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Item 1. Business

2023-03-16 compared with 2022-04-01 · 457 added, 851 removed, 628 unchanged (68% of the section changed)

BioPharma is a pre-clinical biotechnology company developing novel therapeutic candidates targeting ferroptosis, an emerging new anti-cancer

mechanism resulting in iron mediated cell death (“IMCD”) for treatment resistant cancers.

The most advanced product candidate

which we own is HSB-1216, an IMCD inducer, targeting a variety of solid tumors.

In a clinical pilot study conducted in Germany by the

University of Heidelberg, the active drug in HSB-1216 was found to reduce tumor burden in treatment resistant cancers, including triple

negative breast cancer (“TNBC”) and epithelial carcinomas.

Our goal is to submit an investigational new drug application

(“IND”) to the U.S.

Food and Drug Administration (“FDA”) in 2023 and start a clinical study with HSB-1216 in

mechanism resulting in iron mediated cell death (“IMCD”), and targeted immuno-oncology novel biologics, for the treatment

drug resistant cancers.

Our most advanced product candidate, HSB-1216, is an IMCD inducer, targeting a variety of solid tumors.

clinical pilot study conducted at the University of Heidelberg, Germany, the active drug in HSB-1216 was found to reduce tumor burden

in treatment resistant cancers, including triple negative breast cancer (“TNBC”) and epithelial carcinomas.

We utilize Quatramer™,

our proprietary tumor targeting platform, to enhance the uptake of HSB-1216 in the tumor microenvironment (“TME”) with an

extended duration of action and minimal off-target toxicity.

Our goal is to submit an investigational new drug application (“IND”)

Food and Drug Administration (“FDA”) and initiate a clinical study with HSB-1216 in the second half of 2023;

however, no assurance can be provided that our IND will be accepted by the FDA in 2023, if at all.

If our IND is accepted by the

FDA, our HSB-1216 clinical study will focus on expanding upon the clinical pilot study conducted in Germany.

If we are able to start

our clinical study with HSB-1216 in 2023, we anticipate that initial clinical data from such trial will be released either the end of

2023 or early 2024.

We use Quatramer™, our proprietary tumor targeting platform, to enhance the uptake of HSB-1216 in the tumor

microenvironment (“TME”) with an extended duration of action and minimal off-target toxicity.

In addition, TridentAI, our

artificial intelligence precision medicine platform, is used to identify biomarkers in our clinical programs to target specific patient

If our IND is accepted by the FDA,

our HSB-1216 clinical studies will focus on expanding upon the clinical pilot study conducted in Germany.

If we are able to initiate

our clinical study with HSB-1216 in the second half of 2023, we anticipate that clinical data from such trial will be released either

late 2024 or early 2025.

discovery of regulated cell death processes, such as apoptosis and autophagy, has enabled novel target discovery for drug development.

Ferroptosis, a form of IMCD, is an emerging regulated cell death process which decreases intracellular iron or the Labile Iron Pool (“LIP”),

Cancer cells increase the LIP leading to unregulated cell growth and metabolism.

Decreasing the LIP, induces iron-led ROS production

and lipid peroxidation, two key hallmarks of ferroptosis/IMCD.

HSB-1216 binds iron in the cytoplasm of cancer cells and decreases the

a known factor required for cell growth.

Cancer cells promote increase in the LIP leading to unregulated cell growth and metabolism.

Decreasing the LIP, induces iron-led reactive-oxygen species (“ROS”) production and lipid peroxidation, two key hallmarks

of ferroptosis/IMCD, which lead to regulated cell death.

HSB-1216 sequesters iron in the cytoplasm of cancer cells and decreases the

LIP, thereby inducing ferroptosis/IMCD, leading to regulated cell death.

Areas of interest for the development of HSB-1216 are as a treatment

of solid tumors, including TNBC, uveal melanoma, glioblastoma multiforme, head and neck squamous cell carcinoma and other treatment resistant

cancers with high unmet need.

of solid tumors, including small cell lung cancer (“SCLC”), TNBC, uveal melanoma, glioblastoma multiforme, head and neck

squamous cell carcinoma and other drug resistant cancers with high unmet need.

is a tumor targeting platform which allows us to leverage and exploit key tumor targets and novel emerging pathways such as IMCD to facilitate

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By efficiently extending the circulation half-life, as

well as targeting delivery to the tumor site, Quatramer traps drugs into the TME.

This emerging orthogonal anti-cancer approach utilizes

a fundamental recognized mechanism of iron mediated tumor growth and metabolism.

We are building a portfolio of long-acting, potent anti-cancer

drug candidates using our Quatramer platform.

uses an artificial intelligence precision medicine platform to identify novel biomarkers.

TridentAI integrates diverse public datasets,

including The Cancer Genome Atlas (“TCGA”) to identify novel gene signatures to stratify patients prospectively in clinical

Quatramer tumor targeting also allows us to segment patients by exploiting TridentAI’s findings by (i) synthetic lethal

sensitivities with novel combinations, (ii) pursue undruggable targets such as c-myc and (iii) target tumors with a high degree

of cell plasticity indicative of recurrent/drug resistant phenotype.

well as targeting delivery to the tumor site, Quatramer preferentially traps drugs in the TME.

This emerging orthogonal anti-cancer approach

leverages a fundamental recognized mechanism of iron mediated tumor growth and metabolism.

We are building a portfolio of long-acting,

potent anti-cancer drug candidates using our Quatramer platform.

Quatrabody™ provides an entry into development of next generation immune-oncology (“IO”) biologics including, bispecific

and trispecific antibodies, antibody-drug conjugates (“ADCs”), CAR-T, CAR-NKs among others.

Quatrabodies capitalize on the

long half-life of tumor targeting Quatramers combined with Picobodies™ bovine-derived antibody “knob” domains which

have potential to access and bind more tightly to “undruggable” epitopes better than full sized antibodies.

HSB-1940 is a

combination of programed cell death protein 1 (“PD-1”) targeting Picobodies bound to the surface of Quatramers.

have the potential for delivering an increased drug payload to the tumor with a longer half-life while targeting novel “undruggable”

epitopes of well-established and validated IO targets such as PD-1.

Product Candidates and Research Programs

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Pipeline Chart

intend to submit an IND with the FDA for HSB-1216 in 2023, for HSB-888 in 2024, for HSB-510 in 2024 and for HSB-114 in 2025;

no assurance can be provided that our INDs will be accepted by the FDA based on our anticipated timeline, if at all.

intend to submit INDs to the FDA to gain approval to initiate clinical studies in the second half of 2023 for HSB-1216 and in 2025 for

both HSB-3215 and HSB-1940;

however, no assurance can be provided that our INDs will be accepted by the FDA based on our anticipated

timeline, if at all.

Lead Candidates

our most advanced product candidate which we intend to develop in the clinic in 2022 for multiple high unmet need solid tumors, is an

IMCD inducer delivered using our proprietary carrier, Quatramer.

We intend to submit an IND application to the FDA and obtain clinical

data to support our strategy in 2023;

however, no assurance can be provided that our IND will be accepted by the FDA in 2023, if at all.

HSB-1216 exploits a key feature of certain tumors that rely on an excessive LIP within the cell to modify the dysregulated iron microenvironment

We have received orphan drug designation (“ODD”) in small cell lung cancer (“SCLC”) and uveal melanoma

for HSB-1216’s active drug.

In a clinical pilot study conducted in Germany by the University of Heidelberg, HSB-1216’s active

drug was studied in 7 patients with positive results in heavily pre-treated and therapy resistant cancers.

By design, HSB-1216 circulates

systemically after an intravenous injection and concentrates in the TME of solid tumor masses.

The localization of HSB-1216 has been

demonstrated in multiple in vivo models with pharmacodynamic signals showing significant decreases in tumor size after multiple

weekly injections.

HSB-1216 - IMCD Mechanism of Action:

Shifting the Intracellular Redox Balance

a tumor concentrating therapeutic, HSB-1216 has the potential to be used in cancer patients who have failed standard-of-care therapies

our most advanced product candidate which we intend to prepare for advancement into the clinic for multiple high unmet need solid tumors,

is an IMCD inducer delivered using the Quatramer, our proprietary tumor targeting platform.

We intend to submit an IND application to

the FDA and obtain clinical data to support our strategy in the second half of 2023;

however, no assurance can be provided that our IND

will be accepted by the FDA in 2023, if at all.

HSB-1216 exploits a key feature of certain tumors that rely on an excessive LIP inside

the cell to modify the dysregulated iron microenvironment of cancer.

We have received orphan drug designation (“ODD”) in

SCLC and uveal melanoma for HSB-1216’s active drug.

In a clinical pilot study conducted at the University of Heidelberg, Germany,

HSB-1216’s active drug was studied in seven patients with positive results in heavily pre-treated and therapy resistant cancers.

By design, HSB-1216 circulates systemically after an intravenous injection and concentrates in the TME of solid tumor masses.

The localization

of HSB-1216 has been demonstrated in multiple in vivo pre-clinical models with pharmacodynamic signals showing significant decreases

in tumor size after weekly injections over time.

How Drug-resistant Persister Cancer Cells, Using Ferroptosis/IMCD, Hijack Intracellular Iron for Unregulated Growth and the Potential

Role of HSB-1216

ability to target drug-resistant persister cancer cells has the potential to be used in cancer patients who have failed standard-of-care

for treatment resistant tumors without any approved therapies.

We intend to submit an IND to the FDA for approval in 2023 and, if such

IND is timely submitted and approved, we anticipate initial data either the end of 2023 or early 2024;

however, no assurance can be provided

that our IND will be accepted by the FDA in 2023, if at all.

Chemotherapy,

an important part of antitumor treatment, exerts anticancer effects by killing cancer cells, and anthracycline-based regimens have been

and continue to be the mainstay of treatment for a vast majority of tumors.

The clinical applications of anthracycline regimens, above

certain dose ranges have limited use due to adverse events, including cumulative lifetime doses resulting in cardiotoxicity.

The nonspecific

accumulation of anthracyclines, such as doxorubicin and similar agents in non-target tissues such as cardiac cells, continues

to be a problem.

second product candidate, HSB-888, is a dual-loaded IMCD inducer coupled with our ultra-low dose next generation anthracycline analogue

for solid tumors.

HSB-888 is in IND-enabling studies, and we intend to develop such product candidate in the clinic in 2024 for multiple

sarcomas after we submit an IND to the FDA for HSB-888 in 2024;

however, no assurance can be provided that our IND will be accepted by

the FDA in 2024, if at all.

The components of HSB-888 are two anticancer drugs with complementary mechanisms of actions.

has granted one of the drug components of HSB-888 a Rare Pediatric Disease Designation and ODD for pediatric osteosarcoma.

other drug component in HSB-888 is our next generation anthracycline analogue approved and marketed in China and Japan which has

potent antitumor activity and is indicated for multiple tumor types, with an improved therapeutic index compared to doxorubicin.

We believe targeting the agent in our proprietary dual-loaded Quatramer with our novel IMCD inducer may confer key benefits for multiple

reasons, including a synergistic ultra-low-dose approach as well as leveraging a key differentiating mechanism of iron-mediation to kill

the tumor and reduce off target toxicities simultaneously.

HSB-888 – Structure & Mechanism

has the potential to be used in solid tumors whereby a potent anthracycline may be effective but prohibitive in current available forms

due to their off-target effects.

We intend to include data from our own pre-clinical studies as well as the human data available from

Japanese and Chinese studies in our IND which we intend to submit in 2024 and, if such IND is timely submitted and approved, we anticipate

top-line clinical data in 2024;

however, no assurance can be provided that our IND will be accepted by the FDA in 2024, if at all.

Other Candidates

own HSB-510, which is a novel highly targeted bifunctional inhibitory compound in Quatramer with single digit nanomolar IC50 against

PI3K-delta and HDAC6, which is also known to downregulate c-myc , a highly pursued and yet undruggable cancer drug target.

Quatramer platform achieves optimal tumor targeting and bioavailability of the highly potent targeted small molecule.

Through an ongoing

Cooperative Research and Development Agreement with the National Center for Advancing Translational Sciences (“NCATS”), part

of the National Institutes of Health (“NIH”), we analyzed novel dual Class I phosphoinositide 3-kinases (“PI3K”)/histone

deacetylases (“HDAC”) inhibitors and a lead compound which showed good antiproliferative activity against multiple oncology

This compound obtained ideal pharmacokinetic properties in our proprietary Quatramer, while maintaining specific HDAC6-PI3K-delta

We intend to continue our collaborative effort with NCATS through our collaboration.

In addition, we intend to submit an

IND to the FDA for HSB-510 in 2024;

however, no assurance can be provided that our IND will be accepted by the FDA in 2024, if at all.

HSB-510 - Structure

own HSB-114, which is a novel immunotherapeutic agent that uses our proprietary Quatramer platform to deliver the human tumor

necrosis factor-alpha (“TNF-alpha” or “TNF-α”) gene into cancer cells.

Finding ways to selectively increase

intratumoral TNF-alpha levels in tumors while managing the toxicity associated with such approaches remains a major unmet need.

we have developed a novel approach to include a peptide-DNA complex, which preferentially releases genetic material and localizes

into the nucleus of the delivered cancer cell and has been demonstrated to be highly effective in achieving a desired tumor

response in our pre-clinical oncology models using TNF-alpha.

We believe this intratumoral expression of secreted cytokines, such as

TNF-alpha, represents a novel approach for inducing anti-tumor activity and potentially reprogramming the tumor immune microenvironment,

and we intend to develop this technology further to strengthen our pipeline.

We intend to submit an IND to the FDA for HSB-114 in 2025;

however, no assurance can be provided that our IND will be accepted by the FDA in 2025, if at all.

HSB-114 - Structure

We intend to submit an IND to the FDA for approval in the second half

of 2023 and, if such IND is timely submitted and approved, we anticipate clinical data either late 2024 or early 2025;

however, no assurance

can be provided that our IND will be accepted by the FDA in 2023, if at all.

our second product candidate, is an

anti-HER2 monoclonal antibody candidate.

The ErbB or HER family of cell surface proteins are some of the most well-known and validated oncology drug targets including ErbB2 or

HER2 (human epidermal growth factor receptor) and Erb3 or HER3.

The family of antibodies and biologics against HER2 starting with HERCEPTIN ®

(trastuzumab) approved in 1998 for breast cancer, one of the first few anti-cancer antibodies, as well as PERJETA ®

(pertuzumab), KADCYLA ® (ado-trastuzumab emtansine) and PHESGO ® (Pertuzumab/trastuzumab/hyaluronidase) reported

2022 sales of greater than $8 billion for Roche/Genentech.

Antibodies against HER2 and HER3 bind to different domains of the extracellular

portion of the proteins or epitopes with trastuzumab primarily binding the extracellular domain IV of HER2.

HER2 is a validated tumor

antigen for antibody drug conjugates to treat HER2 positive cancers with two approved antibodies, Roche/Genentech’s KADCYLA ®

and Daiichi Sankyo/AstraZeneca’s ENHERTU ® .

Biomedical Science Institute (“ABSI”) has developed technology to target unique functional epitopes of the cancer targets

HER2 and HER3.

Monoclonal antibodies being developed at ABSI are unique from the currently approved anti-HER2 antibodies.

ABSI has granted

us an exclusive option to license technology from ABSI to develop HER2 and HER3 antibodies, including multi-specific and Quatramer-

based therapeutics incorporating portions of the antibodies.

These antibodies could be incorporated into proprietary multi-format biologics

(bi- and tri-specific antibodies, ADCs (antibody drug conjugates), CAR-T and CAR-NKs, in Quatramers and Quatrabodies) against drug resistant

cancers including HER2-positive metastatic breast cancer, gastric cancer, lung cancer and ovarian cancer.

The ABSI option terminates on March 24, 2023, unless extended by the parties.

third product candidate, HSB-1940, is a Quatrabody, a proprietary IO biologic,

in development targeting PD-1.

We entered into a research collaboration and product license agreement with Minotaur Therapeutics, Inc.

(“Minotaur”) and a commercial license agreement with Taurus Biosciences, LLC (“Taurus”), for use of certain technology,

including OmniAb antibodies, to advance Picobodies ™ against novel, undruggable epitopes in high-value validated IO targets

starting with PD-1.

The technologies of Hillstream and Minotaur will be combined under the license from

Taurus to discover, develop and advance biotherapeutics against high-value validated IO targets.

Picobodies are bovine-derived antibody

“knob” domains comprised of cysteine-rich ultralong complementary determining region (“CDR”) H3 sequences of

30-40 amino acids weighing ~3-4 KDa, which have the potential to access challenging undruggable epitopes better than full size antibodies

combining Quatramers, with their long half-life, coated with a PD-1 Picobody to create HSB-1940, we believe we can more efficiently target

novel epitopes with greater binding affinity than approved anti-PD-1 antibodies.

We further believe that the development of HSB-1940

is a step toward enabling us to enter the rapidly growing IO market with additional targets thereafter.

Other Product Candidates

intend to further develop our pipeline with novel bispecific monoclonal antibodies.

These bispecific antibodies are planned to simultaneously

bind to two different antigens or to two different epitopes on the same antigen.

Whether two different antigens or two epitopes on the

same antigen, the bispecific antibody could bind its targets either on the same cell ( cis ) or on to different cells ( trans ).

Our strategy involves targeting PD-1 combined with a known, validated undisclosed antigen (HSB-9646) or using HER2 instead of PD-1 (HSB-0059),

while naturally occurring antibodies typically only target one epitope on one antigen.

At this time, we have de-prioritized the expenditures

and related activities associated with TridentAI, HSB-510, HSB-114 and HSB-888.

technology platform enables us to generate a pipeline of early-stage product candidates spanning multiple targets in oncology utilizing

diverse payloads to treat rare and treatment resistant tumors.

While the payloads in our most advanced product candidates, HSB-1216 and

HSB-888, are novel, and have pilot and extensive human data in multiple solid tumors, any solid tumor or non-oncologic disease requiring

delivery of a peptide, protein or biologic is conceivably a candidate for our technology.

Our early-stage product candidates are focused

on rare and treatment resistant diseases;

however, we believe our technology could potentially deliver meaningful benefit across a wide

range of oncologic and viral diseases.

We have tested several peptides, nucleic acids, proteins, small molecules and antibody constructs

against multiple targets.

While the payload in our most advanced product candidate, HSB-1216, is

novel, and has pilot human data in multiple solid tumors, any solid tumor or non-oncologic disease requiring delivery of a peptide, protein

or biologic is conceivably a candidate for our Quatramer technology.

Our early-stage product candidates such as HSB-3215 and HSB-1940

are focused on rare and treatment resistant diseases;

however, we believe our technology could potentially deliver meaningful benefit

across a wide range of oncologic and viral diseases.

We have tested several peptides, nucleic acids, proteins, small molecules and antibody

constructs against multiple targets.

Platform Technologies

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by a reduction in their ability to activate their killing effect of the cancer.

Tumor Vasculature

Quatramer Tumor Targeting Platform with Versatile Payload Delivery

proprietary Quatramer technology overcomes the limitations that have hampered development of nanoscale and liposome derived products

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Quatramers ultimately breakdown into known metabolites such as lactic acid and ethanol.

Artificial Intelligence

uses an artificial intelligence precision medicine platform to identify novel biomarkers.

TridentAI integrates diverse public datasets,

including TCGA to identify novel gene signatures to stratify patients prospectively in clinical trials.

Quatramer tumor targeting also

allows us to segment patients by exploiting TridentAI’s findings by (i) synthetic lethal sensitivities with novel combinations,

(ii) pursue undruggable targets such as c-myc and (iii) target tumors with a high degree of cell plasticity indicative of recurrent/drug

resistant phenotype.

TridentAI platform:

the ability to create a Ferroptomics Atlas which integrates diverse multi-omics datasets including not only genomics, epigenetics

and transcriptomics but also emerging proteomics data which enable identification of dynamical re-wiring of intra-tumoral signaling

circuitry designed to target IMCD;

the ability to identify biomarkers that potentially differentiate between progression of cancer plasticity and correlate it to degree

of sensitivity to a synthetically lethal target that is induced with standard-of-care treatment and development of resistance;

designed to classify and select patients that are most likely to respond to treatment.

TridentAI is designed to establish clinical development

combine the benefits of tumor targeting and long half-life of Quatramers with novel Picobodies to enter into development of next generation

IO therapeutics.

Quatrabodies capitalize on the knob domains from bovine-derived antibodies which have the potential to access “undruggable”

epitopes on validated tumor targets better than full sized antibodies.

Picobodies are the smallest known antibody fragment, comprised

of ultra-long CDR H3 sequences of 30-40 amino acids rich with cysteines that create tightly folded structures capable of binding recessed

Quatrabodies Combine Quatramers’ Tumor Targeting and Long Half-Life with Knobs, the Smallest Known Antibody Fragments, Targeting

Undruggable Epitopes

derived from mouse or human sources use the surface formed by CDRs on the variable regions of the heavy chain/light chain heterodimer,

which typically forms a relatively flat binding surface.

Bovine’s ultralong CDR-H3 regions form an independently folding mini-domain,

which protrudes far out from the surface of the antibody and forms a “stalk and knob” structure which is diverse in both

its sequence and disulfide patterns.

The “knob” (Picobody) component can be expressed as an independent antigen binding domain.

At ~4-6 kDa, these are three times smaller than a camelid “nanobody” and are the smallest known antibody fragment.

atypical antigen binding sites of bovines potentially provide the ability to interact with different antigenic determinants, particularly

recessed or concave surfaces, compared to traditional antibodies.

Key Programs:

HSB-1216 and HSB-888

HSB-1216, HSB-3215 and HSB-1940

have leveraged our proprietary technologies and are developing multiple product candidates with differentiated profiles designed to address

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Our HSB-1216 product candidate is an IMCD inducer delivered by our proprietary Quatramer platform.

We intend to submit an IND to the FDA for approval in 2023 and, if such IND is timely submitted and approved, we anticipate initial data

either at the end of 2023 or early 2024;

however, no assurance can be provided that our IND will be accepted by the FDA in 2023,

Our HSB-888 product candidate is a dual-loaded IMCD inducer that is coupled with our ultra-low dose next generation anthracycline

analogue for solid tumors.

We intend to include data from our own pre-clinical studies as well as the human data available from Japanese

and Chinese studies to submit an IND to the FDA in 2024 and, if such IND is timely submitted and approved, we anticipate top-line clinical

data in 2024;

however, no assurance can be provided that our IND will be accepted by the FDA in 2024, if at all.

We intend to submit an IND to the FDA to gain approval to initiate clinical studies in the second half of 2023 and, if such IND is timely

submitted and approved, we anticipate initial data will be released either late 2024 or early 2025;

however, no assurance can be provided

that our IND will be accepted by the FDA in 2023, if at all.

We intend to submit an IND for HSB-3215 (anti-HER2 antibody with novel conformational

epitopes) and HSB-1940 (our first Quatrabody targeting PD-1), subject to successfully completing pre-clinical identification and characterization

as well as IND enabling studies in 2024.

Our Novel Iron-Medicated Cell Death Inducer

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and cellular respiration, essential for normal growth and propagation.

However, iron also produces reactive oxygen species (“ROS”)

via a chemical process in which there is a catalytic decomposition of hydrogen peroxide by ferrous ions, known as the Fenton reaction.

This process may cause damage to the membrane lipid and DNA caused by ROS, known as lysosomal membrane permeabilization (“LMP”)

rupturing and killing the cell by spilling its contents into the surrounding microenvironment and causing degradation in the surrounding

extracellular milieu.

Emerging evidence suggests iron may have a twofold role on cells, both stimulating cell growth and causing cell

death, particularly a new form named ferroptosis, first described by the accumulation of iron-dependent lipid peroxides.

However, iron also produces ROS via a chemical process in which

there is a catalytic decomposition of hydrogen peroxide by ferrous ions, known as the Fenton reaction.

This process may cause damage

to the membrane lipid and DNA caused by ROS, known as lysosomal membrane permeabilization (“LMP”) rupturing and killing the

cell by spilling its contents into the surrounding microenvironment and causing degradation in the surrounding extracellular milieu.

Emerging evidence suggests iron may have a twofold role on cells, both stimulating cell growth and causing cell death, particularly a

new form named ferroptosis, first described by the accumulation of iron-dependent lipid peroxides.

Role of Iron in Growth of Drug-Resistant Persister Cancer Cells and Mechanism of Action of HSB-1216

that has been published by us with respect to the active drug of HSB-1216 targeting chemotherapy resistant tumors suggests that it sequesters

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with high unmet need.

HSB-1216 Mechanism of Action

HSB-1216 – Ferroptosis/IMCD Mechanism of Action:

Shifting the Intracellular Redox Balance

of the standard limitations to achieving successful cancer therapies is the manifestation of multidrug resistance (“MDR”)

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specific mechanisms of HSB-1216’s active drug.

data from third parties suggest that the specific mechanisms of HSB-1216’s active drug are three-fold which include a novel selective

iron-induced cell death known as ferroptosis, an ability to reverse a phenomenon known as epithelial-mesenchymal transition (“EMT”),

as well as an ability to evade the ABC transporters, of which the latter two are linked to multidrug resistance to commonly used cancer

chemotherapies.

Data with HSB-1216’s Active Drug

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Based on these findings, the compound

was therapeutically used in a “first-in-man” clinical pilot study conducted in Germany by the University of Heidelberg with

was therapeutically used in a “first-in-man” clinical pilot study conducted at the University of Heidelberg, Germany, with

a cohort of 7 patients with metastatic breast, ovarian and head and neck cancers in which tumor and metastatic regression were observed

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(1 of the head and neck and the other of the vulva).

Administration of 200– 250 μ g·kg −1 of active

drug intravenously every second day for three weeks in these patients resulted in partial regression of tumor metastasis.

active drug therapy resulted in tachycardia and mild tremor for 30–60 minutes after administration but lacked side effects observed

with conventional chemotherapeutic drugs, such as myelodepression, neutropenia, alopecia, nausea and vomiting, or gastrointestinal, thromboembolic,

and neurological side effects.

Administration of 200- 250 μ g·kg −1 of active drug

intravenously every second day for three weeks in these patients resulted in partial regression of tumor metastasis.

Intravenous active

drug therapy resulted in tachycardia and mild tremor for 30-60 minutes after administration but lacked side effects observed with conventional

chemotherapeutic drugs, such as myelosuppression, neutropenia, alopecia, nausea and vomiting, or gastrointestinal, thromboembolic, and

neurological side effects.

Only 2 of the 7 cases are described in the publication relating to this trial, both of which are detailed

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of intravenous (“IV”) treatment at a dose of 200 µg·kg -1 given every other day.

After 12 cycles, there

was a marked regression of the subcutaneous thoracic metastases (Figure 10).

A biopsy of the metastatic tissue, as investigated by molecular

histopathology, demonstrated that approximately 85% of the cells had undergone apoptosis.

Additionally, serum levels of the tumor marker

Ca 15-3 decreased from 14.3 U/mL before therapy to 7.2 U/mL after therapy.

Similarly, serum levels of Carcinoembryonic antigen, another

tumor marker, declined from 50.8 ng/mL to 15.5 ng/mL posttreatment.

These results demonstrate that the drug was not only able to kill

hard-to-treat cancers, but also more differentiated tumor cells and more importantly, highly indolent tumor cells displaying efficient

mechanisms of resistance to cytotoxic drugs, radiation, and induction of apoptosis.

After 12 cycles,

there was a marked regression of the subcutaneous thoracic metastases (Figure 7).

A biopsy of the metastatic tissue, as investigated

by molecular histopathology, demonstrated that approximately 85% of the cells had undergone apoptosis.

Additionally, serum levels of

the tumor marker Ca 15-3 decreased from 14.3 U/mL before therapy to 7.2 U/mL after therapy.

Similarly, serum levels of Carcinoembryonic

antigen, another tumor marker, declined from 50.8 ng/mL to 15.5 ng/mL posttreatment.

These results demonstrate that the drug was not

only able to kill hard-to-treat cancers, but also more differentiated tumor cells and more importantly, highly indolent tumor cells displaying

efficient mechanisms of resistance to cytotoxic drugs, radiation, and induction of apoptosis.

Clinical Pilot Study

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The patient received 14 IV

administrations of the drug at a dose of 200 µg·kg -1 given every other day plus erlotinib 150 mg daily for 30 days.

Significant tumor regression was observed 30 days after combination therapy, based on clinical inspection of the tumor, as well as decreased

serum level of squamous cell carcinoma (“SCC”) antigen from 11.3 ng/mL before combination therapy to 0.13 ng/mL after therapy.

Three months post-treatment, SCC levels increased to 3.2 ng/mL, and clinical inspection demonstrated significant tumor progression.

administrations of the drug at a dose of 200 µg·kg -1 given every other day plus erlotinib 150 mg daily for 30

Significant tumor regression was observed 30 days after combination therapy, based on clinical inspection of the tumor, as well

as decreased serum level of squamous cell carcinoma (“SCC”) antigen from 11.3 ng/mL before combination therapy to 0.13 ng/mL

after therapy.

Three months post-treatment, SCC levels increased to 3.2 ng/mL, and clinical inspection demonstrated significant tumor

experiencing numerous marked adverse effects with erlotinib (including fatigue, anorexia, nausea, and inappetence), the patient refused

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4 weeks, and 4 months post-treatment, based on clinical inspection of the local tumor and no marked changes in SCC.

2012 – Human Serum Levels of the Tumor Marker Squamous Cell Carcinoma in vitro

2012 - Human Serum Levels of the Tumor Marker in Squamous Cell Carcinoma in vitro

results demonstrate that the drug is able to induce partial clinical regression of heavily pretreated and therapy-resistant cancers,

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drugs in regular cancer cells, potentially playing a central role for HSB-1216-based combination therapies in the future treatment of

HSB-1216 Inhibits Tumor Growth in SCLC Mouse Model

HSB-1216 Inhibits Tumor Growth in Mouse Model of SCLC

to the National Cancer Institute’s Surveillance, Epidemiology and End Results, there are anticipated to be more than 230,000 new

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Clinical Plan in Solid Tumors

intend to submit an IND for our HSB-1216 product candidate for solid tumors to the FDA in 2023, and, if approved, we plan to conduct

a Phase 1 clinical trial to obtain human pharmacokinetic data and dose optimization data on our formulation thereafter;

however, no assurance

can be provided that our IND will be accepted by the FDA in 2023, if at all.

Based on the data obtained from pre-clinical studies, we

believe a Phase 1 basket trial can be conducted in the US with HSB-1216 where there are limited therapies.

Even with the advent of immune

checkpoint inhibitors (“ICIs”), there remains a large patient population which either does not benefit from allowing HSB-1216

to potentially prolong survival in ICI failures as well as recurrent disease patients.

Our Dual-Loaded IMCD inducer and Ultra-Low Dose Next Generation Anthracycline

HSB-888 product candidate has a component selected in pre-clinical screens for its similar cytotoxic activity to doxorubicin accompanied

by its reduced cardiac toxicity.

The component drug has been in use in Japan for more than two decades, and our clinical studies support

its claim of similar efficacy to doxorubicin but with reduced toxicity.

We intend to obtain approval of this product in the United States

as a drug that can be used in the treatment protocol of recurrent osteosarcoma.

HSB-888 combination could be a more tolerable therapy

which may improve response rates, overall survival, and quality of life.

We intend to submit an IND to the FDA in 2024 and, if approved,

we plan to initiate a clinical trial in recurrent pediatric osteosarcoma.

active drugs of HSB-888 have been used clinically to treat tumors such as osteosarcoma, breast cancer, lymphoma and acute myeloid leukemia

(“AML”) in countries outside the US such as Germany, Japan, China and India.

One component compound has shown lower cardiotoxicity

and greater antitumor effect than other anthracycline agents, commonly used in these tumors, due to the fact that it is taken up by tumor

cells to a higher degree than other drugs in its class.

This rapid uptake into tumor cells causes targeted incorporation into the cell’s

DNA and causes cell cycle arrest.

in multidrug-resistant cells, we believe HSB-888 can disrupt cell cycle kinetics.

Currently, the most important impediment to improving

outcomes of patients with osteosarcoma is the clinical resistance to the primary chemotherapy, MAP, which is widely used.

One of HSB-888’s

active drugs has been shown to be taken up by tumor cells approximately 170 times faster than doxorubicin and distributes its DNA into

tumor nucleus and intercalates.

In MDR osteosarcoma cell lines (MG63/DOX), the drug was shown to have a marked cell inhibitory effect

in both resistant and sensitive cells.

a retrospective Chinese study of relapsed and refractory osteosarcoma conducted by a third party, 3 of 23 evaluable patients who received

only one of the active drugs of HSB-888 with cisplatin, had partial responses, with 1 patient after 7 cycles achieving disease free progression

for more than 29 months.

In another Chinese study, the 5-year disease-free survival (“DFS”)

rate of the patients treated with the drug was 70.2%, significantly higher than that of the DOX-based regimen-treated group (53.1%).

The drug decreased the lung metastatic rate significantly compared with the DOX-based regimen (19.1% vs.

36.7%, p =0.045),

as well as the relapse rate (31.9% vs.

49.0%, p =0.067).

The compound also showed

lower rates of alopecia (63.8% vs.

85.7%, P =0.012), nausea and vomiting (51.1% vs.

79.6%, p =0.003), and mucositis (48.9% vs.

75.6%, p =0.003).

It also resulted in lower cardiac toxicity and demonstrated that it is better than the DOX-based regimen in terms of the 5-year DFS rate,

pulmonary metastasis rate, relapse rate and side effects .

These data suggest that an updated regimen utilizing HSB-888 delivering

two active drugs in refractory cases in a setting that would use high-dose methotrexate along with a platinum-drug may be warranted,

and we intend to study these patients in a clinical trial, due to the high unmet need in this population.

Low Dose Strategy

Chemotherapies

like anthracyclines, including doxorubicin and others in its class, have been used for decades as mainstay therapy in combination with

other drugs for multiple tumor types, including osteosarcoma as first-line therapy.

The most important issue is that although the regimen

may benefit patients in this setting, there is a dose-limiting cumulative effect on the patient with these cytotoxic approaches whereby,

after a maximum accumulation of dose over multiple cycles, the class of drug can longer be used in the recurrent setting for patients.

components of our HSB-888 product candidate are two anticancer drugs with distinct and complementary mechanisms of actions (ferroptosis

and DNA intercalation) which together constitute an active combination for treating osteosarcoma.

We investigated whether the efficacy

of this combination could be improved by controlling drug ratios following in vitro and vivo administration.

The combinations

were evaluated systematically for drug ratio-dependent synergy in vitro using multiple tumor cell lines.

In vitro screening

informatics on drug ratio-dependent cytotoxicity identified a consistently antagonistic region between active drugs at various molar

ratios, which also showed multiple synergistic ratios, dependent on the chemical characteristics of either DNA intercalating active drugs

combined with a ferroptosis inducer.

Co-formulations of these two agents were developed that maintained a fixed drug ratio for stability

and release profiling over broad timelines.

Drug ratio-dependent antitumor activity was demonstrated in vitro and in vivo for

these ratios and improved antitumor activity was observed for the Quatramer 1:3 molar ratio of DNA intercalator:ferroptosis inducer (designated

HSB-888) compared to drug cocktails in models tested.

HS-888, is a fixed-ratio formulation of DNA intercalator and ferroptosis inducer,

and a near-clinical candidate for development.

our proprietary molar ratio as seen by its in vitro and in vivo efficacy profile enables a low dose to be administered

that is presumably 5-fold to 10-fold less than the traditional DNA intercalator therapy that is currently utilized in multiple high unmet

need tumor types.

This low dose strategy may allow clinicians to treat a variety of tumor types requiring cytotoxic chemotherapy without

the burden of dose-limiting toxicities for traditional chemotherapy.

Synergy and Combination Index

research suggests cancer drug combination may act in synergy, additively or antagonistic based on drug ratios of the separate compounds

While this relationship can be evaluated readily in

vitro where drug ratios can be controlled, the translation of such information in vivo

is complex due to the fact that individual drugs administered separately may be distributed,

metabolized and eliminated differently.

This prevents control of the drug ratio following administration and may result in exposure of

cancer cells to antagonistic drug ratios with a corresponding loss of therapeutic activity.

approach with a combination of two drugs in HSB-888 as a dual drug-loaded formulation with our Quatramer strategy circumvents multiple

hurdles when compared with administering compounds separately.

distinguishing feature of our technology is our proprietary Quatramer delivery platform which maintains drug combinations at the desired

ratio after in-vivo administration.

Drug combinations used to treat cancer are often encompassed with drugs which are highly varied

in chemical and physical composition as well as properties.

Subsequently, formulating such drug combinations with unrelated features

into a single pharmaceutical approach that discharges both agents at the same or pre-determined different rates in the body as well as

in the tumor tissue of choice presents a significant technical challenge.

We have developed the Quatramer platform to provide versatility

in controlling drug loading to specified drug loading and release rates with the precise retention properties for therapeutic agents

from drug classes important for unmet need pharmaceutical development to benefit cancer patients.

have specifically identified cell-based screens and identified synergistic drug combinations of HSB-1216 and HSB-888 which have markedly

different chemical attributes.

With respect to our combination approach, we have controlled the ratio of the compounds in the delivery

when prepared, maintained the ratio of the compounds within the carrier system while circulating in the blood and have ensured the release

at the proper synergistic ratios when delivered to the tumor.

This approach allows for the combination product HSB-888 to have different

physicochemical properties of the original drugs and allows for the co-formulation and coordinated release of both drugs with widely

different properties from the same particle.

HSB-888 is 5 times more potent in synergy with HSB - 1216 in vitro

Combination Drug Clinical Development Plan

intend to submit an IND to the FDA for HSB-888 in 2024 and, if approved, thereafter progress our program into a Phase 1 study to identify

the dose of our formulation that would optimize the pharmacokinetic profile of the drug in line with the known cellular and human kinetic

profiles in Japanese and Chinese studies;

however, no assurance can be provided that our IND will be accepted by the FDA in 2024, if

We intend to work with the FDA to further progress a Phase 2 trial in a refractory sarcoma setting in patients who would benefit

due to the cumulative doses of anthracycline regimens these patients have already received.

We intend to develop our combination strategy

that incorporates our Quatramer platform using HSB-888, a dual drug-loaded formulation that may be synergistic in mechanism to explore

improved outcomes in these patients.

Sarcoma Market Potential

in a broad sense are tumors which are mesenchymal in nature capable of forming in connective tissue, blood, lymphatic and vessels, believed

to also effect bone and soft tissue.

They are rare and account for 1% of cancers, yet encompass about 13% of cases under the age of 20.

Most common in bone are osteosarcoma and Ewing’s sarcoma, while those arising from soft tissue are commonly rhabdomyosarcomas.

Other sarcomas, such as desmoplastic small round cell and synovial sarcoma are more common into adolescence and young adulthood.

of these tumors are treated with combination strategies including surgery, radiotherapy and traditional chemotherapy of various kinds

with 5-year survival rates of 60-70% depending on histology and metastatic disease at diagnosis.

Metastatic disease has a poor prognosis

at about 20-30% 5-year survival, while recurrent disease is even worse at less than 20%.

Recurrent osteosarcoma, either initially non-respondent

to treatment or returning after an initial response, occurs in about 30-50% of patients with local disease and upwards of 80% in metastatic

The most frequent site of metastasis as well as recurrence is the lungs, and often times these patients undergo surgical resection

of the tumor prior to continuing on therapy.

Research has suggested that patients can benefit from multiple surgeries, but this does

not obviate the need for systemic treatments to mitigate or eradicate the disease in recurrent cases, a significant high unmet need.

Other than palliative approaches using bone-seeking radiopharmaceuticals, limited agents have been approved for this high unmet need

tumor, predominantly in children and young adults.

Vascular endothelial growth factor inhibitors

as well as mechanistic target of rapamycin inhibitors and immunotherapy have been studied

but none have been conclusive in elucidating a regimen that could be FDA-approved for this disease.

Ewing’s sarcoma, the second

most common bone sarcoma when it recurs, has a dismal prognosis with a 5-year overall survival less than 10%.

Frontline therapy consists

of vincristine, doxorubicin, cyclophosphamide, ifosfamide and etoposide in alternating cycles of interval compressed treatment.

chemotherapy regimens are used in frontline treatment, there remains no standard backbone therapy for recurrent or refractory cases.

Rhabdomyosarcoma, the most common soft tissue tumor in young adults, has been historically treated with vincristine, actinomycin D, and

cyclophosphamide as standard-of-care for the last 50 years.

Desmoplastic round cell tumors as well synovial sarcomas are much more aggressive

sarcomas and have had no new interventions in recurrent and refractory disease.

All of these sarcomas, effecting younger patients, share

the commonality of very poor prognoses when the cancer recurs or becomes refractory to standard-of-care treatment protocols, creating

a vital urgency for novel treatments in these tumor types.

Our Novel Bifunction HDAC6-PI3K-Delta Inhibitor Downregulates ¬c-myc

HSB-510 product candidate is a novel highly targeted bifunctional inhibitory compound in Quatramer with single digit nanomolar IC50 against

PI3K-delta and HDAC6, which is also known to downregulate c-myc , a highly pursued and yet undruggable cancer drug target.

Quatramer platform achieves optimal tumor targeting and bioavailability of the highly potent targeted small molecule.

In October 2020,

we renewed our Cooperative Research and Development Agreement with NCATS.

The agreement enables NCATS to use our Quatramer drug delivery

platform in formulations of HDAC-PI3K-delta dual inhibitors for the treatment of rare cancers, including AML and acute lymphoid leukemia

series of compounds were rationally designed and synthesized as novel dual PI3K/HDAC inhibitors by incorporating a histone

deacetylase pharmacophore into a PI3K inhibitor (Idelalisib) via an optimized linker.

Several of these dual inhibitors were highly

potent (IC50 < 10 nM) and selective against PI3Kγ, -delta and HDAC6 enzymes and exhibited good antiproliferative activity against

multiple cancer cell lines.

The lead compound induced necrosis in several mutant and FLT3-resistant AML cell lines and primary blasts

from AML patients, while showing no cytotoxicity against several select normal cells.

Target engagement of PI3K-delta and HDAC6 by the

lead were demonstrated in specific cells using the cellular thermal shift assay.

The compound also showed ideal pharmacokinetic properties

in mice via intraperitoneal administration which provides a means to examine the biological effects of inhibiting these two enzymes with

a single molecule, either in vitro or in vivo .

conducted by NCATS have shown that by disrupting multiple compensatory cytoprotective pathways, HDAC6-PI3K-delta dual inhibitors have

therapeutic value.

Our primary objective in conjunction with NCATS was encapsulation of NCATS’ developed HDAC6-PI3K-delta dual

inhibitors into our proprietary, tumor infiltrating Quatramer platform to enhance delivery to malignant cells.

intend to continue our collaborative effort with NCATS through our Cooperative Research and Development Agreement, and we intend to expand

such agreement and execute a license to this novel HDAC-PI3K-delta dual inhibitor to move the compound through further pre-clinical testing

and into IND-enabling work.

HDAC6 & PI3K-delta Inhibitor

are an important class of epigenetic enzymes that regulate gene expression by removing acetyl groups from ε-amino lysine residues

HDACs play an important role in regulating expression of various proteins, including tumor suppressors and transcription

Dysregulation of HDACs is involved in cancer initiation and proliferation.

HDAC inhibition has emerged as a therapeutic approach

for cancer and several inhibitors, including Vorinostat (“SAHA”), Romidepsin, Belinostat, Panobinostat, and Chidamide, have

been approved in recent years Pan-HDAC inhibitors, such as Panobinostat and SAHA, modulate the acetylation status of a wide range of

protein targets leading to a therapeutic response;

however, these molecules also have undesirable side-effects, including hematological,

gastrointestinal, and cardiac toxicity with less than disable efficacy.

I PI3Ks are lipid kinase enzymes that transduce signals from cell surface receptors (RTK, GPCR, etc.) to downstream effectors (AKT, mTOR,

etc.), leading to a variety of cellular processes, including cell proliferation, survival, differentiation, metabolism, and angiogenesis.

Specifically, class I PI3Ks phosphorylate phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P2 or PIP2) in vivo to form the secondary messenger

phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P3 or PIP3).

The PI3Kα and PI3Kβ isoforms are ubiquitously expressed,

whereas PI3Kγ and PI3K-delta expression is limited to leukocytes.

Aberrant regulation of class I PI3Ks has been implicated in several

cancer types, and their inhibition continues to be an active cancer therapeutic area with at least four approved PI3K inhibitor drugs

(Idelalisib, Copanlisib, Duvelisib, and Alpelisib) and several others in ongoing clinical trials.

Despite tremendous progress in the

discovery of PI3K inhibitors (“PI3Ki”) over the past decade, clinical trials conducted by third parties with PI3Ki as a monotherapy

have shown poor efficacy prompting their evaluation in combination therapies and/or developing PI3K-based multitarget drugs.

both PI3K and HDAC inhibitor drugs are limited by insufficient efficacy and resistance mutations, there is strong evidence that simultaneous

inhibition of both PI3K and HDAC can synergistically inhibit tumor growth and address these limitations by improving efficacy, limiting

resistance, and providing a better therapeutic window than single inhibitors.

HSB-510 - Mechanism

(TNF-alpha DNA) for Metastatic Soft Tissue Sarcoma

identified in 1975, cloned in 1984 and named for its ability to induce necrosis of induced-sarcomas in mice, is a chemokine with potent

tumoricidal properties.

However, severe systemic toxicity (capillary leakage, disseminated coagulopathy, acidosis and shock) limited

its use as an anticancer agent, until procedures were developed to use the cytokine in the clinic where high concentrations were infused

into isolated limbs of sarcoma and melanoma subjects.

It has since been shown that direct intratumoral injection can augment ICIs by

slowing progression of tumors in various models, with unreliable efficacy due to the fact that levels of TNF produced must be sufficient

to attract specific T cells to the tumor via signaling, notwithstanding TNF’s direct antitumor necrotic effects.

Despite the potential

to activate tumor cell death, physiological intratumoral levels of sufficient TNF concentrations are unlikely to induce cancer regression

in patients utilizing the current strategies available to deliver this potent cytokine.

Finding ways to selectively increase intratumoral

TNF levels in tumors while managing the toxicity associated with such approaches remains a major unmet need.

HSB-114 product candidate is a novel immunotherapeutic agent which uses our proprietary Quatramer technology to deliver the human TNF-α

gene to cancer cells.

Previous immunotherapeutic strategies, including the payload of HSB-114, pHSB-114, used adenovector technology

requiring replication deficient gene deletions and complex manufacturing controls in order to deliver the gene to the desired cells,

although posed a theoretical risk of systemic toxicity and adjacent tissue damage due to overflow of TNF-α in blood from the tumor,

had some dose-limited toxicities.

In early phase trials of pHSB-114 in combination with radiotherapy

conducted by GenVec Inc.

(“GenVec”), significant clinical activity was observed in patients with metastatic melanoma, soft

tissue sarcoma and locally advanced esophageal cancer.

Anti-tumor activity was also observed in patients with pancreatic, rectal, and

head and neck cancers.

However, a Phase 3 trial conducted by GenVec in patients with locally advanced pancreatic cancer failed to demonstrate

a survival benefit prompting discontinuation of the development of this agent.

believe our novel non-viral immunotherapeutic TNF-α gene therapy, HSB-114, builds on the pHSB-114 clinical development program with

improved scalability and tunability providing efficacy with an overall enhanced safety profile to potentially minimize dose-limited toxicities.

We have developed HSB-114 via a modified Quatramer delivery system which includes a peptide-DNA

complex designed for maintaining the balance of DNA condensation and intracellular release and nuclear localization.

For delivery in

vivo , the system circumvents the challenge of DNA-nanoparticle serum interactions that have limited this field from progressing without

use of a viral vector delivery scheme.

Our results demonstrate that this approach is highly effective in conferring TNF-induced anti-tumor

activity in the absence of toxicity ( Figure 5 ).

Our findings further indicate that this

system maybe broadly applicable for expression of intratumoral cytokines that promote immune recognition and destruction.

2017 – Antitumor Activity of HSB-114 in Mouse Model

Data with pHSB-114

Phase 1 studies conducted by a third party evaluated TNF-α gene transfer therapy using a radiation-inducible polymer combined with

ionizing radiation therapy in patients with soft tissue sarcoma and solid tumors.

This combination therapy optimizes the therapeutic

index of TNF-α by facilitating a synergistic supra-additive interaction between the two therapeutic modalities by selective destruction

of the tumor vasculature leading to tumor necrosis.

Further, this strategy allows for direct cellular toxicity by locally targeted induction

of high concentrations of TNF-α within the tumor with minimal systemic toxicity.

The studies, summarized below, provide preliminary

evidence that pHSB-114 + radiotherapy is feasible, well tolerated, and provides a potential alternative to isolated limb perfusion.

I Study in Soft Tissue Sarcoma of the Extremities

Phase 1 dose-escalation study evaluated pHSB-114 and concomitant ionizing radiation therapy for up to 5 weeks in 14 adult patients with

soft tissue sarcoma of an extremity.

pHSB-114 was administered by intratumoral injection, twice weekly during the first week and once

weekly during weeks 2-5 of radiation therapy.

Three escalating dose levels of pHSB-114 were administered, with 3-6 patients treated per

dose level, starting with a dose of 4 × 10 9 particle units (“pu”) and escalating in 1-log increments to a

dose of 4 × 10 11 pu or until the maximal tolerated dose (“MTD”) was reached.

There was no intrapatient dose

Concomitant single-daily fractionated radiation was administered 5 days per week (total dose, 36-50.4 Gy).

Surgery was performed

in 11 patients whose tumor was resectable 3–9 weeks after radiotherapy ended.

objective tumor response was observed in 11 patients, or 85%;

of these, 2 were complete responses and 9 were partial responses.

11 patients who had surgery, all were resected with negative margins.

Pathological complete response was observed in 2 of the 11 patients.

Of the 8 patients who had partial response, 4 had ≥ 95% tumor necrosis, which prognostically carries an improved long-term survival.

Of the 2 patients who did not have surgery and received pHSB-114 for palliation, 1 had stable disease and the other had partial response.

Tumor response assessment was not consistent between results obtained via computed tomography (“CT”) and those obtained via

histological assessment after resection, whereby CT scans showed less response than pathological assessment in 9 of the 11 patients who

had surgery, suggesting that the magnitude of the true anti-tumor response rate of pHSB-114 with ionizing radiation may be underestimated

by CT scans, particularly if performed shortly after the end of treatment.

Research in Treating COVID-19

Coronaviruses

(“CoVs”) are important human and animal pathogens, and at the end of 2019, a novel coronavirus emerged as the cause of a

cluster of pneumonia cases in Wuhan, China.

Since then the virus identified as severe acute respiratory syndrome coronavirus 2 (“SARS-CoV-2”)

has been identified to causes the designated as COVID-19.

According to Johns Hopkins Coronavirus Resource Center, the global cases of

COVID-19 have reached over 446 million confirmed cases and more than 6 million reported deaths as of March 7, 2022.

there are no specific clinical features which can reliably distinguish COVID-19 from other viral respiratory infections, development

of dyspnea, anosmia and myalgias were strongly associated with a positive microbiologic test.

There has been much research on finding

effective vaccines and therapeutics against SARS-COV-2, including remdesivir, chloroquine or hydroxychloroquine, convalescent plasma

and other antibody based therapies, as well as IL-6 inhibitors, direct and indirect acting antivirals, immunomodulatory agents as well

as antibiotics including azithromycin, and anti-helminthics such as ivermectin are all in various stages of testing and clinical development.

has been reported that CoVs present and adhere to host cells via Angiotensin-Converting Enzyme-2 (“ACE-2”) receptor-mediated

endocytosis, which is a pH-dependent process.

In this process, Spike (S) protein plays a major role in receptor binding and membrane

fusion of SARS-CoV-2 for access into host cells.

It is a large transmembrane protein on the surface of the virus consisting of two subunits,

including the S1 subunit necessary to fit with the ACE-2 receptor for viral entry.

Subsequent to binding, SARS-CoV-2 enters the cytosol

of the host cell, by pH-dependent proteolytic cleavage of spike protein by transmembrane protease serine 2, a plasma membrane-anchored

protease that participates in proteolytic cascades of several human proteins, including those relevant to the normal function of the

human prostate.

This host protein primes the S1 subunit and promotes viral uptake and host cell entry.

Then, the combination of viral

and host cell membranes occurs in acidified endosomes, permitting viral genomes to affect host cells with the aid of the S2 subunit.

HSB-1218 product candidates uses our Quatramer tunable technology to encapsulate a potent antiviral and deploy the agent either systemically

or in an inhaled formulation to target SARS-CoV-2.

Evidence suggests the payload of HSB-1218’s active drug inhibits replication

of viral RNA in the cytoplasm by altering the pH.

We believe this product candidate has the potential to prevent the entry of SARS-CoV-2

into the cytosol and prevent membrane fusion (a pH-dependent process).

Further, it has been reported to interact with the S-protein,

and impact ACE-2 attachment and impede the release of viral RNA into the cytoplasm identifying the active component as a potential

antiviral agent against SARS-CoV-2.

2021 we conducted studies in BSL3 laboratory to assess activity of HSB-1218 against SARS-CoV-2 virus grown in Vero E6 cells.

demonstrated that treating tissue culture cells with HSB-1218 either before or after challenge with SARS-CoV-2 virus can protect cells

from virus induced cytotoxicity and significantly reduce the accumulation of virus titers in culture supernatants.

In pre-treatment experiments,

treatment of cells with 5 micromolar HSB-1218 had the most significant impact on both inhibition of virus induced cytotoxicity and virus

titers at 72 hours post-infection and treatment with as little as 1 micromolar HSB-1218 reduced virus titers below the limit of detection

at 24 hours post-infection.

Treatment of cells with 10 micromolar HSB-1218 following infection reduced virus titers in the culture supernatant

below the level of detection and inhibited virus induced cytotoxicity.

We are continuing further mechanistic studies in order to identify

the antiviral effect of HSB-1218 against SARS-CoV-2.

HSB-1218 - Dose dependent effect of HSB-1218 in an in vitro COVID-19 Model

believe HSB-1218, which utilizes our Quatramer delivery technology, may offer an approach for effective use of this agent as an antiviral

delivered to the site of infection in attacking SARS-CoV-2, and we intend to continue to develop this compound and seek government and

other funding to further develop this program.

intend to submit an IND for our HSB-1216 product candidate for solid tumors to the FDA in the second half of 2023, and, if approved,

we plan to conduct a Phase 1 clinical trial to obtain human pharmacokinetic data and dose optimization data on our formulation

however, no assurance can be provided that our IND will be accepted by the FDA in 2023, if at all.

Based on the data

obtained from pre-clinical studies, we believe a Phase 1 basket trial can be conducted in the US with HSB-1216 where there are

limited therapies.

Even with the advent of immune checkpoint inhibitors (“ICIs”), there remains a large patient

population which either does not benefit from allowing HSB-1216 to potentially prolong survival in ICI failures as well as recurrent

disease patients.

ErbB or HER family of cell surface proteins are some of the most well-known and validated oncology drug targets including ErbB2 or HER2

(human epidermal growth factor receptor) and Erb3 or HER3.

The family of antibodies and biologics against HER2 starting with HERCEPTIN ®

(trastuzumab) approved in 1998 for breast cancer, one of the first few anti-cancer antibodies, as well as PERJETA ®

(pertuzumab), KADCYLA ® (ado-trastuzumab emtansine) and PHESGO ® (Pertuzumab/trastuzumab/hyaluronidase) reported

2022 sales of greater than $8 billion for Roche/Genentech.

Antibodies against HER2 and HER3 bind to different domains of the extracellular

portion of the proteins or epitopes with trastuzumab primarily binding the extracellular domain IV of HER2.

HER2 is a validated tumor

antigen for antibody drug conjugates to treat HER2 positive cancers with two approved antibodies, Roche/Genentech’s KADCYLA ®

and Daiichi Sankyo/AstraZeneca’s ENHERTU ® .

Anti-ErbB2 (HER2) and Anti-ErbB3 (HER3) Antibodies

Quatramers with their long half-life coated with a PD-1 Picobody to create HSB-1940, we believe we can more efficiently target novel

epitopes with greater binding affinity than approved biologics.

We further believe that targeting PD-1 is a step toward enabling us to

enter the rapidly growing IO therapeutics market with additional IO targets such as programed death- ligand 1 (“PD-L1”),

HER-2 and trophoblast cell surface antigen 2 (“TROP-2”).

derived from mouse or human sources use the surface formed by CDRs on the variable regions of the heavy chain (V H )/light chain

(V L ) heterodimer typically forming a relatively flat binding surface which then binds the target protein.

Alternative species,

particularly camelids and bovines, provide a paradigm for antigen recognition through novel domains which form the antigen binding site.

However, for camelids, heavy chain antibodies bind antigen with only a single heavy chain variable region (V H ), in the absence

of light chains.

Meanwhile, in bovines, ultralong CDR-H3 regions form an independently folding mini-domain, which protrudes far out from

the surface of the antibody and forms a “stalk and knob” structure.

The “knob” is diverse in its structure, small

size and weight, sequence and disulfide patterns.

The “knob” (Picobody) component can be expressed as an independent antigen

binding domain with three times smaller size (~4-6 kDa) than a camelid “nanobody” making it the smallest known antibody fragment.

These atypical antigen binding sites of bovines potentially provide the ability to interact with different antigenic determinants or

epitopes, particularly recessed or concave surfaces, compared to traditional full-length mouse or human antibodies.

Quatrabodies Combine Unique Features of the Knob Domain of Bovine-derived Antibodies with Quatramers’ Long Half-life

Mediated Cell Death Inducer Analogues Program

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plasma and blood which dramatically increases the amount of drug available at the disease site while administering a lower dose.

Quatramer Platform - Disintegration

studies have shown that targeted delivery of drugs to a site of action, including tumors, is directly related to the length of time of

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technology allows for a prolonged circulation time whereby there is accumulation at the site of disease prior to being cleared.

Scanning electron microscopy (SEM) of Quatramer

“Leaky” Tumor Vasculature Allows Quatramers to Selectively Accumulate in the TME

size, shape and surface of our Quatramer allows it to escape via gaps in the blood vessels in the TME allowing for release of the payload

8 unchanged sentences

approach to our size tunable vehicles.

Quatramer Platform – Intracellular Payload Delivery and Disintegration

designed size tunable feature of certain of our Quatramer compositions offer further advantages, as certain cleaved materials create

31 unchanged sentences

therapeutics, a highly advantageous platform to deliver low doses of therapeutics directly to tumors.

Artificial Intelligence Platform

cells are constantly undergoing phenotypic switching that may or may not be dependent on the drug target and without additional secondary

genetic mutations but are now understood to engage three different mechanisms:

EMT, Dedifferentiation/Trans differentiation and Treatment-induced

These stepwise phenotypic transitions through a slow cycling state potentially induce a synthetic lethal sensitivity of key

driver functional pathways making them amenable to novel therapeutic strategies.

These phenotypic transitions present novel opportunities

for targeting specific drug pathways and gene circuits which none of the conventional approaches are designed to do.

recognize these dynamical aspects which make cancer a constantly evolving progressive disease and are taking a biomarker-guided approach

to drug development that will maximize treatment benefit for patients.

We are developing TAI, a drug targeting technology platform, to

enable the development of rational therapeutic strategies to target the plasticity of cancer cells associated with drug resistance.

aims to establish clinical development by applying state-of-the-art deep learning artificial intelligence technologies to patient-based

multi-modal datasets.

TridentAI platform:

the ability to create a Ferroptomics Atlas which integrates diverse multi-omics datasets including not only genomics, epigenetics

and transcriptomics but also emerging proteomics data which enable identification of dynamical re-wiring of intra-tumoral signaling

circuitry designed to target IMCD;

the ability to identify biomarkers that potentially differentiate between progression of cancer plasticity and correlate it to degree

of sensitivity to a synthetically lethal target that is induced with standard-of-care treatment and development of resistance;

designed to classify and select patients that are most likely to respond to treatment.

is based on a deep learning engine that identifies synthetic lethal sensitivities associated with degree of cell plasticity using biomarkers

that can be translated for patient selection.

TridentAI is designed to maximize enrichment for patients who are most likely to respond

to treatment and thus de-risks clinical development.

plasticity is a leading contributor to drug resistance

cells are constantly undergoing phenotypic switching that may or may not be dependent on the drug target and without additional secondary

genetic mutations.

Three critical mechanisms are understood to be involved which are engaged more or less simultaneously.

are EMT, dedifferentiation and transdifferentiation, and transient drug-induced tolerance.

EMT is characterized by both morphological

and molecular changes characterized by loss of apical-basal polarity and epithelial cell junctions leading to changes in cellular composition

of basement membrane, altering intra- and inter- cellular signaling, and eventually resulting in metastasis.

the same time, distinct compartments of the epithelium maintained by different pools of resident stem cells begin to transdifferentiate

or even reverse completely and dedifferentiate upon treatment.

For instance, epidermal growth factor

receptor (“EGFR”)-driven non-SCLC are observed to convert towards a SCLC phenotype upon EGFR inhibition and melanoma

cells dedifferentiate progressively through transitory and neural crest-like states under v-raf

murine sarcoma viral oncogene homolog B1 inhibitor treatment.

Cell plasticity is a leading contributor to drug resistance

tumor cells undergo a slow-proliferating drug-tolerant state, called drug-tolerant persisters, before further developing secondary mutational

drug-resistance.

This phenomenon has been observed in glioblastomas, melanomas and non-SCLC.

Collectively,

these stepwise transitions through a slow cycling state potentially induce a synthetic lethal sensitivity of key driver functional pathways

making them amenable to novel therapeutic strategies.

This presents a novel opportunity for drug targeting to identifying treatment-induced,

state-specific, synthetically lethal drug-target pairs.

approaches to drug targeting are limiting

approaches to drug targeting are not equipped to handle the challenges of identifying synthetic lethal drug-target pairs.

Signature-reversion

principles or guilt-by-association strategies used to uncover drug-drug or drug-disease similarity have yielded few successes due to

large transcriptional differences between in vitro long-lived cell lines and in vivo TME.

Chemical similarity approaches have their pitfalls

- errors in chemical structures as well as physiological effects that exist beyond the structural relationship limit the use for drug

Structure-based molecular docking virtual screens, for predicting drug-target pairs, are limited by lack of widespread availability

of 3D protein structures for drug targets and poor predictability of target binding affinity.

Pathway or network-based approaches to

integrate gene expression patterns, protein interactions and genome-wide association study data help identify enrichment of drug targets

but do not yield biomarkers that can be translated for patient selection.

None of these approaches are designed to search for context-specific

synthetic lethal targets.

Conventional approaches to drug repurposing are limiting

is a Deep Learning Engine that identifies synthetic lethal sensitivities associated with degree of cell plasticity

takes a multi-pronged approach to address each of the leading causes of tumor plasticity as the disease progresses namely EMT, dedifferentiation/transdifferentiation,

and transient drug-induced tolerance and sensitivity.

The platform builds on a deep foundation of diverse multi-modal and multi-omic

private and public datasets which include not only genomic and transcriptomic data from patient derived blood or biopsy samples and sublines,

and pan-cancer epigenetic and transcriptional drug response data from TCGA, Cancer Cell Line Encyclopedia and Genomics of Drug Sensitivity

in Cancer, but also human cancer proteome datasets from emerging global efforts that include Human Cancer Proteome Project, The Cancer

Proteome Atlas and The National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium.

Inclusion of proteomics data is

very critical for identifying dynamical re-wiring of intra-tumoral signaling circuitry which is likely to be missed if one looks at the

genomic and transcriptomic level alone.

is a deep learning engine that integrates in vitro and in vivo epigenetic, transcriptomic and proteomic data characterizing

genomic alterations, methylation states, cellular differentiation, and drug tolerance to identify:

fingerprints that deconvolve a heterogenous tumor biopsy into a discrete phenotypic state along a gradient of progressive cellular

of dis-regulated functional pathways that underscore a patient’s pathology;

Indication-specific

synthetic-lethal sensitivities to drugs.

utilizes state-of-the-art convolutional neural networks to classify and select patients based on their tumor-derived multi-comic profiles

thus enabling a targeted synthetic-lethal approach to kill persistent tumor cell populations and treat patients in select indications.

TridentAI identifies synthetic legal sensitivities associated with degree of cell plasticity

maps the phenotypic tumor transition from a high-dimensional landscape onto a quantitative, measurable one-dimensional scale

traces the complex high-dimensional landscape of tumor progression to identify biomarkers that mark milestones in this continuum and

enable quantification of degree of plasticity along the trajectory.

TridentAI’s deep learning engine trains a model that can reduce

this high-dimensional information into a one-dimensional quantitative and measurable scale which provides the degree of plasticity in

a biopsy sample or cell line dataset.

TridentAI’s unbiased search in the vast repository of multi-modal datasets enables identification

of synthetic lethal sensitivities that correlate linearly but contrast with degree of plasticity.

This biomarker-guided, state-specific

approach enables to successfully deconvolve signals from a heterogenous tumor biopsy into a discrete phenotypic state along a gradient

of progressive and divergent cellular plasticity and complementary synthetic lethal sensitivity.

TridentAI maps the phenotypic transition of tumor onto a quantitative, measurable one-dimensional scale

is designed to establish clinical development and deliver on the promise of precision medicine

is designed to deliver on our ultimate goal, which is to identify and treat the right patients that are most likely to benefit from treatment.

Using TridentAI, biomarkers measured in patient blood/biopsy samples will assist in determining the degree of plasticity for a specific

patient, which will then directly inform about a patient’s sensitivity to activation/inhibition of the synthetically lethal target

and probability of successful treatment.

More than just de-risking clinical development, TridentAI aspires to deliver on the promise

of precision medicine by building a platform based on the robust foundation of patient-based biomarker research and deep learning artificial

intelligence technologies.

TridentAI has successfully identified biomarkers correlating dedifferentiation in melanoma with sensitivity

to inhibitors of ferroptosis.

TridentAI is designed to establish clinical development

goal is to disrupt the biotechnology landscape by developing novel therapeutics by leveraging both our targeted-delivery Quatramer platform-based

therapeutics and our TAI platform to address significant unmet medical needs, with a focus on treatments for cancer.

We believe that

our technology has the potential to generate differentiated products that have the potential to treat rare and treatment resistant tumors.

a proprietary tumor targeting platform, with their long

half-life are coated with a Picobody ™ to create unique IO antibodies.

Picobodies are

antibody “knob” domains comprised of cysteine-rich ultralong CDR H3 sequences of 30-40 amino acids, which have the potential

to access challenging epitopes better than full size antibodies can.

We believe we may be able to more efficiently target novel

epitopes with greater binding affinity than approved biologics.

Targeting PD-1, PDL-1, HER-2 and TROP-2 is a step toward enabling us

to enter the rapidly growing IO markets.

Bovine Antibody “Knob” Peptides are the Smallest Independent Antigen Binding Domain

Comparison of Dissociation Constants Amongst Leading PD-1 Antibodies

The Unique and Differentiated Binding Sites for Approved Anti-PD-1 Antibodies

Depiction of Human Antibody, Bovine Knob and the Quatrabody

goal is to disrupt the biotechnology landscape by developing novel therapeutics by leveraging our targeted-delivery Quatramer platform-based

therapeutic to address significant unmet medical needs, with a focus on treatments for cancer.

We believe that our technology has the

potential to generate differentiated products that have the potential to treat rare and treatment resistant tumors.

business strategy includes:

drug candidate, HSB-1216, in solid tumors.

from a clinical pilot study conducted in Germany by the University of Heidelberg led us to progress HSB-1216 into IND-enabling studies

from a clinical pilot study conducted at the University of Heidelberg, Germany, led us to progress HSB-1216 into IND-enabling studies

with the goal of submitting an IND to the FDA in 2023.

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pharmacokinetic profiling as well as bioanalytical assay development.

We engaged in discussions with the FDA in 2020 and expect to use

the 505(b)(1) FDA approval pathway and conduct a Phase 1 trial to obtain initial pharmacokinetic and dosing information in patients.

We intend to evaluate the development of HSB-1216 in other high-unmet need oncology indications, including certain brain, breast and

prostate cancers, and in combination with other cancer therapies.

our combination drug candidate, HSB-888, for pediatric sarcomas.

is in IND-enabling trials with the goal of submitting an IND to the FDA in 2024.

These trials are pre-clinical in nature and include

toxicology and pharmacokinetic profiling as well as bioanalytical assay development.

Based on this data we plan to initiate discussions

with the FDA in 2024 and intend to use the 505(b)(1) FDA approval pathway and conduct a Phase 1 trial for obtaining initial pharmacokinetic

data and determine the optimized dose in patients.

We intend to demonstrate the safety and efficacy in a Phase 2 program in a basket

trial enrolling patients with recurrent cancers due to multiple sarcomas, including Ewing’s sarcoma, rhabdomyosarcoma and eligible

osteosarcoma patients.

our Trident Artificial Intelligence Platform.

is a computational intelligence platform that identifies synthetic lethal sensitivities associated with degree of cell plasticity.

undertake a multi-pronged approach to address each of the leading causes of tumor plasticity as the disease progresses including epithelial

to EMT, dedifferentiation/transdifferentiation, and transient drug-induced tolerance and sensitivity.

The platform builds on a deep foundation

of diverse multi-modal and multi-omic private and public datasets which include not only genomic and transcriptomic data from patient

derived blood or biopsy samples and sublines, and pan-cancer epigenetic and transcriptional drug response data.

After discussions with the FDA, we expect to use the 505(b)(1)

FDA approval pathway and conduct a Phase 1 trial to obtain initial pharmacokinetic and dosing information in patients.

We intend to evaluate

the development of HSB-1216 in other high-unmet need oncology indications, including certain brain, breast and prostate cancers, and

in combination with other cancer therapies.

drug candidate, HSB-3215

ErbB family of cell surface proteins

are some of the most well-known and validated oncology drug targets including ErbB2 or HER2 (human epidermal growth factor receptor) and

Erb3 or HER3.

Antibodies against HER2 and HER3 bind to different domains of the extracellular portion of the proteins or epitopes with

trastuzumab primarily binding the extracellular domain IV of HER2.

HER2 is a validated tumor antigen for antibody drug conjugates to treat

HER2 positive cancers with two approved antibodies, Roche/Genentech’s KADCYLA ® and Daiichi Sankyo/AstraZeneca’s

Monoclonal antibodies being developed at ABSI are unique from the currently approved anti-HER2 antibodies.

has granted us an exclusive option to license certain of its proprietary technology which will allow us to develop HER2 and HER3 antibodies,

including multi-specific and Quatramer- based therapeutics incorporating portions of the antibodies.

The ABSI option terminates on March 24, 2023, unless extended by the parties.

drug candidate, HSB-1940

Quatrabody™ provides an entry into next generation of IO biologics including, bispecific and trispecific antibodies, ADCs, CAR-T,

CAR-NKs and others.

Quatrabodies capitalize on the long half-life of tumor targeting Quatramers, combined with Picobodies™, bovine-derived

antibody “knob” domains which have potential to access and bind more tightly to “undruggable” epitopes better

than full sized antibodies.

HSB-1940 is a combination of the Quatramer and PD-1 targeting Picobodies.

Quatrabodies have the potential

for delivering an increased drug payload to the tumor with a longer half-life while targeting novel “undruggable” epitopes

of well-known and validated IO targets such as PD-1.

our novel platform to develop a pipeline of high value Quatramer leads.

tunability of our technology allows us to efficiently expand our pipeline of Quatramer, both on our own and in collaboration with others,

through various combinations of targeted DNA encoded for anti-tumor cytokines and therapeutic payloads, which enables us to move into

other areas of oncology, including IO whereby we could potentially increase the effectiveness of immune checkpoint inhibitors (“ICIs”).

and commercializing Quatramer in collaboration with leading pharmaceutical companies.

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with industry leaders and strategic pharmaceutical organizations.

our novel platform to develop a pipeline of high value Quatramer leads.

tunability of our technology allows us to efficiently expand our pipeline of Quatramer, both on our own and in collaboration with others,

through various combinations of targeted DNA encoded for anti-tumor cytokines and therapeutic payloads, which enables us to move into

other areas of oncology, including immuno-oncology whereby we could potentially increase the effectiveness of ICIs.

Commercializing

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own HSB-1216 and our other proprietary pipeline and expect to maintain similar rights with respect to other proprietary Quatramer we

We intend to build a focused oncology sales organization to market Quatramer in the United States following FDA approval.

the United States, we expect to rely on collaborators to commercialize proprietary approved Quatramer.

Following FDA approval in the United States, we may partner with a larger biopharmaceutical company as well as potentially build

a focused oncology sales organization to market Quatramer-based therapeutics.

Outside of the United States, we intend to rely on collaborators

to commercialize proprietary approved Quatramer.

to extend and protect our product technology and Quatramer through our intellectual property portfolio.

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include BridgeBio Pharma, Inc.

(Ferro Therapeutic, Inc.), Kojin Therapeutics, Inc., Bayer AG and The Broad Institute of MIT and Harvard,

and Takeda Pharmaceutical Company.

(Ferro Therapeutic, Inc.), Kojin Therapeutics, Inc., Bayer AG, Moderna Inc., Roche/Genentech, Daiichi

Sankyo/Astra Zeneca, Merck, Bristol-Myers Squibb and Takeda Pharmaceutical Company.

commercial opportunity could be reduced or eliminated if our competitors develop and commercialize products that are more effective,

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ability to compete may be affected in many cases by insurers or other third-party payers seeking to encourage the use of generic products.

Generic products are currently on the market, including the therapeutics payload in HSB-1216 and HSB-888, for the indications that we

are pursuing, and additional products are expected to become available on a generic basis over the coming years.

If our drug candidates

achieve marketing approval, we expect that they will be priced at a significant premium over competitive generic products.

Generic products are currently on the market, including the therapeutics payload in HSB-1216, for the indications that we are pursuing,

and additional products are expected to become available on a generic basis over the coming years.

If our drug candidates achieve marketing

approval, we expect that they will be priced at a significant premium over competitive generic products.

most common methods of treating patients with cancer are surgery, radiation and drug therapy, including chemotherapy and targeted drug

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Some of these drugs are branded and subject to patent protection, and others are available on a generic basis, including

drugs in the same therapeutic class as the payloads contained in HSB-1216 and/or HSB-888.

Many of these approved drugs are well established

therapies and are widely accepted by physicians, patients and third-party payers.

In general, although there has been considerable progress

over the past few decades in the treatment of solid tumors and the currently marketed therapies provide benefits to many patients, these

therapies all are limited to some extent in their efficacy and frequency of adverse events, and none of them are successful in treating

all patients.

As a result, the level of morbidity and mortality from solid tumor cancers remains high.

are also a number of products in late-stage clinical development to treat solid tumors including, but not limited to, Merck & Co

drugs in the same therapeutic class as the payloads contained in HSB-1216.

of these approved drugs are well established therapies and are widely accepted by physicians, patients and third-party payers.

although there has been considerable progress over the past few decades in the treatment of solid tumors and the currently marketed therapies

provide benefits to many patients, these therapies all are limited to some extent in their efficacy and frequency of adverse events,

and none of them are successful in treating all patients.

As a result, the level of morbidity and mortality from solid tumor cancers

remains high.

are also a number of products in clinical development to treat solid tumors including, but not limited to, Loxo Oncology (LOXO-292),

Bristol-Myers Squibb (BMS-986016 and nivolumab) Mersana / GlaxoSmithKline (XMT-2056), Zymeworks (zenidatamab) and Eli Lilly & Co

(sintilimab) in addition to those products already on the market such as Merck & Co Inc.

(Keytruda), Bristol-Myers Squibb Co.

(Opdivo), AbbVie Inc.

(Imbruvica), Roche Group (Tecentiq), Regeneron Pharmaceuticals, Inc.

(Libtayo) and Eli Lilly & Co (sintilimab).

These products in development may provide efficacy, safety, convenience and other benefits

that are not provided by currently marketed therapies.

As a result, they may provide significant competition for our product candidates

for which we obtain marketing approval.

commercial success depends on our intellectual property, and we strive to protect it, by, among other things, obtaining, maintaining,

defending, and enforcing our patents in the United States and internationally for our proprietary technology, improvements, platforms,

products and components thereof, novel biological discoveries, new therapeutic approaches and potential indications, and other inventions

that are important to our business.

For our product candidates, generally we initially pursue patent protection covering compositions

of matter, methods of production, and methods of use.

Throughout the development of our product candidates and technologies, we will

seek to identify additional means of obtaining patent protection.

of March 21, 2022, our utility patent portfolio includes six patent families, as set forth below.

These families include issued patents

and pending applications related generally to our polymeric nanoparticle technologies, methods of making our polymeric nanoparticle technologies,

and methods of using our polymeric nanoparticles therapeutically ( e.g ., for delivery of therapeutic compounds).

We own all of

the patents set forth below and currently do not out-license any of our patents to third parties.

Family #1 (HSB-1216;

and HSB-114):

Nanoparticles and A Process of Preparation Thereof

CH, DE, ES, FR, GB, IT, NL

Nanoparticles and A Process of Preparation Thereof

Nanoparticles and a Process of Preparation Thereof

Family #2 (HSB-1216):

Nanoparticles Comprising Salinomycin

Family #3 (HSB-384):

Nanoparticles

Family #4 (HSB-114):

Nanoparticles

Family #5 (HSB-407):

Nanoparticles Comprising Bortezomib

Family #6 (HSB-1216):

Derivatives and Therapeutic Uses Thereof

term of individual patents depends on the legal term for patents in the countries in which they are obtained.

The products in development may provide efficacy,

safety, convenience and other benefits that are not provided by currently marketed therapies.

As a result, they may provide significant

competition for our product candidates for which we obtain marketing approval.

Manufacturing

do not own or operate any facilities in which we can formulate or manufacture our product candidates.

We intend to rely on contract manufacturers

to produce all materials required to conduct pre-clinical studies and clinical trials under current good manufacturing practice (“cGMP”),

with oversight of these activities by our management team.

We have identified alternate sources of supply and other contract manufacturers

that can produce materials for our pre-clinical and clinical trial requirements on a timely basis.

However, if an existing or future

contract manufacturer fails to deliver on schedule, or at all, it may delay or interrupt the development process for our product candidates

which may have an adverse effect on our operating results and estimated timelines.

intellectual property that is available to us is important for our business, and we strive to protect it, including by obtaining, maintaining, defending, and enforcing patent protection in the United States and internationally for our proprietary technology, improvements, platforms, products and components

thereof, novel biological discoveries, new therapeutic approaches and potential indications, and other inventions that are important

to our business.

For our product candidates, generally we initially pursue patent protection covering compositions of matter,

methods of production, and methods of use.

Throughout the development of our product candidates and technologies, we will seek to

identify additional means of obtaining patent protection.

of March 10, 2023, our patent portfolio includes 11 patent families.

families include 14 issued patents and 43 pending applications related generally to our polymeric nanoparticle technologies, methods of

making our polymeric nanoparticle technologies, and methods of using our polymeric nanoparticles therapeutically ( e.g ., for delivery

of therapeutic compounds).

Specifically, our patent portfolio currently includes four issued U.S.

patents, and ten granted patents

in foreign jurisdictions, as well as six pending applications in the U.S.

and 37 abroad.

Patent protection for the earliest-filed family

is expected to expire in 2033, absent any applicable patent term adjustments or extensions, with more recently-filed families expiring

approximately between 2033 and 2042.

We may file other patent applications in the future.

term of individual patents depends upon the legal term for patents in the countries in which they are obtained.

In most countries, including

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a patent may be lengthened by patent term adjustment (“PTA”), which compensates a patentee for administrative delays by the

USPTO in examining and granting a patent or the term of a patent may be shortened if a patent is terminally disclaimed over an earlier

Patent and Trademark Office (“USPTO”) in examining and granting a patent or the term of a patent may be shortened if a patent is terminally disclaimed over an earlier

filed patent.

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expiration of relevant patents, or otherwise fails to satisfy applicable requirements.

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

However, trade secrets and know-how can be difficult to protect.

We take measures to protect and maintain the confidentiality

of proprietary information in order to protect aspects of the business that are not amenable to, or that we do not consider appropriate

for, patent protection.

We require employees, consultants, outside scientific partners, sponsored researchers and other advisors to execute

confidentiality agreements with us on or prior to the commencement of employment or consulting relationships with us.

These agreements

also require such individuals to assign to us any inventions conceived in the course of employment or consulting relationships with us.

have also filed a trademark applications with the USPTO for “HILLSTREAM BIOPHARMA” for pharmaceutical preparations for use

in cancer treatment and therapies” and for “QUATRAMER” for nano particle technologies and nanoparticle technologies

for cancer therapy and treatment, namely, drug delivery agents in the form of nanoparticles that provide controlled release of active

ingredients for a wide variety of pharmaceuticals for the treatment of cancer.

Manufacturing

do not own or operate any facilities in which we can formulate or manufacture our product candidates.

We intend to rely on contract manufacturers

to produce all materials required to conduct pre-clinical studies and clinical trials under current good manufacturing practice (“cGMP”),

with oversight of these activities by our management team.

We have identified alternate sources of supply and other contract manufacturers

that can produce materials for our pre-clinical and clinical trial requirements on a timely basis.

However, if an existing or future

contract manufacture fails to deliver on schedule, or at all, it may delay or interrupt the development process for our product candidates

which may have an adverse effect on our operating results and estimated timelines.

January 14, 2022, we closed the initial public offering of our common stock pursuant to which we issued and sold an aggregate of 3,750,000

shares of our common stock for a purchase price of $4.00 per share.

We received net proceeds of approximately $13.0 million, after deducting

underwriting discounts and commissions and offering expenses borne by us.

connection with the closing of our initial public offering, in January 2022, notes in the aggregate amount of $3,920,640, including interest

accrued thereon, were converted into an aggregate of 1,225,384 shares of our common stock.

As of March 21, 2022, we have no outstanding

convertible notes.

with many biotechnology and pharmaceutical companies, our ability to maintain and solidify our proprietary and intellectual property

position for our products will depend on our success in obtaining effective patent claims and enforcing those patent claims.

our owned pending patent applications, and any patent applications that may be filed in the future or licensed from third parties, may

not result in issuance.

The breadth of claims that may be allowed or enforced in our patents also cannot be predicted.

Any of our issued

patents or patents obtained in the future may be challenged, invalidated, infringed or circumvented.

In addition, because of the extensive

time required for clinical development and regulatory review of a therapeutic product that may be developed, it is possible that, before

any of our products can be commercialized, any related patent may expire or remain in force for only a short period following commercialization,

thereby limiting the protection such patent would afford the respective product and any competitive advantage such patent may provide.

have filed an intent-to-use U.S.

trademark application for “HILLSTREAM

BIOPHARMA” (for “Pharmaceutical preparations for use in cancer treatment and therapies”) in International class 5.

have filed an intent-to-use U.S.

trademark application for “QUATRAMER” and QUATRABODY (both for “Nano particle technologies

and nanoparticle technologies for cancer therapy and treatment, namely, drug delivery agents in the form of nanoparticles that provide

controlled release of active ingredients for a wide variety of pharmaceuticals for the treatment of cancer”) in International class

We also hold a pending U.S.

trademark application for HILLSTREAM BIOPHARMA, claiming use of the mark for “Research and development

in the field of oncology” in International class 42.

Research and Collaboration Agreement and Taurus License Agreement

Hillstream has entered into a research collaboration and product license

agreement with Minotaur and a commercial license agreement with Taurus for use of certain technology, including OmniAb antibodies, to

advance Picobodies against novel, unreachable and undruggable epitopes in high-value validated targets starting with PD-1.

and collaboration agreement and product license agreement is for the development of proprietary targeted biologics, Knob Quatrabodies™

(HSB-1940), against PD-1.

technologies of Hillstream and Minotaur will be combined under the license

from Taurus to discover, develop and advance biotherapeutics against high-value validated IO targets.

Picobodies are bovine-derived antibody

“knob” domains comprised of cysteine-rich ultralong CDR H3 sequences of 30-40 amino acids weighing ~3-4KDa, which have the

potential to access challenging epitopes better than full size antibodies can.

combining Quatramers with their long half-life coated with a PD-1 Picobody ™

to create HSB-1940, Hillstream believes it could more efficiently target novel epitopes with greater binding affinity than approved

anti-PD-1 antibodies.

We further believe that the development of HSB-1940 is a step toward enabling us to enter the rapidly growing IO

market with additional targets thereafter.

Biomedical Research Institute Option Agreement

ABSI has developed technology to target unique functional epitopes of the cancer

targets HER2 and HER3.

Monoclonal antibodies being developed at ABSI are unique from the currently approved anti-HER2 antibodies.

has granted us an exclusive option to license technology to develop HER2 and HER3 antibodies, including multi-specific and Quatramer-based

therapeutics incorporating portions of the antibodies.

These antibodies could be incorporated into proprietary multi-format biologics

(bi- and tri-specific antibodies, ADCs (antibody drug conjugates), CAR-T and CAR-NKs, in Quatramers and Quatrabodies) against drug resistant

cancers including HER2-positive metastatic breast cancer, gastric cancer, lung cancer and ovarian cancer.

The ABSI option terminates on March 24, 2023, unless extended by the parties.

authorities in the U.S.

and other countries extensively regulate the research, development, testing, manufacture, labeling, promotion,

advertising, distribution and marketing of pharmaceutical products such as those being developed by us.

In the U.S., the FDA regulates

such products under the FDCA and its implementing regulations.

Failure to comply with applicable FDA requirements, both before

and after approval, may subject us to administrative and judicial sanctions, such as a delay in approving or refusal by the FDA to approve

pending applications, warning letters, product recalls, product seizures, total or partial suspension of production or distribution,

injunctions and/or criminal prosecution.

and other countries extensively regulate the research, development, testing, manufacture, labeling,

promotion, advertising, distribution and marketing of pharmaceutical products such as those being developed by us.

In the U.S., the

FDA regulates such products under the Federal Food, Drug, and Cosmetic Act (“FsDCA”) and its implementing regulations.

Failure to comply with applicable FDA requirements, both before and after approval, may subject us to administrative and judicial

sanctions, such as a delay in approving or refusal by the FDA to approve pending applications, warning or untitled letters, product

recalls, product seizures, total or partial suspension of production or distribution, injunctions and/or criminal

Food and Drug Administration Regulation

States Drug Development

the United States, the FDA regulates drugs, medical devices and combinations of drugs and devices, or combination products, under the

FDCA and its implementing regulations.

the United States, the FDA regulates drugs, medical devices and combinations of drugs and devices, or combination products, under

the FDCA and its implementing regulations.

Drugs are also subject to other federal, state and local statutes and regulations.

of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local and foreign statutes and regulations

requires the expenditure of substantial time and financial resources.

process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local and foreign statutes

and regulations requires the expenditure of substantial time and financial resources.

Failure to comply with the applicable U.S.

requirements at any

time during the product development process, approval process or after approval, may subject an applicant to administrative or judicial

These sanctions could include, among other actions, the FDA’s refusal to approve pending applications, withdrawal of

an approval, a clinical hold, untitled or warning letters, requests for voluntary product recalls or withdrawals from the market, product

seizures, total or partial suspension of production or distribution injunctions, fines, refusals of government contracts, restitution,

disgorgement, or civil or criminal penalties.

Any agency or judicial enforcement action could have a material adverse effect on us.

requirements at any time during the product development process, approval process or after approval, may subject an applicant to

administrative or judicial sanctions.

These sanctions could include, among other actions, the FDA’s refusal to approve pending

applications, withdrawal of an approval, a clinical hold, untitled or warning or untitled letters, requests for voluntary product

recalls or withdrawals from the market, product seizures, total or partial suspension of production or distribution injunctions,

fines, refusals of government contracts, restitution, disgorgement, or civil or criminal penalties.

Any agency or judicial

enforcement action could have a material adverse effect on us.

process required by the FDA before a drug may be marketed in the United States generally involves the following:

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of adequate and well-controlled human clinical trials in accordance with an applicable IND and clinical study related regulations,

referred to as Good Clinical Practice (“GCP”), to establish the safety and efficacy of the proposed drug for its

proposed indication;

referred to as Good Clinical Practice (“GCP”), to establish the safety and efficacy of the proposed drug for its proposed

to the FDA of a new drug application (“NDA”);

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they comply with cGMP.

The FDA will not approve the product unless it determines that the manufacturing processes and facilities

are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications.

In addition, before approving an NDA, the FDA may also audit data from clinical trials to ensure compliance with GCP requirements.

the FDA evaluates the application, manufacturing process and manufacturing facilities, it may issue an approval letter or a Complete

Response Letter.

An approval letter authorizes commercial marketing of the drug with specific prescribing information for specific indications.

A Complete Response Letter indicates that the review cycle of the application is complete and the application will not be approved in

its present form.

The FDA will not approve the product unless it determines that the manufacturing processes and facilities are

in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications.

before approving an NDA, the FDA may also audit data from clinical trials to ensure compliance with GCP requirements.

After the FDA evaluates

the application, manufacturing process and manufacturing facilities, it may issue an approval letter or a Complete Response Letter.

approval letter authorizes commercial marketing of the drug with specific prescribing information for specific indications.

Response Letter indicates that the review cycle of the application is complete and the application will not be approved in its present

A Complete Response Letter describes specific deficiencies in the NDA identified by the FDA.

The Complete Response

Letter may require additional clinical data and/or an additional pivotal Phase 3 clinical trial(s), and/or other significant and time-consuming

requirements related to clinical trials, nonclinical studies or manufacturing.

If a Complete Response Letter is issued, the applicant

may either resubmit the NDA, addressing all the deficiencies identified in the letter, or withdraw the application.

Even if such data

and information are submitted, the FDA may ultimately decide that the NDA does not satisfy the criteria for approval.

Data obtained from

clinical trials are not always conclusive, and the FDA may interpret data differently than we interpret the same data.

The Complete Response Letter may require

additional clinical data and/or an additional pivotal Phase 3 clinical trial(s), and/or other significant and time-consuming requirements

related to clinical trials, nonclinical studies or manufacturing.

If a Complete Response Letter is issued, the applicant may either resubmit

the NDA, addressing all the deficiencies identified in the letter, or withdraw the application.

Even if such data and information are

submitted, the FDA may ultimately decide that the NDA does not satisfy the criteria for approval.

Data obtained from clinical trials

are not always conclusive, and the FDA may interpret data differently than we interpret the same data.

is no assurance that the FDA will ultimately approve a product for marketing in the United States, and we may encounter significant difficulties

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subject to extensive and increasing regulation by numerous federal, state, and local government agencies including the FDA, the Office

of Inspector General (“OIG”), the DOJ, the CMS, the Office of Civil Rights, and various state authorities.

of Inspector General (“OIG”), the Department of Justice (“DOJ”), the CMS, the Office of Civil Rights, and various

state authorities.

healthcare laws and regulations that may affect our ability to operate include the following:

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federal civil and criminal false claims laws and civil monetary penalties laws, such as the federal False Claims Act, 31 U.S.C.

3729—3733, impose civil liability on individuals or entities that submit false or fraudulent claims for payment to the federal

The False Claims Act provides, in part, that the federal government may bring a lawsuit against any person whom it believes

has knowingly or recklessly:

presented, or caused to be presented, a false or fraudulent claim for payment or approval to the federal

made, used or caused to be made or used a false statement or a false record to get a claim for payment approved, including

a false or fraudulent claim;

concealed, or knowingly and improperly avoided or decreased, an obligation to pay or transmit money or property

to the federal government;

3729-3733, impose civil liability on individuals or entities that submit false or fraudulent claims for payment to the federal government.

The False Claims Act provides, in part, that the federal government may bring a lawsuit against any person whom it believes has knowingly

or recklessly:

presented, or caused to be presented, a false or fraudulent claim for payment or approval to the federal government;

used or caused to be made or used a false statement or a false record to get a claim for payment approved, including a false or fraudulent

concealed, or knowingly and improperly avoided or decreased, an obligation to pay or transmit money or property to the federal

or conspired to commit any of the foregoing.

1 unchanged sentence

against Medicare and state healthcare programs.

The federal government, including as a result of the passage of the ACA, and a number

of courts have taken the position that claims presented in violation of certain other statutes, including the federal Anti-Kickback Statute

(“AKS”) or the federal physician referral law, 42 U.S.C.

1395nn (the “Stark Law”), can also be considered a violation

of the False Claims Act.

The federal government, including as a result of the passage of the Affordable Care Act

(“ACA”), and a number of courts have taken the position that claims presented in violation of certain other statutes, including

the federal Anti-Kickback Statute (“AKS”) or the federal physician referral law, 42 U.S.C.

1395nn (the “Stark Law”),

can also be considered a violation of the False Claims Act.

number of states have enacted laws that are similar to the federal False Claims Act.

Under Section 6031 of the Deficit Reduction Act

of 2005, as amended, if a state enacts a false claims act that is at least as stringent as the federal statute and that also meets certain

other requirements, the state will be eligible to receive a greater share of any monetary recovery obtained pursuant to certain actions

brought under the state’s false claims act.

As a result, many states have enacted laws that are similar to the federal

False Claims Act and there has been a concomitant increase in state false claims enforcement efforts.

of 2005, as amended, if a state enacts a false claims act that is at least as stringent as the federal statute and that also meets

certain other requirements, the state will be eligible to receive a greater share of any monetary recovery obtained pursuant to

certain actions brought under the state’s false claims act.

As a result, many states have enacted laws that are similar to the

federal False Claims Act and there has been a concomitant increase in state false claims enforcement efforts.

Violations of federal

and state fraud and abuse laws may be punishable by criminal and/or civil sanctions, including significant penalties, fines, disgorgement,

additional reporting requirements and oversight under a corporate integrity agreement or similar agreement to resolve allegations of

noncompliance with these laws, and/or exclusion or suspension from federal healthcare programs, such as Medicare, and debarment from

contracting with the U.S.

Penalties for False Claims Act violations include fines ranging from $11,803 to $23,607 for each

false claim, plus up to three times the amount of damages sustained by the government.

In addition to the provisions of the False Claims

Act, which provide for civil enforcement, the federal government also can use several criminal statutes to prosecute persons who are

alleged to have submitted false or fraudulent claims to the government for payments.

Additionally, private parties may initiate qui

tam whistleblower lawsuits against any person or entity under the False Claims Act in the name of the federal government, as well

as under the false claims laws of several states, and may share in the proceeds of a successful suit.

Generally, federal and state governments

have made investigating and prosecuting healthcare fraud and abuse a priority.

and state fraud and abuse laws may be punishable by criminal and/or civil sanctions, including significant penalties, fines,

disgorgement, additional reporting requirements and oversight under a corporate integrity agreement or similar agreement to resolve

allegations of noncompliance with these laws, and/or exclusion or suspension from federal healthcare programs, such as Medicare, and

debarment from contracting with the U.S.

Penalties for False Claims Act violations include fines ranging from $13,508 to

$27,018 for each false claim adjusted each year for inflation, plus up to three times the amount of damages sustained by the government.

In addition to the

provisions of the False Claims Act, which provide for civil enforcement, the federal government also can use several criminal

statutes to prosecute persons who are alleged to have submitted false or fraudulent claims to the government for payments.

Additionally, private parties may initiate qui tam whistleblower lawsuits against any person or entity under the False Claims

Act in the name of the federal government, as well as under the false claims laws of several states, and may share in the proceeds

of a successful suit.

Generally, federal and state governments have made investigating and prosecuting healthcare fraud and abuse a

Federal “Stark” Law

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§ 1395nn) prohibits referrals or ordering by a physician of “designated health services,”

which include pharmaceuticals and drugs that are payable, in whole or in part, by Medicare or Medicaid, to an entity in which the

physician or the physician’s immediate family member has an investment interest or other financial relationship, subject to several

Financial relationships that are implicated by the Stark Law can include arrangements ranging from marketing arrangements

and consulting agreements to medical director agreements with physicians who order our products.

The Stark Law also prohibits billing

for services rendered pursuant to a prohibited referral.

which include pharmaceuticals and drugs that are payable, in whole or in part, by Medicare or Medicaid, to an entity in which the physician

or the physician’s immediate family member has an investment interest or other financial relationship, subject to several exceptions.

Financial relationships that are implicated by the Stark Law can include arrangements ranging from marketing arrangements and consulting

agreements to medical director agreements with physicians who order our products.

The Stark Law also prohibits billing for services rendered

pursuant to a prohibited referral.

Several states have enacted laws similar to the Stark Law.

These state laws

may cover all (not just Medicare and Medicaid) patients.

Many federal healthcare reform proposals in the past few years have attempted

to expand the Stark Law to cover all patients as well.

If we violate the Stark Law, our financial results and operations could be adversely

Penalties for violations include denial of payment for the services, significant civil monetary penalties, and exclusion from

the Medicare and Medicaid programs.

These state laws may cover all (not just

Medicare and Medicaid) patients.

Many federal healthcare reform proposals in the past few years have attempted to expand the Stark Law

to cover all patients as well.

If we violate the Stark Law, our financial results and operations could be adversely affected.

for violations include denial of payment for the services, significant civil monetary penalties, and exclusion from the Medicare and

Medicaid programs.

and State Anti-Kickback Statutes

94 unchanged sentences

and Farrington.

At February 27, 2023, Hillstream BioPharma, Inc.

has one wholly-owned subsidiary, HB Pharma Corp.

website address is www.hillstreambio.com .

14 unchanged sentences

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