Hillstream Biopharma is a biotechnology company developing novel therapeutic candidates targeting ferroptosis, an emerging new anti-cancer mechanism resulting in iron mediated cell death (IMCD) for drug resistant and devastating cancers.   Hillstream’s most advanced candidate, HSB-1216, expected to enter clinical trials in 2023, targets ferroptosis, an emerging new anti-cancer mechanism resulting in iron mediated cell death (IMCD) for drug resistant and devastating cancers. Hillstream’s most advanced candidate is HSB-1216, an IMCD modulator, whose active drug was found to be efficacious in a clinical pilot study in Germany in drug resistant tumors, including triple negative breast cancer and epithelial carcinomas. Hillstream intends to initiate IND discussions with the FDA in first half of 2023. Hillstream uses Quatramer™, a proprietary tumor targeting platform which extends duration of action and minimizes off-target toxicity, with HSB-1216 as well as biologics, mRNA, peptides and other modalities in the tumor microenvironment. Quatrabody™ conjugates immuno-oncology targets with greater binding affinity than approved therapies. Hillstream Quatramers with novel biologics developed against proprietary undruggable epitopes of PD-1 and other validated will enter the rapidly growing immuno-oncology therapeutics market leading with HSB-1940, targeting PD-1, followed by additional targets including PD-L1, HER-2, TROP-2 and now MUC1-C.

Development expected to capitalize upon tumor targeting Quatramers™

MUC1-C could be effective against a number of drug resistant cancers such as metastatic triple negative breast cancer (TNBC), small cell lung cancer (SCLC), merkel cell carcinoma (MCC) and neuroendocrine prostate cancer (NEPC)

BRIDGEWATER, N.J., Jan. 31, 2023 (GLOBE NEWSWIRE) — Hillstream BioPharma, Inc. (Nasdaq: HILS) (“Hillstream”, or the “Company”), a biotechnology company developing novel therapeutic candidates targeting ferroptosis, an emerging new anti-cancer mechanism resulting in iron mediated cell death for drug resistant and devastating cancers, today announced signing an exclusive option agreement with Dana-Farber Cancer Institute to license technology targeting the MUC1-C oncoprotein.

The MUC1 gene was identified by Dr. Donald Kufe, Distinguished Physician and Researcher at Dana-Farber and based on its overexpression in human cancers. Dr. Kufe’s long-standing work has supported the premise that prolonged activation of MUC1-C in settings of chronic inflammation promotes cancer.

Dr. Kufe has demonstrated that MUC1-C is necessary for multiple hallmarks of the cancer cell, including (i) the persister cell (PC) state, (ii) drug resistance, (iii) immunosuppression, and (iv) poor clinical outcomes. Importantly, he has found a marked MUC1-C dependency for cancer stem cells (CSCs) derived from highly aggressive TNBCs, SCLCs, MCCs and NEPCs. Based on these findings, MUC1-C has emerged as an exceptional target for cancer treatment with agents developed in the Kufe laboratory.

Dana-Farber has granted under an exclusive option agreement to Hillstream Biopharma Inc., certain of its proprietary technology which if converted to an exclusive license agreement, will allow Hillstream to develop anti-MUC1-C antibodies to selectively deliver Hillstream’s Quatramer-based lead candidate HSB-1216 targeting CSC by the induction of ferroptosis. This approach combining HSB-1216 with conjugation to MUC1-C antibodies is highly synergistic for the elimination of CSCs, which is needed for long term responses and cures.

“We look forward to this unique opportunity to work with Dr. Kufe and Dana-Farber,” said Randy Milby, CEO of Hillstream. “This agreement allows Hillstream to leverage our Quatramer platform to advance anti-MUC1-C agents targeting CSCs for the treatment of highly aggressive tumors, which represents a major unmet need for patients.”

  ____________

Quatramer Platform

Quatramer is tumor-targeted platform with capacity to deliver drug and biologic combinations

Quatramer is a tumor targeting platform which allows us to leverage and exploit key tumor targets and novel emerging pathways such as IMCD to facilitate the delivery of potent drugs directly to the TME, while sparing healthy tissue. 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.

Quatramer based compounds with therapeutic cargoes from our product pipeline include DNA-based contents which hijack the tumor’s genetic code and kill the tumor from within by generating an array of cancer killing cytokines, such as TNF-alpha and potentially others. The platform’s tunability stems from the fact that the system can be modified and adjusted to deliver single or multiple ratios of payloads in order to optimize synergistic mechanisms of action in lower doses in order to eradicate rare cancers and treatment resistant tumors with minimal or no treatment options.

TridentAI Platform

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

Trident, as the name suggests, takes a multi-pronged approach to address each of the leading causes of tumor plasticity as the disease progresses namely Epithelial-to-mesenchymal transition, 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 The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (GDSC), but also human cancer proteome datasets from emerging global efforts that include Human Cancer Proteome Project (HUPO; Cancer-HPP), The Cancer Proteome Atlas (TCPA) and The National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium (CPTAC). 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.

Trident 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:

Biomarker fingerprints that deconvolve a heterogeneous tumor biopsy into a discrete phenotypic state along a gradient of progressive cellular plasticity, Network of dis-regulated functional pathways that underscore a patient’s pathology, and Indication-specific synthetic-lethal sensitivities to drugs

Trident 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.

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

Trident 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. Trident’s Deep Learning Engine trains a model that can reduce this high-dimensional information into a one-dimensional quantitative and measurable scale which informs what is the degree of plasticity in a biopsy sample or cell line dataset. Trident’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.

Trident is designed to de-risk clinical development and deliver on the promise of precision medicine

Trident is designed to deliver on Hillstream Bio’s ultimate goal, which is to identify and treat the right patients that are most likely to benefit from treatment. Using Trident, 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, Trident 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.

The Hillstream Biopharma Pipeline

HSB-1216: Novel Inducer of Iron-Mediated Cell Death

Iron is a central player in cancer progression and metastasis and dysregulated in tumors. Certain cancer cells rely on an increased labile iron pool (LIP) which fosters tumor growth, metastasis and relapse. HSB-1216 (Hillstream’s lead compound) normalizes the LIP in tumors and causes cell death by de-linking cancer’s addiction to iron. HSB-1216, is a novel and potent inducer of a powerful mechanism involving iron-mediated cell death. This process which sequesters iron in lysosomes allows HSB-1216 to cause lysosomal membrane permeabilization of hard-to-treat cancer cells – causing them to rupture and stop replicating. An area of interest for the development of HSB-1216 are rare cancers with high unmet need.

HSB-1216 is for multiple, therapy resistant or high unmet need solid tumors. HSB-1216 exploits a key feature of certain tumors that rely on an excessive LIP within the cell to modify the dysregulated iron microenvironment of cancer. In our Phase 1 study we intend to test HSB-1216 in a variety of solid tumors. Although we have received orphan drug designation (ODD) in small cell lung cancer for HSB-1216’s active drug, we may pursue ODD in multiple indications. HSB-1216 has the potential to be used in cancer patients who have failed standard-of-care therapies in solid tumors. HSB-1216 is being advanced to alleviate these devastating consequences due to a lack of therapies.

HSB-888: Novel Inducer of Iron-Mediated Cell Death + Ultra Low-Dose Anthracycline

The components of HSB-888 are two anticancer drugs with distinct and complementary mechanisms of actions which together constitute an active combination for treating sarcomas. Hillstream 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 payloads at various molar ratios, which also showed multiple synergistic ratios, dependent on the chemical characteristics of either DNA intercalating payload combined with an inducer of iron-mediated cell death.

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 a specific molar ratio of DNA intercalator:inducer of iron-mediated cell death (designated HSB-888) compared to drug cocktails in models tested. HSB-888, is a fixed-ratio formulation of DNA intercalator:inducer of iron-mediated cell death, and a lead near-clinical candidate for development in multiple sarcomas.

HSB-510: Novel Bi-Functional Inhibitor for Solid Tumors & Leukemias

HSB-510 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. The Quatramer platform achieves optimal tumor targeting and bioavailability of the highly potent targeted small molecule. HSB-510’s active drug, in co-development via a Cooperative Research and Development Agreement with the National Center for Advancing Translational Sciences, part of the National Institutes of Health, induced necrosis in several mutant and FLT3-resistant acute myeloid leukemia (AML) cell lines and primary blasts from AML patients, while showing no cytotoxicity against several normal cells. The FLT-3 gene is associated with high risk of relapse and poor clinical outcomes upon treatment with conventional chemotherapy in AML patients. Target specific engagement of PI3K-delta and HDAC6 was further demonstrated using the cellular thermal shift assay. HSB-510 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.

HSB-114: TNF-alpha DNA

HSB-114 is a novel immunotherapeutic agent which uses our proprietary Quatramer technology to deliver tumor necrosis factor-alpha (TNF-alpha or TNF-α) gene into cancer cells. Previous immunotherapeutic strategies used adenovector technology requiring replication deficient gene deletions and complex manufacturing controls in order to deliver the TNF-alpha gene, but posed a theoretical risk of systemic toxicity and adjacent tissue damage due to overflow of TNF-alpha in blood from the tumor, resulting in some dose-limiting toxicities. We believe our novel non-viral immunotherapeutic TNF-alpha gene therapy, HSB-114, builds on the previous clinical development program with improved scalability and tunability to treat metastatic soft tissue sarcomas.

Hillstream BioPharma Announces Development of Proprietary Targeted Biologics, Knob Quatrabodies™ (HSB-1940) against PD-1, by combining Quatramers™ with OmniAb’s Picobodies™, via a Collaboration Agreement, against Novel, Unreachable and Undruggable Epitopes in High Value Validated Targets

Collaboration allows Hillstream to enter the rapidly growing Immuno-oncology therapeutics market

By capitalizing on the long half-life of tumor targeting Quatramers™ combined with OmniTaur™-derived Picobodies™, the lead program, HSB-1940, is being developed to target PD-1

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 epitopes

BRIDGEWATER, N.J., Dec. 01, 2022 (GLOBE NEWSWIRE) — Hillstream BioPharma, Inc. (Nasdaq: HILS) (“Hillstream”, the “Company”) today announced the development of proprietary targeted biologics, Knob Quatrabodies™ (HSB-1940) against PD-1. Hillstream signed separate collaboration agreements with a subsidiary of OmniAb, Inc. (Nasdaq: OABI) (“OmniAb”) and with Minotaur Therapeutics, Inc. (“Minotaur”) to advance Picobodies against novel, unreachable and undruggable epitopes in high-value validated targets starting with PD-1.

The technologies of Hillstream and Minotaur will be combined under a previously disclosed license from OmniAb to discover, develop and advance biotherapeutics against high-value validated targets. Picobodies are antibody “knob” domains comprised of cysteine-rich ultralong complementary determining region (CDR) H3 sequences of 30-40 amino acids, which have the potential to access challenging epitopes better than full size antibodies can.

By 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 biologics. Targeting PD-1 is a step toward enabling Hillstream to enter the rapidly growing Immuno-oncology (IO) therapeutics market with additional IO targets after PD-L1.

Dr. Vaughn Smider, Founder and Chief Executive Officer of Minotaur, stated, “We are excited to contribute our expertise to help in combining OmniAb’s OmniTaur-derived ultralong CDR H3 antibody fragments and Hillstream’s tumor-targeting Quatramers to discover and develop novel next-generation targeted cancer therapeutics.”

Antibodies derived from mouse or human sources use the surface formed by complementarity determining regions (CDRs) on the variable regions of the heavy chain/light chain heterodimer, which typically forms a relatively flat binding surface. 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, 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 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. These 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.

Randy Milby, Chief Executive Officer of Hillstream, stated, “The Picobodieswhich OmniAb brings to this collaboration combined with our Quatramers to create a novel and disruptive Knob Quatramer platform will be a great addition to our portfolio starting with HSB-1940. We are doubly excited that Dr. Vaughn Smider, a pioneer in the discovery, engineering and understanding of these unique proteins, will be leading Minotaur’s services. The Quatramer is a key Hillstream platform which is now poised to create novel therapeutics using “smart carriers” with multiple approaches for enhancing targeted cancer immunotherapy.”