TOBI TM platform to create novel multi-functional immunotherapeutics to rejuvenate our immune system.

With our platform technology, we have generated product candidates that are designed to direct the immune system against solid tumors, therapy-induced senescence and the adverse side effects triggered by existing standard-of-care treatments for cancer, and hematological cancers.

We have also developed product candidates that are designed to direct the immune system against inflammation allowing for the potential to treat a wide variety of autoimmune and proinflammatory diseases.

Our approach is to develop immunotherapies that eliminate the main drivers of chronic inflammation by addressing the underlying development and sustainment of these factors, as depicted in the image below:

Our unique approach is to utilize our internally-developed TOBI platform to create novel multi-functional immunotherapeutics to rejuvenate the immune system.

Our approach is to develop immunotherapies that reduce or eliminate the main drivers of chronic inflammation by addressing the underlying development and sustainment of these processes, as depicted in the image below:

The Science of Chronic Inflammation

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However, in addition to cytotoxic activity, chemotherapy also can cause tumor cells to enter a TIS state with SASP characteristics.

The persistence of viable and metabolically active senescent tumor cells after chemotherapy has been attributed to worsen overall survival in patients.

Chemotherapy targets rapidly proliferating cancer cells, exposes a stressor to normal cells which drive them into senescence, paracrine effects of inflammatory factors, or SASP factors, secreted by these senescent cells, and epigenetic changes induce these cells to more aggressive cancer stemness.

The persistence of viable and metabolically active senescent tumor cells after chemotherapy has been attributed to worse overall survival in patients.

Chemotherapy exposes a stressor to rapidly proliferating cancer cells, which drives them into senescence, triggers paracrine effects of inflammatory factors, or SASP factors, secreted by these senescent cells, and promotes epigenetic changes that induce these cells to more aggressive cancer stemness.

Systemic chemotherapy has also been found to elevate normal tissue senescence.

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Survivors from childhood cancers post-chemotherapy treatment also have been found to have high rates of developing secondary cancer, spinal disorders, and pulmonary diseases in adulthood.

Furthermore, it is well established that clinical use of chemotherapies is associated with long-term damage to normal tissues and organs resulting from accumulation of TIS cells and proinflammatory SASP factors.

Therefore, we believe that therapeutic approaches that alleviate chemotherapy-induced senescent cells and SASP factors in normal tissue may lead to a better quality of life for cancer patients.

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Inflammasomes are large, multimeric protein complexes that are another contributing factor to chronic inflammation.

Their assembly in innate immune cells and other cells is triggered by a variety of stimuli and culminates in the activation of Caspase-1 which then cleaves pro-interleukin (“IL”)-1ß

to IL-1ß.

Their assembly in innate immune cells and other cells is triggered by a variety of stimuli and culminates in the activation of Caspase-1 which then cleaves pro-IL-1β

to IL-1β.

To date, diverse inflammasomes have been discovered.

Among the various inflammasomes identified, the nucleotide-binding oligomerization domain, leucine-rich repeat-containing receptor (“NLR”) family pyrin domain-containing three NLR (“NLRP3”) inflammasome is best characterized.

The NLRs are recognized as the key sensors of pathogens and danger signals known as PAMPs and DAMPs.

The NLRs are recognized as the key sensors of pathogens and danger signals triggered by molecules known as PAMPs and DAMPs.

The NLRP3 inflammasome has a two-step activation mechanism:

“priming”, which entails induction of pro-IL-1ß

and NLRP3, and “activation”, wherein a functional inflammasome complex is assembled following uptake of PAMPs or DAMPs.

“priming”, which entails induction of pro-IL-1β

and NLRP3, and “activation”, wherein a functional inflammasome complex is assembled following recognition of PAMPs or DAMPs.

The pathology of various diseases, including Alzheimer’s disease, Parkinson’s disease, and atherosclerosis has been linked to hyperactivation of the NLRP3 inflammasome.

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Without addressing both processes, a chronic, low-grade inflammatory environment will persist, resulting in a diverse range of pathological manifestations including cancer, atherosclerosis, diabetes, and neurodegeneration.

Senolytic for Senescence Cell Clearance and Senomorphic for SASP Neutralization

Immune Cell Mediated Senescence Cell Clearance and Senomorphic for SASP Neutralization

Senescent cells are caused when a normal cell is exposed to various stress factors, many of which are simply a part of living and aging.

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SASP factors come in many different types, depending on the stressor and the cell type exposed to that stressor, but one thing they have in common is that they drive chronic, low-grade inflammation.

For example, TGF-ß

For example, TGF-β

is considered one of the key SASP factors that induces or accelerates and maintains a senescent phenotype in various cell types including fibroblasts, bronchial epithelial cells, and cancers in an autocrine/paracrine manner.

Thus, to neutralize these pathways, a drug must be a senolytic agent that reduces senescent cells, as well as a senomorphic agent that eliminates SASP factors.

Thus, to neutralize these pathways, a drug must be a senolytic agent that reduces senescent cells, as well as a senomorphic agent that reduces SASP factors.

Current clinical efforts to counteract TIS and age-related senescent cell activity have focused on senolytic chemical drugs that selectively induce senescent cell death and senomorphic chemical drugs that reduce the secretion of SASP factors.

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Further, the specificity, toxicity, and optimal treatment schedule of these pharmaceutical agents in the cancer setting have yet to be determined.

We have developed an alternative approach to eliminate senescent cells using well-characterized protein immunotherapeutics including those that stimulate effector immune cells and reduce TGF-β

We have developed an alternative approach to reduce senescent cells using well-characterized protein immunotherapeutics including those that stimulate effector immune cells and reduce TGF-β

This approach is supported by our findings that TIS tumor cells upregulate NKG2D and other ligands on their surface for efficient recognition and killing by effector NK cells and CD8 + T cells.

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HCW9218 is a unique combination of a TGF-β

receptor, that neutralizes TGF-β

secreted by tumors, combined with IL-15, a potent cytokine that stimulates the NK and CD8 + T cell cytotoxicity.

receptor, which neutralizes TGF-β

secreted by tumors, combined with IL-15, a potent cytokine that stimulates NK and CD8 + T cell proliferation and cytotoxicity.

In our scientific publications, we reported that HCW9218 can activate immune cells to infiltrate into tumors to directly eliminate TIS cancer cells.

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Therefore, TGF-β

neutralization combined with activation of effector immune cells should be considered as a part of the strategy for

senescent cell removal and reduction of SASP factors.

neutralization combined with activation of effector immune cells should be considered as a part of the strategy for senescent cell removal and reduction of SASP factors.

For a more detailed discussion, see the Company’s pivotal scientific paper entitled, “Immunotherapeutic HCW9218 Augments Anti-Tumor Activity of Chemotherapy via NK Cell-Mediated Reduction of Therapy-Induced Senescent Cells,”

published in Molecular Therapy .

published in Molecular Therapy in April 2022.

Deactivation of Inflammasomes by Activating T reg Cells

To date, therapeutic approaches to reduce aberrant inflammasome activity have focused on inhibitors of various inflammasome components (i.e., NLRP3 and other NLRs, ASC, Caspase-1) and downstream mediators of inflammation (i.e., IL-1ß, IL-18, gasdermin D, etc.).

This approach is validated based on the regulatory approval of three biologics that inhibit IL-1ß

To date, therapeutic approaches to reduce aberrant inflammasome activity have focused on inhibitors of various inflammasome components ( i.e.

, NLRP3 and other NLRs, ASC, Caspase-1) and downstream mediators of inflammation ( i.e.

, IL-1β, IL-18, gasdermin D, etc.).

This approach is validated based on the regulatory approval of three biologics that inhibit IL-1β

activity (anakinra, a recombinant form of the naturally occurring IL-1Ra;

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and canakinumab, a humanized monoclonal antibody specific for neutralizing IL-1ß).

Together, these molecules are approved for treatment of cryopyrin-associated periodic syndrome, a multisystemic IL-1ß–mediated disease due to a gain of function in NLRP3;

Together, these molecules are approved for treatment of cryopyrin-associated periodic syndrome, a multisystemic IL-1β–mediated disease due to a gain of function in NLRP3;

rheumatoid arthritis;

systemic juvenile idiopathic arthritis and other auto-inflammatory diseases.

We believe there is considerable interest in therapeutics that specifically block inflammasome activity upstream.

We believe there is considerable interest in other therapeutics that specifically block inflammasome activity upstream of IL-1β.

However, these product candidates are still in early phase clinical testing and their bioavailability, off- and on-target toxicity, and utility profiles are still being evaluated.

Our approach is to deactivate inflammasome pathways in monocytes and macrophages through the immunosuppressive activities of T reg cells induced by our immunomodulator molecules.

This approach does not rely on inhibiting specific inflammasome components but rather utilizes natural processes of the immune system to attenuate and rebalance chronic self-perpetuating proinflammatory responses.

In relevant animal models, we have observed encouraging results using HCW9302 to activate and expand T reg cells for treatment of atherosclerosis and diabetes.

HCW9302 Reduces Atherosclerosis Plaques Induced by High Fat Diet in ApoE -/- Mice

HCW9302 Reduces Atherosclerotic Plaques Induced by High Fat Diet in ApoE -/- Mice

Preclinical Data Showing Attenuation of Progression of Atherosclerosis

(A) Histochemical staining of aorta root sections and graphical comparisons of the atherosclerotic lesion formation (“H&E”) between control and HCW9302 treated ApoE deficient mice fed with a Western diet (“WD”).

(B) En face analysis of atherosclerotic lesions in the aorta including the arch, thorax, and abdomen from control and HCW9302 treated ApoE deficient mice fed with a WD.

Data in (A,B) are expressed as mean ±

SEM (n = 13-14).

Statistical analysis using a 2-tailed, unpaired “t”

(D) Reduction of pro-atherosclerotic transcriptomes in aortas of ApoE -deficient mice.

(C,D) The Wald test was used to generate p-values and log2 fold changes for RNA-Seq analysis.

Genes with an adjusted p-value < 0.05 and absolute log2 fold change > 1 were called as differentially expressed genes for each comparison.

Frontiers in Immunology , “A Novel Interleukin-2-Based Fusion Molecule, HCW9302, Differentially Promotes Regulatory T Cell Expansion to Treat Atherosclerosis in Mice,”

Zhu, X., et al., January 2023.

In RNA-Seq analysis performed on whole aorta of WD-fed ApoE deficient mice, we found that HCW9302 treatment resulted in changes of gene expression profiles consistent with reduced atherosclerotic lesions and enhanced tissue regeneration.

For more details, see the Company’s pivotal scientific paper, entitled, “A Novel Interleukin-2-Based Fusion Molecule, HCW9302, Differentially Promotes Regulatory T Cell Expansion to Treat Atherosclerosis in Mice,”

published in Frontiers in Immunology in January 2023 .

Our goal is to develop transformative immunotherapies to lengthen health span by disrupting the link between cellular senescence, chronic inflammation, and age-related diseases.

Our strategy for efficiently validating our approach includes the following key components:

Focus resources on internally-developed intellectual property, including molecules, TOBI TM platform, and manufacturing processes, without relying on third-party licensing for key intellectual property.

Our TOBI TM platform is a new approach to construct multi-functional fusion proteins and fusion protein complexes, using a novel TF-based scaffold platform.

Multiple protein targets (e.g.

cytokine, scFvs, ligands, etc.) can be packaged as a single molecule to engage immuno-stimulatory functions and address many signaling pathways simultaneously.

Fusion protein complexes have ex vivo and in vivo applications for stimulating NK and T cells.

Over 30 molecules have been created and characterized internally for ex vivo (i.e., to support cell therapies) and in vivo (i.e., as injectables) activation and expansion of NK, CD8 + T, Tscm, and T reg cells.

Fusion protein complexes are readily purified using internally-developed affinity chromatography.

Purified fusion protein complexes are highly stable immunotherapeutics.

Large-scale cGMP manufacturing runs have been demonstrated.

Focus our resources on the development of two primary internally-developed molecules for which we can establish strong IP protection, best activity in animal models, and a well-tolerated safety profile when administered by subcutaneous injection.

The activity of HCW9218 has been established in multiple in vivo animal studies, including reduction of cellular senescence and SASP factors in naturally-aged mice and elimination of cancer senescent cells caused by therapy-induced senescence to enhance efficacies of chemotherapies and remove the off-target effects caused by chemotherapy.

We have completed in vivo animal studies demonstrating the activity of HCW9218 in reversing Type 2 Diabetes and as an anti-fibrotic agent.

We have demonstrated the activity of HCW9302 to treat autoimmune and age-related diseases in relevant animal models.

Focus on cancer indications in initial clinical development of our lead product candidate, HCW9218, in indications with high unmet medical need or where side effects of standard-of-care therapy diminishes health span.

Cancer is our gateway indication.

We received FDA clearance to proceed with a Company-sponsored Phase 1b clinical trial to evaluate HCW9218 in refractory pancreatic cancer.

The Masonic Cancer Center at University of Minnesota received FDA clearance to proceed with an Investigator-sponsored Phase 1 clinical trial to evaluate HCW9218 in patients with solid tumors, such as breast, ovarian, colorectal and prostate cancers.

We expect to initiate both of these trials in the first half of 2022, but we cannot provide any assurance that the clinical sites will be ready to initiate the planned clinical trials on a timely basis, or at all.

Clinical trials will allow us to evaluate the development of our novel immunotherapeutics as we attempt to augment the efficacy of chemotherapy against cancer while minimizing its side effects.

Our clinical trial design will be designed to have clear, objective endpoints against which we can measure the success of our cancer treatment.

Because of our highly efficient design for neutralizing TGF-ß, we have targeted cancer indications with TGF-ß

mediated immunosuppression and a fibrotic tumor microenvironment (i.e., pancreatic, breast cancer).

We are focusing on difficult-to-treat indications for which there is high unmet medical needs.

If we are able to successfully complete our ongoing Phase 1/1b trials in cancer studies and establish safety and dosage, we intend to expand to indications other age-related diseases.

Clinical trials allow us to evaluate the development of our novel immunotherapeutics as we attempt to augment the efficacy of chemotherapy against cancer while minimizing its side effects.

As and to the extent we advance in clinical trials for cancer, we are initially focusing on clinical trials to evaluate HCW9218 as an adjuvant therapy to existing standard-of-care treatments.

Because of our highly efficient design for neutralizing TGF-β, we have targeted cancer indications with TGF-β

mediated immunosuppression and a fibrotic tumor microenvironment ( i.e.

, pancreatic and ovarian).

We plan to advance well-characterized immunotherapeutics with multiple mechanisms of action:

effector immune cell activation, suppression of TGF-ß, reduction of senescent cells (i.e., senolytics), and reduction of SASP (i.e., senomorphics).

effector immune cell activation, suppression of TGF-β, reduction of senescent cells, and reduction of SASP ( i.e.

, senomorphics).

Focus on autoimmune indications with high unmet medical need in initial clinical development of our lead product candidate, HCW9302.

IND-enabling activities and toxicology studies required for submission of an IND to evaluate HCW9302 in an autoimmune indication are expected to be completed in the second half of 2022, followed soon thereafter with an IND submission to evaluate HCW9302 in an autoimmune indication.

We have not yet submitted the IND, nor can we guarantee when the IND will be submitted.

IND-enabling activities and toxicology studies required for submission of an IND to evaluate HCW9302 in an autoimmune indication are expected to be completed in the first half of 2023, followed soon thereafter with an IND submission to evaluate HCW9302 in an autoimmune indication.

We have not yet submitted the IND, nor can we guarantee when the IND will be submitted, if at all.

Leverage established clinical trial network.

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Our founder and clinical development team have a track record of success in developing immuno-oncology therapeutics from bench to bedside.

We have selected leading NCI-designated Comprehensive Cancer Centers as potential clinical sites for our multi-center, Company-sponsored trial.

We are working with these institutions and Principal Investigators from these institutions to complete the required internal review processes for study start-up.

Because the discussions with these clinical sites and Principal Investigators are not finalized, we are not certain we will be successful in reaching an agreement with any or all of these institutions.

The course of these discussions and whether we might need to identify alternative clinical sites could impact the start date for our clinical trials.

Any delays in our clinical trials could increase our costs and slow down the development and approval process, which could harm our commercial prospects.

Expand clinical evaluation of senolytic/senomorphic product candidates to other age-related indications following establishment of a safe treatment regimen in cancer patients for HCW9218.

We may need pre-IND meetings for other cancer and non-cancer indications to determine if additional nonclinical toxicology studies are required.

We are conducting preclinical research studies to evaluate HCW9218 in liver cancer and NAFLD that we believe may support a future clinical study.

We are conducting preclinical research studies to evaluate HCW9218 in metabolic disease indications, specifically Type 2 Diabetes, leveraging our ability to reduce senescent cells and reduce SASP factors.

Out-license limited rights for certain HCW molecules outside of primary focus.

We intend to continue to seek partners for out-licenses for our internally-developed molecules with strong clinical potential that are part of our clinical development focus (i.e., adoptive cell therapies).

We consider this an attractive source of nondilutive financing.

Explore co-development or regional deals with big pharma for lead molecules.

We are actively seeking co-development deals for the further advancement of our lead molecules, including clinical development, and commercialization.

We are actively assessing whether it is advantageous for the Company to out-license rights to certain regional markets.

Our primary goal is to enter a co-development deal on the best terms possible, so we will not enter such a transaction if we conclude it is optimal for the Company to enter a big pharma co-development deal for worldwide rights.

Our Internally-Developed TOBI TM Platform

TOBI TM (Tissue factOr-Based fusIon) platform is a new approach to construct multi-functional fusion proteins and fusion protein complexes using a novel TF protein scaffold.

For our active clinical trials to evaluate HCW9218 in cancer indications, most of the clinical sites are NCI-designated Comprehensive Cancer Centers.

These clinical sites service large regions and due to their excellence often attract patients far from their local regions.

Identify non-dilutive financing events that allow us to advance the clinical development of our lead product candidates.

We intend to pursue several different avenues for non-dilutive financing events, including out-licensing non-core applications and market rights, cooperative agreements, strategic collaborations and project financing.

Explore co-development deals with big pharma for lead molecules in the longer term.

Our primary goal is to enter a co-development deal on the best terms possible, so we targeting to enter into a co-development deal after Phase 2 human clinical data is available.

Our Internally-Developed Tissue factOr-Based fusIon (“TOBI”) Platform

Our TOBI discovery platform is a new approach to construct multi-functional fusion proteins and fusion protein complexes using a novel TF protein scaffold.

The extracellular domain of human TF was selected as it has a rigid elongated structure comprised mainly of ß-sheets with its N- and C-termini located at distal ends of the polypeptide, permitting genetic fusions of other protein domains without anticipated steric interference.

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When co-expressed in CHO cells, the fusion proteins form a soluble stable heterodimeric complex through high-affinity interactions between IL-15 and IL-15Rα

This approach offers an alternative to immunoglobulin (Fc) and other

engineered protein scaffolds, which typically require introduction of multiple mutations or other non-human sequences or complicated in vitro assembly/purification methods to generate bi- or multi-specific complexes.

Using the TOBI TM platform, we have constructed more than 30 fusion complexes comprising various cytokines, ligands, receptors, and single-chain antibodies, including disease-targeting antibodies and immune checkpoint inhibitors.

This approach offers an alternative to immunoglobulin (Fc) and other engineered protein scaffolds, which typically require introduction of multiple mutations or other non-human sequences or complicated in vitro assembly/purification methods to generate bi- or multi-specific complexes.

Our internally-developed TOBI discovery platform was featured in an article authored by the Company and published in July 2021 in the peer-reviewed journal Cancer Immunology Research .

Using the TOBI platform, we have constructed more than 30 fusion complexes comprising various cytokines, ligands, receptors, and single-chain antibodies, including disease-targeting antibodies and immune checkpoint inhibitors.

The modular fusion components are carefully selected to stimulate, inhibit, and/or target specific immune responses using a knowledge-based disease-relevant strategy and in many cases, are designed to provide synergistic and balanced activities for optimal therapeutic benefit.

The resulting fusion proteins are rigorously tested in state-of-the-art cell culture systems and disease-specific animal models to verify their utility for the intended clinical use and targeted indications.

TOBI TM also provides a scalable approach for generating large-scale cGMP-grade heteromeric fusion protein complexes to support clinical applications.

Our internally-developed TOBI TM discovery platform was featured in an article authored by the Company and published in the peer-reviewed journal Cancer Immunology Research .

Pipeline and Overview of TOBI TM Product Candidates

Our focus for clinical development is our two lead product candidates, HCW9218 and HCW9302.

The initial clinical trials to evaluate HCW9218 are in several cancer indications.

The FDA has permitted our Company-sponsored, first-in-human Phase 1b clinical trial to proceed to evaluate HCW9218 in patients with advanced pancreatic cancer.

In addition, the Masonic Cancer Center at University of Minnesota received FDA clearance to proceed with a Phase 1 Investigator-sponsored clinical trial to evaluate HCW9218 in patients with other types of advanced solid tumors with progressive disease after prior chemotherapy.

We expect to initiate both of these trials in the first half of 2022.

For HCW9302, we expect to complete IND-enabling activities in the second half of 2022.

Upon the completion of IND-enabling activities, we intend to submit an IND to evaluate HCW9302 in the autoimmune indication, alopecia areata.

For our lead molecules, once the safe dose level and regimen are defined in initial clinical trials, we intend to expand into clinical trials to evaluate our lead molecules in other age-related pathologies.

For HCW9218, these include fibrotic diseases (e.g., non-alcoholic fatty liver disease, or NAFLD), liver cancer, and dysfunctional metabolic disorders (e.g., Type 2 diabetes);

and for HCW9302, these include autoimmune diseases and other proinflammatory diseases, such as coronary artery disease.

We have out-licensed limited rights for our molecules, HCW9201 and HCW9206, to develop cell-based therapy treatments.

Our clinical-stage molecule, HCW9201, is currently being evaluated in a pair of Phase 2 clinical trials for a cell-based therapy treatment for r/r AML by our licensee.

The School of Medicine at Washington University in St.

Louis is the sponsor for both trials.

The pipeline for our lead immunotherapeutic programs is summarized below:

(1) This is an Investigator-Sponsored clinical trial with the Masonic Cancer Center at University of Minnesota.

The solid tumor clinical trial is a “basket trial”

that will include patients with breast, ovarian, prostate, and colorectal cancers.

(2) Available for license from HCW Biologics for ex vivo T reg cells expansion.

(3) Wugen licensed HCW9201, a clinical-stage molecule, from HCW Biologics for limited rights to develop cell-based therapy treatments.

HCW Biologics has retained all other rights to HCW9201.

TOBI also provides a scalable approach for generating large-scale current Good Manufacturing Practice (“cGMP”)-grade heteromeric fusion protein complexes to support clinical applications.

Advances in immuno-stimulatory and anti-immunosuppressive therapeutics have revolutionized cancer treatment.

However, novel immunotherapeutics with these dual functions are not frequently constructed.

We have used our TOBI TM platform to construct a heterodimeric bifunctional fusion molecule, HCW9218, capable of immuno-stimulatory as well as anti-immunosuppressive activity.

HCW9218 is comprised of extracellular domains of the human TGF-ß

We have used our TOBI platform to construct a heterodimeric bifunctional fusion molecule, HCW9218, capable of immuno-stimulatory as well as anti-immunosuppressive activity.

HCW9218 is comprised of extracellular domains of the human TGF-β

receptor II and a human IL-15/IL-15 receptor α

HCW9218 potently activates NK cells and CD8 + T cells in vitro and in vivo to promote their proliferative and metabolic activities and enhances their cytotoxicity against tumor targets.

This fusion complex also exhibited TGF-ß

neutralizing activity in vitro and sequestered plasma TGF-ß

This fusion complex also exhibited TGF-β

neutralizing activity in vitro and sequestered plasma TGF-β

in mice and non-human primates.

In animal models, HCW9218 displayed strong anti-tumor activity mediated by NK cells and CD8 + T cells, and increased infiltration of NK cells and CD8 + T cells into tumors.

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HCW9218 may serve as a novel therapeutic to simultaneously provide immunostimulation and lessen immunosuppression associated with tumors and other age-related diseases.

The figures below show that HCW9218 has the potential to augment the efficacy of chemotherapy (doxetaxel, DTX) in the presence and absence of therapeutic antibodies (TA99) in mice bearing melanoma tumors (upper left panel).

These results correlated with the ability of HCW9218 to eliminate TIS cancer cells induced by DTX (upper center and right panels).

Additionally, HCW9218 reduced TIS and SASP factors in normal tissues related to therapy induced adverse effects (lower panels), indicating that HCW9218 acts as a senolytic and senomorphic agent.

Preclinical Studies in Animal Models

HCW9218 Enhances Anti-Tumor Activity of Chemotherapy and Therapeutic Antibodies

and Reduces TIS Senescent Cells and SASP Factors in Tumors and Normal Tissues

In our published scientific reports, we also observed in preclinical studies that HCW9218 could enhance the anti-tumor efficacy of immune checkpoint blockade (anti-PD-L1 antibody, α-PD-L1) via T-cell infiltration into the tumor avoiding immunosuppressive factors in the tumor microenvironment, or TME.

As we state in our published scientific papers reporting results of preclinical studies, we also observed that HCW9218 could enhance the anti-tumor efficacy of immune checkpoint blockade (anti-PD-L1 antibody, α-PD-L1) via T-cell infiltration into the tumor avoiding immunosuppressive factors in the tumor microenvironment, or TME.

HCW9218 Enhances Anti-Tumor Activity of Immune Checkpoint Blockade

Moreover, HCW9218 enhanced the anti- tumor efficacy of chemotherapy against human pancreatic tumors in a xenograft model.

Molecular Therapy, “Immunotherapeutic HCW9218 Augments Anti-Tumor Activity of Chemotherapy via NK Cell-Mediated Reduction of Therapy-Induced Senescent Cells,”

Chaturvedi, P., et al., April 2022.

Moreover, HCW9218 enhanced the anti-tumor efficacy of chemotherapy against human pancreatic tumors in xenograft mouse models.

Induction of senescence tumor cells in human SW1990 pancreatic cancer cells was observed following treatment with nab-paclitaxel and gemcitabine (A+G), standard-of-care chemotherapies (left panel).

Further, HCW9218 treatment significantly enhanced A+G chemotherapy activity by controlling tumor growth and prolonging survival of SW1990 tumor-bearing mice (center and right panels).

The results of these studies support clinical development of HCW9218 in combination with chemotherapies and other immune therapies in patients with solid tumors, including pancreatic cancer.

HCW9218 Enhances Anti-Tumor Activity of Chemotherapy

in Mice Bearing Human SW1990 Pancreatic Tumor Xenografts

Two clinical trials of HCW9218 have been permitted to proceed by the FDA.

The first is a Company-sponsored, multi-center Phase 1b clinical trial for a dose escalation study of HCW9218 as monotherapy in refractory patients with advanced pancreatic cancer.

We plan to enroll up to 24 patients in five NCI-designated centers, with the primary objectives of the study being to determine safety, maximum tolerated dose, and the recommended Phase 2 dose (“RP2D”).

After determining the RP2D, we expect the Phase 2 portion of this clinical trial to include a cohort of patients receiving HCW9218 as monotherapy and a cohort of patients receiving HCW9218 as an adjunct to chemotherapy.

The Phase 2 dose expansion portion aims to enroll up to 42 patients at the RP2D with primary objectives to determine the 6-month progression free survival rate and safety.

The secondary objectives of this study are objective response rate, overall survival, time to progression, and duration of response.

We have identified several NCI-designated Comprehensive Cancer Centers as potential clinical sites, all of which are progressing through their internal process for review.

We will not be able to finalize our selection of a particular clinical site until the internal review is complete and approval is granted to participate in the clinical study.

If any of the sites we have selected declines to participate in the study, we will need to identify alternative sites, which may delay the initiation of the trial.

Once we do proceed, the time required to complete the study will depend on the number of cohorts required to determine RP2D and the time that is required to enroll patients to participate in the study.

The second clinical trial of HCW9218 in a cancer indication is an Investigator-sponsored trial for the Phase 1 portion of a clinical trial for dose escalation study of HCW9218 as a monotherapy in solid tumors, such as breast, ovarian, prostate and colorectal cancers.

We believe that the results of these studies support clinical development of HCW9218 in combination with chemotherapies and other immune therapies in patients with solid tumors, including pancreatic cancer.

HCW9218 Enhances Anti-Tumor Efficacy of Chemotherapy

Against Human SW1990 Pancreatic Tumor Cells in Xenograft Mouse Models

Molecular Therapy, “Immunotherapeutic HCW9218 Augments Anti-Tumor Activity of Chemotherapy via NK Cell-Mediated Reduction of Therapy-Induced Senescent Cells,”

Chaturvedi, P., et al., April 2022.

HCW9218 is a clinical-stage program, currently active in two Phase 1/1b clinical trials to evaluate HCW9218 in cancer indications.

At the 2022 Society for Immunotherapy of Cancer (“SITC”) conference, a preliminary human clinical data readout was presented by the Principal Investigator of the Phase 1 clinical trial to evaluate HCW9218 monotherapy in chemo-refractory/chemo-resistant solid tumor cancers sponsored by Masonic Cancer Center, University of Minnesota.

Data showed all subjects had a robust proliferation of blood NK cells, ranging from 77% to 97% Ki67-positivity by Day 8 after dosing for each treatment cycle.

HCW9218-mediated increases in blood NK cell percentages and counts were also observed.

Responses were sustained through Day 15, a biological effect beyond that previously observed for other IL-15 agonists.

These results are depicted in the graph below.

Preliminary Human Data Readout UMN Trial from SITC 2022:

NK Cell Responses

In addition, preliminary human data of this clinical trial also showed that there was a modest increase in blood CD8 + T cell proliferation at Day 8 after each treatment cycle.

The results are depicted in the graph below.

Preliminary Human Data Readout UMN Trial from SITC 2022:

HCW9218-Mediated Changes % of Ki67 + CD8 + T Cells

The preliminary data of this clinical trial also showed that there was a 50% reduction of the serum TGF-β1 in subjects treated at the 0.25 mg/kg HCW9218 dose level.

The 0.50 mg/kg HCW9218 dose level was able to almost completely neutralize serum TGF-β1.

HCW9218 treatment did not change serum levels of IL-1α, IL-1β, IL-6, IFN, or TNF.

These results are depicted in the graph below.

Together, these results verify that HCW9218 stimulates immune cells and reduces TGF-β

activity in patients with cancer in a dose- and schedule-dependent manner, consistent with our published results observed in preclinical tumor efficacy models.

Preliminary Human Data Readout UMN Trial from SITC 2022:

Reduction of Serum TGF-β

Cancer and Other Age-Related Diseases

HCW9218 is being evaluated for the treatment of cancer indications in two clinical trials.

The first is a Company-sponsored, multi-center Phase 1b/2 clinical trial for a dose escalation study of HCW9218 as monotherapy in patients with chemo-refractory/chemo-resistant pancreatic cancer.

There are currently four clinical sites participating in this trial, including the Center for Cancer Research, Medical University of South Carolina (an NCI-designated Comprehensive Cancer Center), Washington University in St.

Louis (an NCI-designated Comprehensive Cancer Center), and HonorHealth Research Institute.

We may enroll up to 24 patients in four clinical sites for the Phase 1b part of the pancreatic trial.

The primary objectives of the Phase 1b study is to determine safety, maximum tolerated dose, and the recommended Phase 2 dose, or RP2D.

To date, there have been no dose-limiting toxicities reported in this trial.

We expect to complete the Phase 1b study to evaluate HCW9218 in pancreatic cancer in 2023.

After determining the RP2D, we expect to submit an IND protocol amendment to the FDA for the Phase 2 portion of this clinical trial to include patients receiving HCW9218 as an adjunct to chemotherapy.

In the Phase 2 dose expansion portion, we intend to enroll up to 40 patients at the RP2D with primary objectives to determine the 6-month progression free survival rate and evaluate the safety profile of HCW9218.

The secondary objectives of this study are to determine the objective response rate, overall survival, time to progression, and duration of response.

However, there can be no assurance that we will be able to advance to a Phase 2 study, since we have not yet completed the Phase 1b study, and we have not established safety and RP2D.

Moreover, there can be no assurance that the FDA will authorize us to initiate our planned clinical trials on a timely basis, or at all, when we apply for authorization to proceed with a Phase 2 study.

The second active clinical trial to evaluate HCW9218 in a cancer indication is an Investigator-sponsored trial for the Phase 1 portion of a clinical trial for dose escalation study of HCW9218 as a monotherapy in solid tumors, such as breast, ovarian, prostate and colorectal cancers.

The sponsor is the Masonic Cancer Center at the University of Minnesota, a leading NCI-designated cancer center.

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Depending on the toxicities observed in the treated patients, between 12 and 24 patients may be enrolled.

There has not yet been a decision on the design of later phases of this clinical trial, if Phase 1 is successfully completed.

We believe, based on the results of our animal studies that HCW9218 has the potential to be an effective immunotherapy against pancreatic cancer, a very aggressive malignancy which is refractory to other immunotherapies including immune checkpoint blockade.

has been shown to play a major role in promoting immunosuppression responses and fibrosis in the TME as well as inducing epithelial–mesenchymal transition (“EMT”) of pancreatic tumor cells, which facilitates their migratory and invasive capabilities.

As a result, elevated serum TGF-ß

levels have been shown to correlate with a poor prognosis in patients with pancreatic cancer.

Early phase clinical studies have provided evidence that strategies to decrease TGF-ß

levels or signaling can provide clinical benefit, including objective responses and prolonged survival, in certain patients with advanced/metastatic pancreatic cancer.

Studies in pancreatic tumor mouse models, including research performed in our laboratories, support evaluation of combination therapies including chemotherapy to enhance antigen presentation by tumors, TGF-ß

antagonist to reduce TME immunosuppression and immuno-stimulatory agents to augment anti-tumor T cell and NK cell responses.

We have targeted advanced, chemo-resistant solid tumors in our clinical programs in cancer, all of which are difficult-to-treat and have large, unmet medical needs:

Pancreatic Cancer is the 11th most commonly diagnosed cancer in the U.S., but it is the 3rd leading cause of cancer-related deaths.

It has a 10.8% five-year survival rate.

Long-term prognosis for pancreatic cancer depends on the size and type of the tumor, lymph node involvement and degree of metastasis at the time of diagnosis.

Unfortunately, pancreatic cancer usually shows little or no symptoms until it has advanced and spread.

Therefore, most cases are diagnosed at later, more difficult-to-treat stages.

in 2021, there were 60,430 new cases and 48,220 deaths from pancreatic cancer.

The average age at the time of diagnosis is 70 years of age.

Solid tumors represent approximatively 90% of adult human cancers.

In 2022, in the U.S.

alone, it is believed there will be an estimated 1.9 million new cancer cases diagnosed and more than 600,000 cancer deaths, which are increasing with an aging population.

The Investigator-sponsored trial being conducted by the Masonic Cancer Center at University of Minnesota to evaluate HCW9218 is focused on the treatment of advanced solid tumor cancer after failure of initial treatments.

Various studies have revealed that 95% of cancer drugs for solid tumors fail.

This research highlights the high unmet medical need for novel therapies to treat advanced solid tumors.

Age-Related Diseases Driven by Senescence

We are conducting extensive preclinical research on HCW9218 for senescent cell removal (senolytic) and SASP factor reduction (senomorphic) in various relevant animal models, including those for solid tumors, metabolic dysfunction, and chronological aging.

Our initial data suggest that HCW9218 functions as a potent senolytic and senomorphic agent.

We plan to determine the dose level and regimen from our cancer trials and then we intend to apply the dose level and treatment regimens to evaluate HCW9218 for age-related diseases, such as NAFLD and diabetes.

Type 2 Diabetes affects approximately 30.8 million Americans, and another 88 million American adults have pre-diabetes.

Our ultimate goal is to use HCW9218 in combination with HCW9302 to address neurodegenerative diseases, such as Alzheimer’s Disease, Parkinson’s Disease, and age-related Macular Degeneration.

To date, there have been no dose-limiting toxicities reported in this trial.

Based on results of the Phase 1 study to evaluate HCW9218 in solid tumors, we expect to select RP2D in the in the first half of 2023.

If we are successful in completing the objectives of the Phase 1 study, we intend to advance at least one Phase 2 study to evaluate HCW9218 in a single cancer indication, such as ovarian cancer.

However, we have not yet completed the Phase 1 study to evaluate HCW9218 in solid tumor cancers, and we have not established safety and RP2D.

Further, there can be no assurance that the FDA will authorize us to initiate our planned clinical trials on a timely basis, or at all, when we apply to the FDA for authorization to proceed with a Phase 2 study.

We believe, based on the preliminary results of the ongoing first-in-human Phase 1/1b clinical trials, HCW9218 may have the potential to be an effective immunotherapy against difficult-to-treat solid tumor cancers that are very aggressive malignancies and refractory to other immunotherapies including immune checkpoint blockade.

We are gathering data from ongoing studies in search of preliminary evidence that our approach to decreasing TGF-β

levels or signaling may be able to provide clinical benefit.

If and when we advance to the next phase of our clinical studies, we intend to evaluate HCW9218 in two cancer indications that are two of the most difficult-to-treat and thus deadliest of cancers:

Pancreatic cancer has the highest mortality rate of all major cancers.

Incidence rates of pancreatic cancer have gone up by around 1% each year since 2000, and the death rate has very slowly increased each year since the mid-2000s.

In 2023, 64,050 Americans are expected to be diagnosed with pancreatic cancer in the United States, and more than 50,550 are expected to die from the disease.

Worldwide, an estimated 495,773 people were diagnosed with pancreatic cancer and an estimated 466,000 people died from the disease in 2020.

If the cancer is detected at an early stage when surgical removal of the tumor is possible, the 5-year survival rate is 42%.

About 13% of people are diagnosed at this stage.

If the cancer has spread to surrounding tissues or organs, the 5-year survival rate is 14%.

For the 52% of people who are diagnosed after the cancer has spread to a distant part of the body, the 5-year survival rate is 3%.

(See American Society of Clinical Oncology and American Cancer Society.)

Ovarian Cancer ranks 5th in cancer deaths among women in the United States, accounting for more deaths than any other cancer of the female reproductive system.

Worldwide, ovarian cancer is the 7th most common cancer in woman.

By 2040, the number of women around the world diagnosed with ovarian cancer is projected to rise almost 42% to 445,721.

The number of women dying from ovarian cancer each year is projected to increase to 313,617 an increase of over 50% from 2020.

Five-year ovarian cancer survival rates vary among countries.

For example, in more developed countries, current rates range from 36% to 46%.

However, in some countries the figure is much lower.

Overall, survival rates fall well below that for other cancers.

This cancer mainly develops in older women.

About half of the women who are diagnosed with ovarian cancer are 63 years or older.

(See World Ovarian Cancer Coalition and American Cancer Society.)

T reg cells are essential mediators of peripheral tolerance and the global immunoregulatory potential in hosts to self and non-self-antigens.

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Alternations in T reg cell development, homeostasis or function can predispose these cells to affect a variety of disease conditions including allergy, autoimmunity, graft rejection, cancer, and response to immunotherapies.

Current research is focused on developing novel therapies to enhance T reg cell functions in vivo through use of cytokines and small molecule drugs to support endogenous T reg cell proliferation or activation, ex vivo manipulated T reg cells in autologous adoptive cell therapy to promote immunoregulation in settings of autoimmunity, or antigen-specific T reg cells, including chimeric antigen receptor T reg (“CAR-T reg ”) cells, to strengthen tolerance in allergies.

We have employed our TOBI TM platform to create HCW9302, an IL-2-based fusion molecule, to expand T reg cells in vivo and ex vivo as an injectable or cell-based strategy to reduce inflammation and to treat a wide variety of autoimmune and age-related diseases.

In relevant animal models, we have also observed encouraging results using HCW9302 to activate and expand T reg cells for treatment of atherosclerosis and diabetes.

We are currently conducting IND-enabling activities required to prepare for submission of an IND for a Phase 1b clinical trial to evaluate HCW9302, administered by subcutaneous injection.

The timing for this submission will depend on the completion of nonclinical toxicology studies and availability of research material, as well as finalizing the clinical protocol.

The nonclinical toxicology studies are expected to be completed by the end of 2022, which we intend to follow with the submission of an IND for a Phase 1B clinical trial to evaluate HCW9302 in an autoimmune indication in the first half of 2023.

Current research is focused on developing novel therapies to enhance T reg cell functions in vivo through the use of cytokines and small molecule drugs to support endogenous T reg cell proliferation or activation, ex vivo manipulated T reg cells in autologous adoptive cell therapy to promote immunoregulation in settings of autoimmunity, or antigen-specific T reg cells, including chimeric antigen receptor T reg (“CAR-T reg ”) cells, to strengthen tolerance in allergies.

We have employed our TOBI platform to create HCW9302, an IL-2-based fusion molecule, to expand T reg cells in vivo and ex vivo as an injectable or cell-based strategy to reduce inflammation and to treat a wide variety of autoimmune and age-related diseases.

In relevant animal models, we have also observed, in our view, encouraging results using HCW9302 to activate and expand T reg cells for treatment of atherosclerosis and diabetes.

For further details, see Frontiers in Immunology , “A Novel Interleukin-2-Based Fusion Molecule, HCW9302, Differentially Promotes Regulatory T Cell Expansion to Treat Atherosclerosis in Mice,”

Zhu X., et al., January 2023.

We are currently conducting IND-enabling activities required to prepare for submission of an IND to evaluate HCW9302, administered by subcutaneous injection.

The timing for this submission will depend on the completion of nonclinical toxicology studies and testing and release of drug product, as well as finalizing the clinical protocol.

The nonclinical toxicology studies are expected to be completed in the first half of 2023.

We intend to follow with the submission of an IND for a Phase 1b/2 clinical trial to evaluate HCW9302 in an autoimmune indication, which we expect to occur in the second half of 2023.

However, we have not submitted the IND for the planned trial, and we cannot provide any assurance that the FDA will authorize us to initiate our planned clinical trials on a timely basis, or at all.

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HCW9302 exhibits increased biological activity with an extended half-life, compared to IL-2.

The three graphs below illustrate the results of characterization studies:

IL-2 activity of HCW9302 was compared with Proleukin, the currently approved IL-2 drug, using a standard CTLL-2 cell proliferation assay.

Center panel:

HCW9302 was found to have >5-fold higher IL-2 activity than Proleukin.

We observed the half-life of HCW9302 was 6.2 hours in mice following subcutaneous administration (3 mg/kg) versus 20 minutes for Proleukin.

HCW9302 Exhibits Increased Biological Activity with an Extended Half-Life Compared to IL-2

HCW9302 Half-Life is 6.2 Hours versus IL-2 Half-Life of 20 minutes

Autoimmune and proinflammatory diseases

We have conducted extensive preclinical research on HCW9302 for deactivation of inflammasomes to temper the pro-inflammatory environment it creates in relevant animal models, including those for atherosclerosis.

The two graphs below illustrate the results of characterization studies.

HCW9302 exhibits increased biological activity (depicted in graph on the left) with an extended half-life (depicted in graph on the right), compared to IL-2.

Additionally, we found that HCW9302 exhibited an estimated 1,000-fold higher affinity for IL-2Rα

(present on T reg cells) in comparison to IL-2.

HCW9302 could be administered to mice at a dosing range that expanded and activated T reg cells but not CD4 + effector T cells.

These findings indicate that HCW9302 is a more suitable immunotherapeutic for expanding and activating T reg cells in vivo than IL-2.

HCW9302 Compared to IL-2:

Results of Characterization Studies

Frontiers in Immunology , “A Novel Interleukin-2-Based Fusion Molecule, HCW9302, Differentially Promotes Regulatory T Cell Expansion to Treat Atherosclerosis in Mice,”

Zhu, X., et al., January 2023.

For more details, see our paper entitled, “A Novel Interleukin-2-Based Fusion Molecule, HCW9302, Differentially Promotes Regulatory T Cell Expansion to Treat Atherosclerosis in Mice,”

published in Frontiers in Immunology.

Autoimmune and Pro-inflammatory Diseases

We have conducted extensive preclinical research on HCW9302 for deactivation of inflammasomes to temper the pro-inflammatory environment they create in relevant animal models, including those for atherosclerosis.

Our data suggest that HCW9302 functions as a potent agent to stimulate T reg cells that suppress the activity of inflammasome-bearing cells and inflammatory factors.

We intend to determine the dose level and regimen from our initial clinical trial in an autoimmune indication, which we have primarily determined will be alopecia areata, and then we intend to apply the dose level and treatment regimens established in initial clinical studies to evaluate HCW9302 for other autoimmune and proinflammatory diseases, such as atherosclerosis.

We believe NK cells are a promising cellular therapy for cancer, with challenges in the field including effector cell persistence, functional activity, and tumor recognition.

Recent research has shown that priming blood NK cells with a cytokine cocktail of IL-12, IL-15, and IL-18 (“12/15/18”) results in ML-NK cell differentiation and enhanced responses against cancer.

However, the lack of available, scalable cGMP-grade reagents has limited the advancement of this approach beyond early phase clinical trials.

To address this challenge, we employed our TOBI TM platform to combine IL-12, IL-15, and IL-18 receptor engagement in a single protein complex (“HCW9201”).

Further, we have developed cGMP-compliant production cell lines and scalable production processes to allow the generation of large amounts of HCW9201 that meets product quality characteristics for clinical use.

HCW9201 has been extensively evaluated for its capacity to stimulate activation and proliferation signals in human NK cells.

RNA-seq and multidimensional mass cytometry studies have revealed strong parallels between the activities of HCW9201 and IL-12/15/18 in generated ML-NK cells.

Moreover, HCW9201 stimulation improved NK cell metabolic fitness, and resulted in the DNA methylation remodeling characteristic of memory-like differentiation.

NK cells primed with HCW9201 and the 12/15/18 cocktail had similar increases in ML-NK cell cytotoxicity and IFN-g production against leukemia targets.

HCW9201- and 12/15/18-primed NK cells also equivalently controlled leukemia in vivo in NSG mice.

Thus, HCW9201 represents a protein engineering approach that solves many problems associated with multi-signal receptor engagement on immune cells, and HCW9201-primed NK cells will be advanced as an ideal approach for clinical cGMP-grade ML-NK cell production for cancer therapy.

The figures below show that NK cells primed with HCW9201 and 12/15/18 cocktail killed leukemia cells (left) and controlled leukemia tumors in mice (right) better than NK cells primed with IL-15 alone.

We have used our TOBI TM platform to combine cytokine IL-7, IL-15, and IL-21 receptor engagement into a single protein complex:

Although ML-NK cells have been demonstrated to be beneficial in clinical trials, the initially evaluated NK cell products were derived from fresh prepared apheresis lymphocytes from individual matched donors.

Thus, this approach has limitations in the availability of donors and the reproducibility, scalability, and costs of generating clinical-grade ML-NK cells for adoptive cell therapy.

To translate this exciting therapy to many patients, we have developed methods to expand the numbers of NK cells to support a multiple dosing regimen and for multiple patients.

We have extensively tested HCW9206 and demonstrated that this complex can expand ML-NK cells without the use of feeder cells, which is the current process for producing NK cells using a cancer cell line that must be removed from the final drug product.

We intend to determine the safe and effective dose level and regimen of HCW9302 from our initial clinical trial in an autoimmune indication, which we have preliminarily determined will be alopecia areata, and then we intend to apply the dose level and treatment regimens established in initial clinical studies to evaluate HCW9302 for other autoimmune and pro-inflammatory diseases, such as atherosclerosis.

HCW9206 is a fusion protein complex created with our TOBI platform based on common gamma chain (γc) cytokines IL-7, IL-15 and IL-21, which are known to play important roles in NK cell and T cell homeostasis.

HCW Biologics holds the rights to the injectable form of HCW9206 and e x vivo rights are licensed to Wugen.

This molecule is designed to broadly activate the immune system to support expansion of NK cells and T cells ex vivo and in vivo .

We are currently in the discovery stage of an initial program for HCW9206, which is to create an injectable immunotherapeutic to use as an adjuvant for adoptive cell therapy in cancer treatments.

In current NK and ML-NK cell therapies, infused cells are supported in vivo by recombinant human IL-2.

However, this approach has limitations since IL-2 can only support these infused cells for the short term and may induce T reg cells toward immunosuppression.

We believe our preclinical testing of HCW9206 has demonstrated that this complex can support infused NK cells for a long duration and enable NK cells to sustain cytotoxicity against tumor cells.

In addition, we are currently conducting preclinical studies to investigate use of HCW9206 to enhance vaccine efficacy in different vaccine models.

Out-License Programs

We have internally developed over 30 immunotherapeutic molecules and plan to develop additional molecules through our TOBI TM platform.

Our strategy is to focus on the clinical development of our lead product candidates, HCW9218 and HCW9302, as immunotherapeutics for the treatment of age-related diseases, administered by subcutaneous injection.

Our strategy is to out-license molecules and product rights not in our focus area, in particular ex vivo applications.

We expect out-licensing to provide non-dilutive financing to bolster resources available to fund our core programs and possibly commercialize molecules with the potential to be developed successfully by our licensees for disease indications with large, unmet medical needs.

We established our first out-license arrangement in December 2020, when we entered into an exclusive worldwide license agreement with Wugen (the “Wugen License”) for limited rights to develop cell therapy-based treatments using two HCW internally-developed fusion protein molecules and improvements thereto, including a clinical-stage and preclinical stage fusion molecule.

We believe these molecules are capable of generating highly activated ML-NK cells in a short time frame and large-scale NK cell expansion without relying on feeder cells.

Two Phase 2 clinical trials were initiated in January 2021 by the School of Medicine at Washington University in St.

Louis with support from Wugen, in which certain of these licensed molecules were used.

One trial is using ex vivo ML-NK cells, induced by the licensed molecule, against r/r AML with donor leukocyte infusion (“DLI”) after haploidentical stem cell transplantation.

The second Phase 2 clinical trial is also using ex vivo induced ML-NK cells against r/r AML.

We have internally developed over 30 immunotherapeutic molecules and plan to develop additional molecules through our TOBI platform.

Our strategy is to focus on the clinical development of our lead product candidates, HCW9218 and HCW9302, as immunotherapeutics, administered by subcutaneous injection for the treatment of age-related diseases.

Our strategy is to out-license marketing rights to regions and product rights not in our focus area.

We expect out-licensing to provide non-dilutive financing to bolster resources available to fund our core markets and programs and possibly commercialize molecules, with the hope that our licensees achieve success through our licenses.

We established our first out-license arrangement in December 2020, when we entered into an exclusive worldwide license agreement with Wugen for rights to develop cell therapy-based treatments using two HCWB internally-developed fusion protein molecules and improvements thereto, including clinical-stage and preclinical stage fusion molecules, HCW9201 and HCW9206, respectively (the “Wugen License”).

We believe these molecules are capable of generating highly activated cells in a short time frame and large-scale NK cell expansion without relying on feeder cells.

Wugen has exercised its right to sublicense their rights for Greater

The sublicensee is currently conducting a Phase 1 dose escalation trial with ex vivo cells in patients with relapsed/refractory acute myeloid leukemia (R/R AML).

In the United States, Wugen will soon initiate a Phase 1, open-label, dose escalation, and cohort expansion study designed to characterize the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary anti-leukemic activity of WU-NK-101 in R/R AML.

WU-NK 101 is a treatment based on the HCWB licensed molecules.

As licensor, we have limited information rights to clinical data which we are required to treat as nonpublic confidential information.

As licensee, Wugen determines when and if clinical data read outs are disclosed to the public.

As licensee, Wugen, a private company, determines when and if clinical data readouts are disclosed to the public.

We retained manufacturing rights and other rights, including regulatory T cell-based cellular therapy and injectable rights, for licensed molecules under the terms of the Wugen License.

We intend to enter into supply agreements with Wugen to provide cGMP and non-cGMP grade licensed molecules based on industry-standard terms, one agreement for development supply and one agreement for commercial supply.

According to the terms of the Wugen license, Wugen will fund all future clinical development and commercialization activities for any indications utilizing the licensed molecules for cell therapy as covered by the license.

We have the opportunity to receive additional payments for development and commercialization milestones as well as single-digit royalties.

Other TOBI TM Discovery Programs

On June 18, 2021, the Company entered into a master services agreement with Wugen for the supply of materials for clinical development of licensed products.

Thereafter, each purchase transaction must be accompanied by a statement-of-work.

The Company plans to enter into commercialization supply agreement when Wugen enters the commercial stage of their company.

According to the terms of the Wugen exclusive license, Wugen will fund all future clinical development and commercialization activities for any indications utilizing the licensed molecules for cell-based therapy as covered by the license.

In addition to an upfront fee which consisted of a significant equity ownership position in Wugen common stock, we have the opportunity to receive additional payments for development and commercialization milestones as well as single-digit royalties.

Other TOBI Discovery Programs

Our discovery efforts for new product candidates are focused on characterizing and expanding our library of fusion molecules with cytokines, chemokines, ligands, receptors, and internally-developed single-chain antibodies, including fusion domains with increased or decreased biological activity, for cancer and other age-related diseases with an emphasis on neurodegenerative, fibrotic, and autoimmune diseases.

Other TOBI TM discovery programs are summarized in the table below.

Other TOBI discovery programs are summarized in the table below.

Fusion Molecules

Fusion Domains

IL-7, IL-15, IL-21

NK cell and CD8 + T cell stimulation

NK cell and T cell stimulation

Injectable for cancer,

Vaccine efficacy

IL-18, IL-15, IL-12, anti-CD16 scFv

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Cancer, inflammatory diseases

TGRßRII dimer

TGRßRII tetramer

Cancer, fibrotic diseases

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Manufacturing

Our product candidates include molecules that are multi-specific fusion protein complexes, such as HCW9201, HCW9206, and HCW9218;

Our product candidates include internally-developed molecules that are multi-specific fusion protein complexes, such as HCW9201, HCW9206, and HCW9218;

bispecific fusion protein complexes, such as HCW9302;

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We have established internally-developed manufacturing processes for producing these fusion molecules from Chinese hamster ovary (“CHO”) cells at large scale in a cGMP-compliant setting.

On March 14, 2019, we entered into a manufacturing agreement with EirGenix, Inc.

(“EirGenix”), a third-party global contract development and cGMP manufacturer of biologics, for the manufacture of the Company’s internally-developed molecules.

We have a long-standing relationship with a contract manufacturing organization, EirGenix, Inc.

(“EirGenix”), a third-party global contract development and cGMP manufacturer of biologics, for the manufacture of our internally-developed molecules.

By the end of 2019, we successfully launched cGMP production with manufacturing runs adequate to support clinical trials.

During the year ended December 31, 2020, various testing and quality control procedures were conducted on the materials manufactured in 2019-2020 to ensure materials met all expected quality requirements.

During the year ended December 31, 2021, we successfully completed production of four molecules, HCW9101, HCW9201, HCW9218, and HCW9302.

This includes clinical grade materials we need to initiate clinical trials and toxicology studies we have planned for 2022.

Manufacturing, quality control procedures, and vialing will continue for several molecules in 2022, including additional clinical and research grade materials for our licensee.

We currently rely on EirGenix and other third-party manufacturers for the cGMP production of larger quantities of our drug product candidates for our clinical trials.

Our management team and other internal personnel have extensive cGMP manufacturing experience in order to ensure seamless technology transfer and to manage the manufacturing and development processes conducted by third-party manufacturers.

As of December 31, 2022, we successfully completed cGMP production of five molecules, HCW9101, HCW9201, HCW9206, HCW9218, and HCW9302.

This includes clinical grade materials required to complete the toxicology studies for HCW9218 and HCW9302, as well as the quantities required for Phase 1/1b/2 clinical trials to evaluate both molecules.

Manufacturing, quality control procedures, and vialing will continue for several molecules in 2023, including additional clinical and research grade materials for our licensee, Wugen.

We currently rely on EirGenix and other third-party manufacturers for the cGMP production of sufficient quantities of our drug product candidates for our clinical trials.

Our management team and other internal personnel have extensive cGMP manufacturing experience which allows for seamless technology transfer our proprietary manufacturing methods, as well as the ability to manage the manufacturing and development processes conducted by third-party manufacturers.

Our agreements with third-party manufacturers include confidentiality and intellectual property provisions as well as routine quality audits.

In some instances, we have reserved resources from third-party manufacturers for the development and manufacture of our product candidates for near-term clinical programs.

However, we currently obtain our products from these manufactures on a per project basis and do not have long-term supply arrangements in place.

Should any of these manufacturers become unavailable to us for any reason, we believe that there are a number of potential replacements available to us on commercially reasonable terms to meet our future production requirements, although we may incur some delay and cost in qualifying and re-establishing the manufacturing processes at the replacements.

We mitigate this risk by maintaining an inventory of clinical material for clinical trials we expect to initiate in the next 12-24 months.

We do not own or operate facilities for clinical drug manufacturing, storage, distribution, or quality testing.

Currently, all of our clinical manufacturing is outsourced to third-party manufacturers.

We plan to use some of the net proceeds of the IPO to establish our own manufacturing facilities in the US.

We have expertise in building and running cGMP manufacturing facilities for immunotherapeutics.

In addition, our manufacturing process is wholly-owned and developed by us, so we will not rely on a third-party for manufacturing expertise or processes.

Should any of these manufacturers become unavailable to us for any reason, we believe that there are a number of potential alternative contract manufacturers available to us on commercially reasonable terms to meet our future production requirements, although we may incur some delay and cost in qualifying and re-establishing the manufacturing processes at an alternative facility.

We endeavor to mitigate this risk by maintaining an inventory of clinical material for clinical trials we expect to initiate in the next 12-24 months.

On August 15, 2022, we purchased a 36,000 square foot building located in Miramar, Florida.

This facility will serve as our new headquarters.

After refitting this building, we expect to have the capabilities for cGMP clinical drug manufacturing, storage, distribution, and quality testing.

We expect this facility to be operational in the second half of 2024.

The Company has the flexibility to complete the buildout of the manufacturing facility on a longer schedule, should we choose to delay completion.

In the meantime, we will continue to manufacture clinical-grade material with third-party manufacturers.

Our staff has expertise in building and running cGMP manufacturing facilities for immunotherapeutics.

In addition, our manufacturing process is wholly-owned and developed by us, so we do not expect to be reliant on a third-party for manufacturing expertise or processes.

Intellectual Property

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As with other biotechnology and pharmaceutical companies, our ability to secure and maintain intellectual property protection for our product candidates, future products, and other internally-developed technologies will depend on our success in obtaining effective patent coverage and enforcing those patents if granted.

However, we cannot guarantee that our pending patent applications, and any patent applications that we may in the future file, will result in the issuance of patents, or that any issued patents we may obtain will provide sufficient proprietary protection from competitors.

However, we cannot guarantee that our pending patent applications, and any patent applications that we may in the future file, will result in the issuance of patents, or that any issued patents we have obtained or may obtain will provide sufficient proprietary protection from competitors.

Any issued patents that we obtain may be challenged, invalidated, or circumvented by third parties.

In addition to patents, we also rely on trade secrets, know-how and continuing technological innovation to develop and maintain our competitive position.

We seek to protect our internally-developed technology, in part, through confidentiality agreements and invention assignment agreements with our employees, consultants, scientific advisors, contractors and potential collaboratorWe also rely on trade secrets relating to our manufacturing process and on know-how, continuing technological innovation and in-licensing opportunities to develop, strengthen, and maintain our proprietary position in the field of inflammaging that may be important for the development of our business.

We also rely on trade secrets relating to our manufacturing process and on know-how, continuing technological innovation and in-licensing opportunities to develop, strengthen, and maintain our proprietary position in the field of inflammaging that may be important for the development of our business.

We additionally may rely on regulatory protection afforded through data exclusivity, market exclusivity, and patent term extensions, where available.

Internally-Developed Intellectual Property

As of December 31, 2021, we own 61 pending patent applications worldwide, including 11 pending U.S.

utility patent applications, one pending provisional U.S.

patent application, six pending PCT applications, four Hong Kong applications, and 39 pending non-U.S.

national phase patent applications.

As of December 31, 2022, the United States Patent and Trademark Office (the “USPTO”) has granted HCW Biologics two fundamental patents:

The USPTO granted U.S.

11,401,324 to HCW Biologics on August 2, 2022.

This patent contains claims for immunotherapeutic single-chain chimeric polypeptides comprising two target-binding domains on a scaffold made of a soluble tissue factor domain, supporting our lead drug candidate, HCW9302.

The USPTO granted U.S.

11,518,792 to HCW Biologics on December 6, 2022.

This patent contains composition claims for immunotherapeutic multi-chain chimeric polypeptides, supporting our lead drug candidate, HCW9218.

As of December 31, 2022, in addition to these two issued patents, we have 105 pending patent applications worldwide, including 15 pending U.S.

utility patent applications, six pending provisional U.S.

patent applications, one pending Patent Cooperation

Treaty (“PCT”) application, eight Hong Kong applications, and 76 total pending non-U.S.

national phase patent applications and Taiwan patent applications.

Our policy is to file patent applications to protect technology, inventions and improvements to inventions that are commercially important to the development of our business.

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We seek protection, in part, through confidentiality and proprietary information agreements.

Our intellectual property portfolio is in its early stages and is continually evolving during prosecution of our applications.

We own multiple families of patent applications that are directed to our TOBI TM platform technology and our single-chain and multi-chain chimeric polypeptides and methods of use of these polypeptides alone and in combination.

Our intellectual property portfolio is continually evolving during prosecution of our applications.

We own multiple families of patent applications that are directed to our TOBI platform technology and our single-chain and multi-chain chimeric polypeptides and methods of use of these polypeptides alone and in combination.

Single-Chain Chimeric Polypeptides Patent Family

This family includes patent applications with claims directed to compositions of various single-chain chimeric polypeptides created using the TOBI TM platform.

These applications also include methods of use and manufacture thereof and methods of promoting the activation and proliferation of a NK cell or a T cell using our single-chain chimeric polypeptides.

As of December 2021, this family, which includes HCW9302, includes one pending U.S.

utility patent application, and 11 pending patent applications filed in Europe, Australia, Canada, Israel, Japan, New Zealand, Korea, China, Singapore, Hong Kong and Taiwan.

This family includes patent applications with claims directed to compositions of various single-chain chimeric polypeptides created using the TOBI platform.

These applications also include methods of use and manufacture thereof and methods of promoting the activation and proliferation of NK cells or T cells using our single-chain chimeric polypeptides.

As of December 31, 2022, this family, which includes HCW9302, includes U.S.

11,401,324, two pending U.S.

utility patent applications, and 11 pending patent applications filed in Europe, Australia, Canada, Israel, Japan, New Zealand, South Korea, China, Singapore, Hong Kong and Taiwan.

The earliest predicted expiration date of any patent issuing from a patent application in this family is 2039.

Multi-Chain Chimeric Polypeptides Patent Family

This family includes patent applications with claims directed to compositions of various multi-chain chimeric polypeptides created using the TOBI TM platform.

These applications also include methods of use and manufacture thereof and methods of promoting the activation and proliferation of a NK cell or a T cell using our multi-chain chimeric polypeptides.

As of December 2021, this family, which includes claims encompassing HCW9218, HCW9201, HCW9206, HCW9228, HCW9207, and HCW9212, includes three pending U.S.

utility patent applications, and 11 pending patent applications filed in Europe, Australia, Canada, Israel, Japan, New Zealand, Korea, China, Singapore, Hong Kong and Taiwan.

This family includes patent applications with claims directed to compositions of various multi-chain chimeric polypeptides created using the TOBI platform.

These applications also include methods of use and manufacture thereof and methods of promoting the activation and proliferation of NK cells or T cells using our multi-chain chimeric polypeptides.

As of December 2022, this family, which includes claims encompassing HCW9218, HCW9201, HCW9206, HCW9228, HCW9207, and HCW9212, includes U.S.

11,518,792, four pending U.S.

utility patent applications, and 11 pending patent applications filed in Europe, Australia, Canada, Israel, Japan, New Zealand, South Korea, China, Singapore, Hong Kong and Taiwan.

The earliest predicted expiration date of any patent issuing from a patent application in this family is 2039.

With respect to HCW9218, the composition is claimed in one pending U.S.

utility patent application and 11 pending patent applications filed in Europe, Australia, Canada, Israel, Japan, New Zealand, Korea, China, Singapore, Hong Kong and Taiwan.

With respect to HCW9218, the composition is claimed in U.S.

11,518,792 and 11 pending patent applications filed in Europe, Australia, Canada, Israel, Japan, New Zealand, South Korea, China, Singapore, Hong Kong and Taiwan.

With respect to HCW9201, the composition is claimed in one pending U.S.

utility patent application and 11 pending patent applications filed in Europe, Australia, Canada, Israel, Japan, New Zealand, Korea, China, Singapore, Hong Kong and Taiwan.

Wugen has obtained an exclusive license to these patent applications limited to use of the licensed chimeric polypeptides in manufacturing of certain cellular therapy products.

utility patent application and 11 pending patent applications filed in Europe, Australia, Canada, Israel, Japan, New Zealand, South Korea, China, Singapore, Hong Kong and Taiwan.

Wugen has obtained an exclusive license to these patent applications limited to use of the licensed chimeric polypeptides in manufacturing certain cellular therapy products.

With respect to HCW9206, the composition is claimed in one pending U.S.

utility patent application and 11 pending patent applications filed in Europe, Australia, Canada, Israel, Japan, New Zealand, Korea, China, Singapore, Hong Kong and Taiwan.

Wugen has obtained an exclusive license to these patent applications limited to use of the licensed polypeptides in manufacturing of certain cellular therapy products.

utility patent application and 11 pending patent applications filed in Europe, Australia, Canada, Israel, Japan, New Zealand, South Korea, China, Singapore, Hong Kong and Taiwan.

Wugen has obtained an exclusive license to these patent applications limited to use of the licensed polypeptides in manufacturing certain cellular therapy products.

Methods of Culturing and Methods of Expansion and Proliferation

These two families include patent applications with claims directed to methods of promoting the activation and proliferation of NK cells through the use of our single-chain or multi-chain chimeric polypeptides for ex vivo cell therapy use.

As of December 2021, these two families, which include methods of using HCW9201 and HCW9206, includes two pending U.S.

As of December 2022, these two families, which include methods of using HCW9201 and HCW9206, include two pending U.S.

utility patent applications and 15 pending patent applications filed in Europe, Australia, Canada, Israel, Japan, South Korea, Singapore, Hong Kong and China.

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The earliest predicted expiration date of any patent issuing from a patent application in the second of these two families is 2040.

Wugen has obtained an exclusive license to these two patent families limited to use in manufacturing of certain cellular therapy products.

Wugen has obtained an exclusive license to these two patent families limited to use in manufacturing certain cellular therapy products.

Treating Age Related Disorders

These four families include patent applications with claims directed to methods of killing or reducing the number of senescent cells in a subject using our single-chain or multi-chain chimeric polypeptides.

As of December 2021, these four families, which include methods of using HCW9218, HCW9228 and HCW9302, include three pending U.S.

utility patent applications, one pending provisional U.S.

patent application, three pending PCT applications, and six pending patent applications filed in Europe, Australia, Canada, Israel, Japan, Hong Kong and China.

As of December 2022, these four families, which include methods of using HCW9218, HCW9228 and HCW9302, include four pending U.S.

utility patent applications, one pending PCT application, and 23 pending patent applications filed in Europe, Australia, Canada, Israel, Japan, Hong Kong, South Korea, New Zealand, Singapore and China.

The earliest predicted expiration date of any patent issuing from a patent application in the first of these three families is 2039.

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As of December 2022, this family, which includes methods of using HCW9213 and HCW9302, includes one pending U.S.

utility patent application and one pending PCT application.

utility patent application and 10 pending patent applications filed in Australia, New Zealand, Singapore, Israel, Europe, Canada, Japan, China, Hong Kong and South Korea.

The earliest predicted expiration date of any patent issuing from a patent application in this family of applications is 2041.

This family includes patent applications with claims directed to anti-CD26 scFv antibodies.

As of December 2021, this family, which includes composition claims for HCW9106, includes one pending PCT application.

As of December 2022, this family, which includes composition claims for HCW9106, includes one pending U.S.

utility patent application and five pending patent applications filed in Australia, Canada, Europe, China, and Japan.

The earliest predicted expiration date of any patent issuing from a patent application in this family of applications is 2041.

The various methods of use of our chimeric polypeptides covered in our portfolio broadly include:

The various methods of use of our chimeric polypeptides covered in our portfolio include:

ex vivo cellular therapy use;

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When possible, we expect to apply for patent term extensions for future patents covering our product candidates and their methods of use.

We have filed five U.S.

trademark applications for our corporate name, corporate logo, and the TOBI TM platform.

We have filed four pending U.S.

trademark applications for our corporate name and corporate logo.

We have an International Registration for the mark HCW BIOLOGICS for pharmaceutical research and development services, among other related services, in Class 42 and four national trademark applications pending therefrom with one registration issued in the European Union.

In the future, we intend to file applications for trademark registrations in connection with our Company, our product candidates, and other technologies in various jurisdictions, including the United States as the products are further developed.

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Wugen Exclusive License Agreement

In December 2020, we entered into an exclusive worldwide license agreement with Wugen (the “Wugen License”), for rights to use certain HCW fusion protein molecules to develop, manufacture, and commercialize their cellular therapy products.

In December 2020, we entered into an exclusive worldwide license agreement with Wugen, for rights to use certain HCWB fusion protein molecules to develop, manufacture, and commercialize their cellular therapy products.

The term of the agreement will expire on a product-by-product and country-by-country basis, upon the later of (i) the expiration of the last-to-expire valid patent claim or (ii) ten (10) years from the first commercial sale of such product.

As consideration for the Wugen License, HCW received shares of Wugen’s common stock equivalent to a 10% ownership interest in Wugen as of the effective date of the Wugen License.

The upfront payment for the license fee consisted of common stock of Wugen that had a fair value of $1.6 million on the effective date of the Wugen License.

We also agreed to sell Wugen non-financial assets for $2.5 million, including cGMP-grade clinical materials needed in order to begin Phase 2 clinical trials in January 2021.

As consideration for the Wugen License, HCWB received shares of Wugen’s common stock, which are currently equivalent to a 5.8% ownership interest in Wugen.

We may receive additional payments in the future, based upon the occurrence of certain development milestones with a value of over $200 million.

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We retained all other rights and use of the licensed molecules outside of Wugen’s right to use the molecules to develop, manufacture, and commercialize cellular therapy products.

Wugen’s rights are limited to use of the licensed molecules in cellular therapy products, which products are a pharmaceutical or biological product, process or therapy that contains or comprises cells (including without limitation, CIML NK cells or T cells) that have been engineered, modified, or otherwise manipulated ex vivo , but excludes regulatory T cell-based cellular therapy products.

Wugen’s rights are limited to use of the licensed molecules in cellular therapy products, which are pharmaceutical or biological products, processes or therapies that contain or comprise cells (including without limitation, CIML NK cells or T cells) that have been engineered, modified, or otherwise manipulated ex vivo , but excludes regulatory T cell-based cellular therapy products.

Our retained rights include use of the molecules for injectable therapy product, regulatory T cell-based cellular therapy products, and manufacturing rights to the licensed molecules.

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Contract Research Agreements

We have certain contract research agreements with contractors that were entered into the two years ended December 31, 2021 for the (i) screening and identification of specific human antibodies to three particular proteins that influence the cellular-senescence process, (ii) hybridoma development, (iii) cell line improvement, and (iv) research to support pre-clinical studies.

We have certain contract research agreements with contractors that were entered during the two years ended December 31, 2022 for the (i) screening and identification of specific human antibodies to three particular proteins that influence the cellular-senescence process, (ii) hybridoma development, (iii) cell line improvement, and (iv) research to support pre-clinical studies.

We own all rights to the resulting intellectual property, including the antibodies, sequences, and data.

To date, we have received several sequences and hybridomas from the contractors.

For certain contractors, we are obligated to pay one (1) future milestone payment upon filing and acceptance of an IND for each respective human antibody or protein from cell line, however no additional future development or financial obligations are due under these contractor research agreements.

For certain contractors, we are obligated to pay one future milestone payment upon filing and acceptance of an IND for each respective human antibody or protein from cell line;

however no additional future development or financial obligations are due under these contract research agreements.

The biotechnology and pharmaceutical industries are characterized by rapidly advancing technologies, intense competition, and a strong emphasis on internally-developed products.

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These competitors also compete with us in establishing clinical trial sites and patient registration for clinical trials necessary to advance the clinical development of our product candidates.

Although our novel approach is unique from most other existing or investigational therapies across the disease areas where we are focusing our development, we will need to compete with currently approved therapies, and potentially those currently in development if they are approved.

Although we believe our novel approach is different from most other existing or investigational therapies across the disease areas where we are focusing our development, we will need to compete with currently approved therapies, and potentially those currently in development if they are approved.

We are aware of several marketed and investigational products in our leading disease areas, including but not limited to the products and competitors discussed below.

We compete in the segments of the pharmaceutical, biotechnology, and other related markets that develop cancer therapies.

There are many other companies that have commercialized or are developing cancer therapies, including large pharmaceutical and biotechnology companies, such as AstraZeneca/MedImmune, Bristol Myers Squibb, Merck, Novartis, Pfizer, and Roche/Genentech.

We face significant competition from pharmaceutical and biotechnology companies that target specific tumor-associated antigens using immune cells or other cytotoxic modalities.

These generally include immune cell redirecting therapeutics (e.g., T cell engagers), adoptive cellular therapies (e.g., CAR-Ts), antibody drug conjugates, targeted radiopharmaceuticals, targeted immunotoxin, and targeted cancer vaccines.

As we expand to other indications, we will focus on the treatment of fibrotic diseases, including NAFLD, or non-alcoholic fatty liver disease.

N AFLD is an umbrella term that encompasses the entire spectrum of fatty liver disease, from isolated steatosis to NASH, or non-alcoholic s teatohepatitis.

These generally include immune cell redirecting therapeutics ( e.g.

, T cell engagers), adoptive cellular therapies ( e.g.

, CAR-Ts), antibody drug conjugates, targeted radiopharmaceuticals, targeted immunotoxin, and targeted cancer vaccines.

We intend to expand to other indications, such as the treatment of fibrotic diseases, including NAFLD, or non-alcoholic fatty liver disease.

NAFLD is an umbrella term that encompasses the entire spectrum of fatty liver disease, from isolated steatosis to NASH, or non-alcoholic steatohepatitis.

There are currently no FDA approved therapies for the treatment of NAFLD.

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Most of the drugs currently in development for NAFLD are focused on decreasing liver fat or improving liver inflammation as opposed to direct liver anti-fibrotic approaches.

There are a number of companies developing product candidates for NAFLD including Pliant Therapeutics, Intercept, Pfizer Inc., Gilead, AbbVie, Novartis, AstraZeneca plc, Eli Lilly & Company, GlaxoSmithKline plc, Amgen, Inc., BMS, Johnson & Johnson, Merck & Co., Inc., Roche, Sanofi S.A., Takeda Pharmaceuticals, Novo Nordisk, Genfit SA, Madrigal Pharmaceuticals, Inc., Viking Therapeutics, Inc., Cirius Therapeutics, Inc., NGM Biopharmaceuticals, Akero Therapeutics, Inc.

and Metacrine, Inc.

With respect to our lead internally-developed product candidate, HCW9218, we are not aware of any other competing clinical-stage companies with a first-in-class immunotherapeutic that utilizes multiple mechanisms of action, including the cytokine-based activation of immune cells and neutralization of TGF-ß

There are a number of companies developing product candidates for NAFLD including Pliant Therapeutics, Intercept, Pfizer, Gilead, AbbVie, Novartis, AstraZeneca, Eli Lilly & Company, GlaxoSmithKline, Amgen, Bristol Myers Squibb Company, Johnson & Johnson, Merck & Co., Genentech, a member of The Roche Group, Sanofi, Takeda Pharmaceuticals, Novo Nordisk, Genfit, Madrigal Pharmaceuticals, Viking Therapeutics, Cirius Therapeutics, NGM Biopharmaceuticals, Akero Therapeutics and Metacrine.

immunosuppression.

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We are not aware of other competing clinical-stage companies with a first-in-class immunotherapeutic for deactivation of inflammasomes and reduction of inflammatory cytokines they release through the activation of T reg cells.

We are aware of several other companies developing programs that utilize IL-2 for the selective expansion of T reg cells, including Amgen Inc., Nektar Therapeutics (in partnership with Eli Lilly & Company), Roche, Merck & Co., Bristol Myers Squibb, and Celgene Corporation (“Celgene”).

We are also aware of other companies with research or preclinical-stage programs in this area, including Synthorx, Inc., Moderna, Inc., and Xencor, Inc.

We are also aware of other companies with PD-1 agonist programs for the treatment of autoimmune diseases, including AnaptysBio, Inc., Celgene, and Eli Lilly & Company.

We are aware of several other companies developing programs that utilize IL-2 for the selective expansion of T reg cells, including Amgen, Nektar Therapeutics (in partnership with Eli Lilly & Company), Genentech, a member of The Roche Group, Merck & Co., Bristol Myers Squibb Company, and Celgene, a subsidiary of Bristol Myers Squibb Company.

We are also aware of other companies with research or preclinical-stage programs in this area, including Synthorx, Moderna, and Xencor.

We are also aware of other companies with PD-1 agonist programs for the treatment of autoimmune diseases, including AnaptysBio, Celgene, a subsidiary of Bristol Myers Squibb Company, and Eli Lilly & Company.

We could see a reduction or elimination of our commercial opportunity if our competitors develop and commercialize products that are safer, more effective, have fewer or less severe side effects, are more convenient or are less expensive than any products that we or our collaborators may develop.

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In addition, the manufacturer of an investigational biologic in a Phase 2 or Phase 3 clinical trial for a serious or life-threatening disease is required to make available, such as by posting on its website, its policy on evaluating and responding to requests for expanding access to such investigational drug or biologic.

After completion of the required clinical testing, a Biologics License Application (“BLA”) is prepared and submitted to the FDA.

After completion of the required clinical testing, a BLA is prepared and submitted to the FDA.

FDA approval of the BLA is required before marketing and distribution of the product may begin in the United States.

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An approval letter authorizes commercial marketing and distribution of the biologic with specific prescribing information for specific indications.

As a condition of BLA approval, the FDA may require a risk evaluation and mitigation strategy (“REMS”), to help ensure that the benefits of the biologic outweigh the potential risks to patients.

As a condition of BLA approval, the FDA may require a risk evaluation and mitigation strategy (“REMS”), to help ensure

that the benefits of the biologic outweigh the potential risks to patients.

A REMS can include medication guides, communication plans for healthcare professionals, and elements to assure a product’s safe use (“ETASU”).

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Disclosure of the results of these trials can be delayed in certain circumstances for up to two years after the date of completion of the trial.

Competitors may use this publicly available information to gain knowledge regarding the progress of development programs.

Competitors may use this publicly available information to gain knowledge regarding the progress of development programs as well as clinical trial design.

Expedited Development and Review Programs

Fast Track Designation and Priority Review

The FDA is required to facilitate the development, and expedite the review, of drugs or biologic products that are intended for the treatment of a serious or life-threatening disease or condition for which there is no effective treatment and which demonstrate the potential to address unmet medical needs for the condition.

Fast track designation may be granted for a product that is intended to treat a serious or life-threatening disease or condition for which there is no effective treatment and preclinical or clinical data demonstrate the potential to address unmet medical needs for the condition.

Fast track designation applies to both the product and the specific indication for which it is being studied.

The sponsor of an investigational biological product may request that FDA designate the product candidate for a specific indication as a fast track product concurrent with, or after, the submission of the IND for the product candidate.

The sponsor of an investigational biological product may request that the FDA designate the product candidate for a specific indication as a fast track product concurrent with, or after, the submission of the IND for the product candidate.

FDA must determine if the product candidate qualifies for fast track designation within 60 days of receipt of the sponsor’s request.

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The sponsor must also provide, and the FDA must approve, a schedule for the submission of the remaining information and the sponsor must pay applicable user fees.

Fast track designation may be withdrawn if FDA believes that the designation is no longer supported by data emerging in the clinical trial process.

Fast track designation may be withdrawn if the FDA believes that the designation is no longer supported by data emerging in the clinical trial process.

Priority review may be granted for products that are intended to treat a serious or life-threatening condition and, if approved, would provide a significant improvement in safety and effectiveness compared to available therapies.

FDA determines at the time of the filing the BLA whether the proposed product would be a significant improvement and therefore receive a priority review designation.

FDA will attempt to direct additional resources to the evaluation of an application designated for priority review in an effort to facilitate the review.

The FDA determines at the time of filing the BLA whether the proposed product would be a significant improvement and therefore receive a priority review designation.

The FDA will attempt to direct additional resources to the evaluation of an application designated for priority review in an effort to facilitate the review.

Breakthrough Therapy Designation

FDA is also required to expedite the development and review of applications for approval of biologics that are intended to treat a serious or life-threatening disease or condition where preliminary clinical evidence indicates that the biologic may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.

Under the breakthrough therapy program, the sponsor of a new product candidate may request that FDA designate the product candidate for a specific indication as a breakthrough therapy concurrent with, or after, the filing of the IND for the product candidate.

FDA must determine if the product candidate qualifies for breakthrough therapy designation within 60 days of receipt of the sponsor’s request.

The FDA is also required to expedite the development and review of applications for approval of biologics that are intended to treat a serious or life-threatening disease or condition where preliminary clinical evidence indicates that the biologic may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.

Under the breakthrough therapy program, the sponsor of a new product candidate may request that the FDA designate the product candidate for a specific indication as a breakthrough therapy concurrent with, or after, the filing of the IND for the product candidate.

The FDA must determine if the product candidate qualifies for breakthrough therapy designation within 60 days of receipt of the sponsor’s request.

The FDA may take certain actions with respect to breakthrough therapies, including holding meetings with the sponsor throughout the development process, providing timely advice to the product sponsor regarding development and approval, involving more senior staff in the review process, assigning a cross-disciplinary project lead for the review team and taking other steps to design the clinical studies in an efficient manner.

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All promotional materials for product candidates approved under accelerated regulations are subject to prior review by the FDA.

The Food and Drug Omnibus Reform Act (“FDORA”) was recently enacted, which included provisions related to the accelerated approval pathway.

Pursuant to FDORA, the FDA is authorized to require a post-approval study to be underway prior to approval or within a specified time period following approval.

FDORA also requires the FDA to specify conditions of any required post-approval study, which may include milestones such as a target date of study completion and requires sponsors to submit progress reports for required post-approval studies and any conditions required by the FDA not later than 180 days following approval and not less frequently than every 180 days thereafter until completion or termination of the study.

FDORA enables the FDA to initiate enforcement action for the failure to conduct with due diligence a required post-approval study, including a failure to meet any required conditions specified by the FDA or to submit timely reports.

Regenerative Medicine Advanced Therapy Designation

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Pediatric Information

Under the Pediatric Research Equity Act (“PREA”), BLAs or supplements to BLAs must contain data to assess the safety and effectiveness of the biological product for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the biological product is safe and effective.

FDA may grant full or partial waivers, or deferrals, for submission of data.

Unless otherwise required by regulation, PREA does not apply to any biological product for an indication for which orphan designation has been granted except that PREA will apply to an original BLA for a new active ingredient that is orphan-designated if the drug is a molecularly targeted cancer product intended for the treatment of an adult cancer and is directed at a molecular target that FDA determines to be substantially relevant to the growth or progression of a pediatric cancer.

administration for each pediatric subpopulation for which the biological product is safe and effective.

The FDA may grant full or partial waivers, or deferrals, for submission of data.

Unless otherwise required by regulation, the PREA does not apply to any biological product for an indication for which orphan designation has been granted except that PREA will apply to an original BLA for a new active ingredient that is orphan-designated if the drug is a molecularly targeted cancer product intended for the treatment of an adult cancer and is directed at a molecular target that the FDA determines to be substantially relevant to the growth or progression of a pediatric cancer.

The Best Pharmaceuticals for Children Act (“BPCA”) provides a six-month extension of any non-patent exclusivity for a biologic if certain conditions are met.

Conditions for exclusivity include the FDA’s determination that information relating to the use of a new biologic in the pediatric population may produce health benefits in that population, FDA making a written request for pediatric studies, and the applicant agreeing to perform, and reporting on, the requested studies within the statutory timeframe.

Applications under the BPCA are treated as priority applications.

Additional Controls for Biologics

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Once a BLA is approved, a product will be subject to certain post-approval requirements.

For instance, FDA closely regulates the post-approval marketing and promotion of biologics, including standards and regulations for direct-to-consumer advertising, off-label promotion, industry-sponsored scientific and educational activities, and promotional activities involving the internet.

For instance, the FDA closely regulates the post-approval marketing and promotion of biologics, including standards and regulations for direct-to-consumer advertising, off-label promotion, industry-sponsored scientific and educational activities, and promotional activities involving the internet.

Biologics may be marketed only for the approved indications and in a manner consistent with the approved labeling.

Adverse event reporting and submission of periodic reports are required following FDA approval of a BLA.

FDA also may require post-marketing testing, known as Phase 4 testing, REMS, and surveillance to monitor the effects of an approved product, or FDA may place conditions on an approval that could restrict the distribution or use of the product.

Adverse event reporting and submission of periodic reports are required following the FDA approval of a BLA.

The FDA also may require post-marketing testing, known as Phase 4 testing, REMS, and surveillance to monitor the effects of an approved product, or the FDA may place conditions on an approval that could restrict the distribution or use of the product.

In addition, quality control, biological product manufacture, packaging, and labeling procedures must continue to conform to cGMP after approval.

Biologics manufacturers and certain of their subcontractors are required to register their establishments with FDA and certain state agencies.

Registration with FDA subjects entities to periodic unannounced inspections by FDA, during which the Agency inspects manufacturing facilities to assess compliance with cGMPs.

Biologics manufacturers and certain of their subcontractors are required to register their establishments with the FDA and certain state agencies.

Registration with the FDA subjects entities to periodic unannounced inspections by the FDA, during which the agency inspects manufacturing facilities to assess compliance with cGMPs.

Accordingly, manufacturers must continue to expend time, money, and effort in the areas of production and quality control to maintain compliance with cGMPs.

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Biosimilarity must be shown through analytical trials, animal trials, and a clinical trial or trials, unless the Secretary of Health and Human Services waives a required element.

A biosimilar product may be deemed interchangeable with a previously approved product if it meets the higher hurdle of demonstrating that it can be expected to produce the same clinical results as the reference product and, for products administered multiple times, the biologic and the reference biologic may be switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biologic.

The first biosimilar was approved in 2015, and the first interchangeable product was approved July 28, 2021.

A biosimilar product may be deemed interchangeable with a previously approved product if it meets the higher hurdle of demonstrating that it can be expected to produce the same clinical results

as the reference product and, for products administered multiple times, the biologic and the reference biologic may be switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biologic.

The first biosimilar was approved in 2015, and the first interchangeable product was approved in 2021.

Complexities associated with the larger, and often more complex, structures of biological products, as well as the process by which such products are manufactured, pose significant hurdles to biosimilar product implementation, which is still being evaluated by the FDA.

A reference biologic is granted 12 years of exclusivity from the time of first licensure, or BLA approval, of the reference product, and no application for a biosimilar can be submitted for four years from the date of licensure of the reference product.

The first biologic product submitted under the biosimilar abbreviated approval pathway that is determined to be interchangeable with the reference product has exclusivity against a finding of interchangeability for other biologics for the same condition of use for the lesser of (i) one year after first commercial marketing of the first interchangeable biosimilar, (ii) 18 months after the first interchangeable biosimilar is approved if there is no patent challenge, (iii) eighteen months after resolution of a lawsuit over the patents of the reference biologic in favor of the first interchangeable biosimilar applicant, or (iv) 42 months after the first interchangeable biosimilar’s application has been approved if a patent lawsuit is ongoing within the 42-month period.

The first biologic product submitted under the biosimilar abbreviated approval pathway that is determined to be interchangeable with the reference product has exclusivity against a finding of interchangeability for other biologics for the same condition of use for the lesser of (i) one year after first commercial marketing of the first interchangeable biosimilar, (ii) 18 months after the first interchangeable biosimilar is approved if there is no patent challenge, (iii) 18 months after resolution of a lawsuit over the patents of the reference biologic in favor of the first interchangeable biosimilar applicant, or (iv) 42 months after the first interchangeable biosimilar is approved if a patent lawsuit is ongoing within the 42-month period.

Other Healthcare Laws

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Other federal statutes pertaining to healthcare fraud and abuse include the civil monetary penalties statute, which prohibits, among other things, the offer or payment of remuneration to a Medicaid or Medicare beneficiary that the offeror or payor knows or should know is likely to influence the beneficiary to order or receive a reimbursable item or service from a particular supplier, and the additional federal criminal statutes created by the Health Insurance Portability and Accountability Act of 1996 (“HIPAA”), which prohibit, among other things, knowingly and willfully executing or attempting to execute a scheme to defraud any healthcare benefit program or obtain by means of false or fraudulent pretenses, representations or promises any money or property owned by or under the control of any healthcare benefit program in connection with the delivery of or payment for healthcare benefits, items or services.

In addition, HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act of 2009, or HITECH, and their respective implementing regulations, including the Final Omnibus Rule published on January 25, 2013, impose obligations on certain healthcare providers, health plans, and healthcare clearinghouses, known as covered entities, as well as their business associates and their subcontractors that perform certain services involving the storage, use or disclosure of individually identifiable health information, including mandatory contractual terms, with respect to safeguarding the privacy, security, and transmission of individually identifiable health information, and require notification to affected individuals and regulatory authorities of certain breaches of security of individually identifiable health information.

In addition, HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act of 2009 (“HITECH”) and their respective implementing regulations, including the Final Omnibus Rule published on January 25, 2013, impose obligations on certain healthcare providers, health plans, and healthcare clearinghouses, known as covered entities, as well as their

business associates and their subcontractors that perform certain services involving the storage, use or disclosure of individually identifiable health information, including mandatory contractual terms, with respect to safeguarding the privacy, security, and transmission of individually identifiable health information, and require notification to affected individuals and regulatory authorities of certain breaches of security of individually identifiable health information.

HITECH increased the civil and criminal penalties that may be imposed against covered entities, business associates and possibly other persons, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorney’s fees and costs associated with pursuing federal civil actions.

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Certain states and local jurisdictions also require the registration of pharmaceutical sales representatives.

Additionally, we may also be subject to state and foreign laws governing the privacy and security of health information in some circumstances, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts.

Additionally, we may also be subject to state and foreign laws governing the privacy and security of health information in some circumstances, many of which differ from one another in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts.

Efforts to ensure that business arrangements with third parties comply with applicable state, federal, and foreign healthcare laws and regulations involve substantial costs.

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Numerous state, federal and foreign laws, govern the collection, dissemination, use, access to, confidentiality, and security of personal information, including health-related information.

In the United States, numerous federal and state laws and regulations, including state data breach notification laws, state health information privacy laws, and federal and state consumer protection laws and regulations, govern the collection, use, disclosure, and protection of health-related and other personal information could apply to our operations or the operations of our partners.

In the United States, numerous federal and state laws and regulations, including state data breach notification laws, state health information privacy laws, and federal and state consumer protection laws and regulations that govern the collection, use, disclosure, and protection of health-related and other personal information could apply to our operations or the operations of our partners.

For example, HIPAA, as amended by HITECH, and their respective implementing regulations, imposes privacy, security and breach notification obligations on certain health care providers, health plans, and health care clearinghouses, known as covered entities, as well as their business associates that perform certain services that involve creating, receiving, maintaining or transmitting individually identifiable health information for or on behalf of such covered entities.

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In addition, certain state and non-U.S.

laws, such as the GDPR govern the privacy and security of personal information, including health-related information, in certain circumstances.

laws, such as the General Data Protection Regulation (the “GDPR”) govern the privacy and security of personal information, including health-related information, in certain circumstances.

Failure to comply with these laws, where applicable, can result in the imposition of significant civil and/or criminal penalties and private litigation.

For example, the CCPA, which went into effect on January 1, 2020, creates new data privacy obligations for covered companies and provides new privacy rights to California residents.

In Europe, the GDPR went into effect in May 2018 and introduces strict requirements for processing the personal data of individuals within the EEA.

For example, the California Consumer Privacy Act (“CCPA”), which went into effect on January 1, 2020, creates new data privacy obligations for covered companies and provides new privacy rights to California residents.

On January 1, 2023, the California Privacy Rights Act (“CPRA”), which substantially amends the CCPA, went into effect.

The CCPA and CPRA provide for unlimited civil penalties for violations, as well as a private right of action for data breaches that is expected to increase data breach litigation.

In Europe, the GDPR went into effect in May 2018 and introduces strict requirements for processing the personal data of individuals within the European Economic Area (“EEA”).

Further, recent legal developments in Europe have created complexity and compliance uncertainty regarding certain transfers of personal data from the EEA.

For example, on July 16, 2020, the CJEU invalidated the Privacy Shield under which personal data could be transferred from the EEA to United States entities who had self-certified under the Privacy Shield scheme.

For example, on July 16, 2020, the Court of Justice of the European Union invalidated the EU-U.S.

Privacy Shield Framework (the “Privacy Shield”) under which personal data could be transferred from the EEA to United States entities who had self-certified under the Privacy Shield scheme.

Moreover, it is uncertain whether the standard contractual clauses will also be invalidated by the European courts or legislature.

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Additionally, following the United Kingdom’s withdrawal from the European Union and the EEA, companies have to comply with the GDPR and the GDPR as incorporated into United Kingdom national law, the latter regime having the ability to separately fine up to the greater of £17.5 million or 4% of global turnover.

The relationship between the United Kingdom and the European Union in relation to certain aspects of data protection law remains unclear, for example around how data can lawfully be transferred between each jurisdiction, which exposes us to further compliance risk.

Coverage and Reimbursement

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Decreases in third-party reimbursement for any product or a decision by a third-party not to cover a product could reduce physician usage and patient demand for the product.

Healthcare Reform

United States Healthcare Reform

Healthcare reforms that have been adopted, and that may be adopted in the future, could result in further reductions in coverage and levels of reimbursement for pharmaceutical products, increases in rebates payable under U.S.

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On September 9, 2021, the Biden administration published a wide-ranging list of policy proposals, most of which would need to be carried out by Congress, to reduce drug prices and drug payment.

The Depart of Health and Human Services, or HHS, plan includes, among other reform measures, proposals to lower prescription drug prices, including by allowing Medicare to negotiate prices and disincentivizing price increases, and to support market changes that strengthen supply chains, promote biosimilars and generic drugs, and increase price transparency.

Many similar proposals, including the plans to give Medicare Part D authority to negotiate drug prices, require drug manufacturers to pay rebates on drugs whose prices increase greater than the rate of inflation, and cap out-of-pocket costs, have already been included in policy statements and legislation currently being considered by Congress.

It is unclear to what extent these and other statutory, regulatory, and administrative initiatives will be enacted and implemented.

The Department of Health and Human Services, or HHS, plan includes, among other reform measures, proposals to lower prescription drug prices, including by allowing Medicare to negotiate prices and disincentivizing price increases, and to support market changes that strengthen supply chains, promote biosimilars and generic drugs, and increase price transparency.

These proposals recently culminated in the enactment of the Inflation Reduction Act (“IRA”) in August 2022, which will, among other things, allow HHS to negotiate the selling price of certain drugs and biologics that CMS reimburses under Medicare Part B and Part D, although only high-expenditure single-source biologics that have been approved for at least 11 years (7 years for drugs) can be selected by CMS for negotiation, with the negotiated price taking effect two years after the selection year.

The negotiated prices, which will first become effective in 2026, will be capped at a statutory ceiling price.

Beginning in January 2023 for Medicare Part B and October 2022 for Medicare Part D, the IRA will also penalize drug manufacturers that increase prices of Medicare Part B and Part D drugs at a rate greater than the rate of inflation.

The IRA permits the Secretary of HHS to implement many of these provisions through guidance, as opposed to regulation, for the initial years.

Manufacturers that fail to comply with the IRA may be subject to various penalties, including civil monetary penalties.

The IRA also extends enhanced subsidies for individuals purchasing health insurance coverage in ACA marketplaces through plan year 2025.

These provisions will take effect progressively starting in 2023, although they may be subject to legal challenges.

We expect that additional state and federal healthcare reform measures could be adopted in the future.

Further, it is possible that governmental action is taken in response to a new COVID‑19 variant or future pandemic.

Other Government Regulation Outside of the United States

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ATMPs comprise gene therapy products, somatic cell therapy products, and tissue engineered products, which are genes, cells, or tissues that have undergone substantial manipulation and that are administered to human beings in order to cure, diagnose or prevent diseases or regenerate, repair or replace a human tissue.

Pursuant to the ATMP Regulation, the Committee on Advanced Therapies (“CAT”), is responsible in conjunction with the CHMP for the evaluation of ATMPs.

Pursuant to the ATMP Regulation, the Committee on Advanced Therapies (“CAT”), is responsible in conjunction with the Committee for Medicinal Products for Human Use (“CHMP”) for the evaluation of ATMPs.

The CHMP and CAT are also responsible for providing guidelines on ATMPs.

3 unchanged sentences

Although such guidelines are not legally binding, compliance with them is often necessary to gain and maintain approval for product candidates.

In the European Union and in Iceland, Norway, and Liechtenstein (together the European Economic Area, or EEA), after completion of all required clinical testing, medicinal products may only be placed on the market after a related Marketing Authorization (“MA”), has been granted.

In the European Union and in Iceland, Norway, and Liechtenstein (together the EEA), after completion of all required clinical testing, medicinal products may only be placed on the market after a related Marketing Authorization (“MA”), has been granted.

MAs can be obtained through, amongst others, a centralized procedure, which is compulsory for certain medicinal products such as ATMPs.

1 unchanged sentence

The centralized procedure is compulsory for certain medicinal products, including medicinal products derived from biotechnological processes, orphan medicinal products, ATMPs, and products with a new active substance indicated for the treatment of AIDS, cancer, neurodegenerative disorders, diabetes, autoimmune diseases, and viral diseases.

It is optional for medicinal products containing a new active substance not yet authorized in the EEA before May 20, 2004, that constitute significant therapeutic, scientific or technical innovations, or for which the grant of a MA through the centralized procedure would be in the interest of public health at EU level.

The timeframe for the evaluation of an application under the centralized procedure is 210 days, excluding clock stops.

5 unchanged sentences

MAs have an initial duration of five years.

The authorization may subsequently be renewed for an unlimited period unless the EC or the national competent authority grants only a five-year renewal.

The authorization may subsequently be renewed for an unlimited period unless the European Commission or the national competent authority grants only a five-year renewal.

Data and Market Exclusivity

5 unchanged sentences

An additional non-cumulative one-year period of marketing exclusivity is possible if during the data exclusivity period (the first eight years of the 10‑year marketing exclusivity period), the MA holder obtains an authorization for one or more new therapeutic indications that are deemed to bring a significant clinical benefit compared to existing therapies.

Products may not be granted data exclusivity since there is no guarantee that a product will be considered by the European Union’s regulatory authorities to include a NCE.

Even if a compound is considered to be a NCE and the MA applicant is able to gain the prescribed period of data exclusivity, another company nevertheless could also market another version of the medicinal product if such company can complete a full marketing authorization application with their own complete database of pharmaceutical tests, preclinical studies, and clinical trials and obtain MA of its product.

Products may not be granted data exclusivity since there is no guarantee that a product will be considered by the European Union’s regulatory authorities to include an NCE.

Even if a compound is considered to be an NCE and the MA applicant is able to gain the prescribed period of data exclusivity, another company nevertheless could also market another version of the medicinal product if such a company can complete a full marketing authorization application with their own complete database of pharmaceutical tests, preclinical studies, and clinical trials and obtain MA for its product.

Post-Approval Regulation

5 unchanged sentences

The holder of a marketing authorization for a medicinal product must also comply with EU pharmacovigilance legislation and its related regulations and guidelines, which entail many requirements for conducting pharmacovigilance, or the assessment and monitoring of the safety of medicinal products.

These pharmacovigilance rules can impose on holders of MAs the obligation to conduct a labor intensive collection of data regarding the risks and benefits of marketed medicinal products and to engage in ongoing assessments of those risks and benefits, including the possible requirement to conduct additional clinical studies or post-authorization safety studies to obtain further information on a medicine’s safety, or to measure the effectiveness of risk-management measures, which may be time consuming and expensive and could impact our profitability.

safety studies to obtain further information on a medicine’s safety, or to measure the effectiveness of risk-management measures, which may be time consuming and expensive and could impact our profitability.

MA holders must establish and maintain a pharmacovigilance system and appoint an individual qualified person for pharmacovigilance, who is responsible for oversight of that system.

9 unchanged sentences

In addition, other national legislation of individual EU Member States may apply to the advertising and promotion of medicinal products and may differ from one country to another.

These laws require that promotional materials and advertising in relation to medicinal products comply with the product’s SmPC as approved by the competent regulatory authorities.

These laws require that promotional materials and advertising in relation to medicinal products comply with the product’s Summary of Product Characteristics (“SmPC”) as approved by the competent regulatory authorities.

The SmPC is the document that provides information to physicians concerning the safe and effective use of the medicinal product.

7 unchanged sentences

In the EU, interactions between pharmaceutical companies and physicians are also governed by strict laws, regulations, industry self-regulation codes of conduct and physicians’

codes of professional conduct both at EU level and in the individual EU Member States.

codes of professional conduct both at the EU level and in the individual EU Member States.

The provision of benefits or advantages to physicians to induce or encourage the prescription, recommendation, endorsement, purchase, supply, order or use of medicinal products is prohibited in the European Union.

35 unchanged sentences

We consider our relationship with our employees to be good.

Corporate Information

We were incorporated in Delaware on April 2, 2018.

Our principal executive offices are located at 2929 N Commerce Parkway, Miramar, FL 33025.

Our telephone number at that location is (954) 842-2024.

References in this Annual Report on Form 10-K to “we,”

“our,”

“us,”

“HCW Biologics,”

and the “Company”

refer to HCW Biologics Inc.

Our corporate website address is www.hcwbiologics.com.

Information contained on our website is not a part of this Annual Report on Form 10-K and the inclusion of our website address in this Annual Report on Form 10-K is an inactive textual reference only.

HCW BIOLOGICS INC.

and TOBI are trademarks of HCW Biologics Inc.

All other brand names or trademarks appearing in this Annual Report on Form 10-K are the property of their respective holders.

Solely for convenience, the trademarks and trade names in this Annual Report on Form 10-K are referred to without the ® and symbols, but such references should not be construed as any indicator that their respective owners will not assert, to the fullest extent under applicable law, their rights thereto.

Available Information

We make available, free of charge through our website, our annual reports on Form 10-K, quarterly reports on Form 10-Q, and current reports on Form 8-K, and amendments to those reports, filed or furnished pursuant to Sections 13(a) or Section 15(d) of the Securities Exchange Act of 1934, as amended, as soon as reasonably practicable after they have been electronically filed with, or furnished to, the SEC.

The SEC maintains an internet site (http://www.sec.gov) that contains reports, proxy and information statements, and other information regarding issuers that file electronically with the SEC.

We make available, free of charge, on or through our website (http://www.hcwbiologics.com), our annual reports on Form 10-K, quarterly reports on Form 10-Q, and current reports on Form 8-K, and amendments to those reports, filed or furnished pursuant to Sections 13(a) or Section 15(d) of the Securities Exchange Act of 1934, as amended, as soon as reasonably practicable after they have been electronically filed with, or furnished to, the SEC.

References to website addresses in this report are intended to be inactive textual references only, and none of the information contained on our website is part of this report or incorporated in this report by reference.

Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business