On November 10, 2022 Repertoire Immune Medicines reported that conducted with the company’s proprietary DECODE platform, which characterizes the cellular response to disease, identifying novel therapeutic targets in human papillomavirus (HPV) 16 and HPV 33-positive tumors (Press release, Repertoire, NOV 10, 2022, View Source [SID1234623775]). This research is part of Repertoire’s collaboration with Dana-Farber Cancer Institute to advance discovery and development of treatments for HPV-positive oropharyngeal (head and neck) cancers and was presented at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) (SITC 2022) 37th Annual Meeting, in Boston.

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"One of the growing challenges in HPV-positive cancer treatment is that we are observing an increase in the prevalence of HPV high-risk genotypes associated with worse outcomes," said Glenn J. Hanna, M.D., director of the Center for Salivary and Rare Head and Neck Cancers at Dana-Farber Cancer Institute.1 "The research we conducted with the DECODE platform suggests that current treatments may not be targeting some key antigens active in these genotypes, which has significant implications for patient treatment. Importantly, we now have data that point to antigens active in driving these malignancies, which we can use to develop novel targeted medicines."

The DECODE platform is a suite of integrated experimental and computational technologies designed to decipher the immune synapse, the complex interface between T cells and the epitopes they recognize. DECODE is being used to assess the immunogenicity profile of HPV 16 and HPV 33-positive tumors in oropharyngeal squamous cell carcinoma (OPSCC). By characterizing the cellular response to these cancers, it is possible to identify the specific epitopes eliciting the strongest T cell activity in tumors and the associated T cell receptors (TCRs) binding those epitopes, identifying what may be ideal targets for immunotherapies.

"Using the DECODE platform, we have a window into the mechanisms involved in the immune surveillance of cancer, which offers us the ability to develop highly selective immune-based medicines," said Anthony Coyle, Ph.D., President, Research and Development, Repertoire Immune Medicines. "The data we presented today from our DECODE platform illustrate the immunogenic profile of HPV 16 and HPV 33-positive tumors, providing us with insights into the specific epitopes that are drivers of these cancers and are targets for new immunotherapies."

HPV infection is a risk factor for several cancers, including OPSCC. Many therapeutic approaches for OPSCC target the epitopes from E6 and E7 antigens of HPV; however, these treatments are not successful for every patient and new approaches based on highly prevalent immunodominant epitopes in both early-stage and relapsed/refractory patients may offer more effective treatment for certain genotypes of HPV-positive OPSCC.

DECODE Discovery in HPV 16 and HPV 33-Positive Oropharyngeal Squamous Cell Carcinoma

In order to better characterize the cellular response to HPV-positive OPSCC across common human leukocyte antigen (HLA) haplotypes, biopsies were collected from patients with HPV 16-positive or HPV 33-positive OPSCC. All samples were assessed using the DECODE platform.

In patients with HPV 16-positive tumors, effective cytotoxic responses were induced by antigens E1 and E2 of HPV, which were substantially greater than the response driven by E5, E6 and E7. These findings suggest HPV 16 E1 and E2-directed immunotherapy may be effective among patients with HPV 16-positive OPSCC expressing these antigens.

HPV 33-positive OPSCC is characterized with an inferior survival rate compared to HPV 16-positive head and neck cancers. To better understand the potential reasons for this difference in outcomes, a comparison of the immunogenic profile of HPV 16 and HPV 33-positive tumors was conducted with DECODE.

HPV 33-positive tumors in this research had fewer cytotoxic CD8+ T cells and fewer activated antibody-secreting B cells compared to HPV 16-positive tumors. In addition, the HPV 33-positive tumors had poor antigen presentation and deficient HPV E7 recognition by T cells. Both genotypes of OPSCC are typically treated with the same standard of care, but the differences observed in the HPV 33-positive tumor composition and cellular phenotype would be expected to lead to a poor immune response and may be the cause of the inferior treatment outcomes observed in the population of patients with this tumor genotype.

Additional detail from this ongoing research is included in Poster #86, HPV16 E1 and E2 elicit a robust cytotoxic immune response in virally driven Oropharyngeal Squamous Cell Carcinoma, and in Poster #1404, HPV33-driven Oropharyngeal Squamous Cell Carcinomas are increasing in prevalence and are characterized by low CD8 infiltration and epitope presentation deficiencies.

These data, as well as the company’s early research in targeting interleukin-2 (IL-2) to solid tumors, will be presented during the poster session at the SITC (Free SITC Whitepaper) congress on Thursday, November 10, through Friday, November 11, 2022, 9:00 a.m. – 9:00 p.m. EST.

About the DECODE Platform

The DECODE platform is a powerful discovery engine that characterizes essential elements of the immune synapse. In particular, the platform identifies T cell receptor-antigen pairs in the context of other important features of the immune synapse, such as T cell function and how antigens are presented by molecules on antigen-presenting cells, known as major human leukocyte antigen, or HLA, molecules. Repertoire intends to utilize these insights into key drivers that govern immune function to design and develop novel immune product candidates.

On November 10, 2022 OncoNano Medicine, Inc. reported the presentation of data on its pre-clinical candidate ONM-501 at the 37th Annual Meeting of the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) in Boston, Massachusetts (Press release, OncoNano Medicine, NOV 10, 2022, View Source [SID1234623774]). ONM-501, OncoNano’s lead therapeutic program in development, is a dual-activating STING (Stimulator of Interferon Genes) agonist advancing towards a first in human trial planned to be initiated in the first half of 2023.

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Previously published data has demonstrated the differentiated mechanism of ONM-501 with dual "burst" and "sustained" STING activation, enhanced cytosolic delivery and tumor retention through encapsulation of an endogenous STING agonist – cGAMP with OnocoNano’s proprietary STING-activating OMNI polymeric micelles. These two mechanisms operate in concert to activate STING and potentiate this activation, providing potent anti-tumor efficacy as a monotherapy and in combination with anti-PD1 in multiple preclinical mouse models with both "hot" and "cold" tumor microenvironments. In vivo PD analysis confirmed STING activation, enhanced tumor lymphocyte infiltration, and tumor PD-L1 upregulation by ONM-501, and demonstrated the target-engagement activity of ONM-501 in multiple species, and high tolerability in rodents and non-human primates, making it a promising therapeutic candidate for clinical evaluation.

"The results presented here confirm many of our hypotheses regarding the potential of ONM-501 to provide a robust therapeutic index of immune activating STING activity that may be differentiated from other STING agonists. This is why we are so buoyed by the continued positive preclinical results for ONM-501, underscoring its potential as a monotherapy and in combination with anti-PD1 in multiple ‘hot’ and ‘cold’ murine syngeneic tumor models," said Kartik Krishnan, MD, PhD, Chief Medical Officer at OncoNano. "We look forward to bringing ONM-501 to the clinic in 2023 as we continue on our mission to deliver critical new treatments to patients in need."

On November 10, 2022 AbCellera (Nasdaq: ABCL) reported the release of new data on its T-cell engager (TCE) platform at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 37th Annual Meeting, to be held virtually and at the Boston Convention & Exhibition Center from November 8 to 12, 2022 (Press release, AbCellera, NOV 10, 2022, View Source [SID1234623773]). AbCellera’s poster presentation describes the expansion, further characterization, and validation of a diverse panel of CD3-binding antibodies that can be used to develop T-cell engagers for cancer treatments.

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"The robust data package we are presenting at SITC (Free SITC Whitepaper) demonstrates that our panel includes antibodies that are distinct from molecules commonly used for CD3 T-cell engager development," said Bo Barnhart, Ph.D., VP, Translational Research at AbCellera. "By combining this panel with the OrthoMab bispecifics platform and high-throughput antibody analytics, we have shown that we can rapidly identify developable T-cell engagers that balance potent cytotoxicity and low cytokine release."

CD3 T-cell engagers are bispecific antibodies that redirect T cells to kill tumor cells. Developing effective T-cell engagers requires two parental antibodies: a CD3-binding arm that fine-tunes T-cell activation and a tumor-binding arm with high specificity for cancer cells. Pairs of parental antibodies that work well together are rare, creating a need for diverse panels of developable antibodies that can be combined and tested at scale to find optimal clinical candidates.

To address the paucity of anti-CD3 antibodies for TCEs, AbCellera used its integrated antibody discovery, characterization, and engineering technologies to discover and validate an extensive panel of fully human CD3-binding antibodies. New data presented at SITC (Free SITC Whitepaper) includes epitope binning analysis, revealing antibodies with species cross-reactivity that bind epitopes distinct from commonly used parental antibodies, such as SP34-2. AbCellera also conducted a second discovery campaign strategically designed to enhance the number of cross-reactive antibodies in the panel, resulting in hundreds of additional unique antibody sequences to be characterized.

Developing bispecific antibodies that potently eliminate cancer cells without inducing toxicity has been a significant challenge limiting T-cell engager development. In a proof-of-concept study, AbCellera used its OrthoMabTM bispecifics platform to create CD3 x EGFR T-cell engagers. High-throughput functional and biophysical assays identified potent tumor-cell killing T-cell engager molecules that maintained low levels of cytokine production without the need for further engineering or optimization.

"We debuted our T-cell engager platform at the AACR (Free AACR Whitepaper) annual meeting in April of this year, and in less than six months, we have greatly expanded the data package supporting this platform," said Murray McCutcheon, Ph.D., Senior VP, Corporate Development at AbCellera. "The remarkable progress demonstrates the speed of AbCellera’s antibody discovery engine, the quality of the antibodies in our T-cell engager panel, and the potential impact it has for partners looking to accelerate development of new cancer treatments."

On November 10, 2022 Ankyra Therapeutics, a biotech company developing targeted immune activating agents for the treatment of cancer, reported that new, preclinical data highlighting the potential of the company’s lead program, ANK-101, an IL-12-based treatment, to deliver potent anti-tumor responses following intratumoral administration will be presented during a poster presentation at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 37th Annual Meeting. SITC (Free SITC Whitepaper) is being held November 10-13, 2022, virtually and in Boston (Press release, Ankyra Therapeutics, NOV 10, 2022, View Source [SID1234623772]).

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IL-12 is a potent cytokine that can promote innate and adaptive anti-cancer immunity, but its clinical development has been limited by toxicity when delivered systemically. Intratumoral administration can expand the therapeutic window of IL-12; however, it is limited by rapid drug clearance from the tumor, thereby reducing efficacy, necessitating frequent administration, and increasing systemic accumulation. To overcome the limitations of traditional cytokine therapeutics, Ankyra has leveraged its Anchored Immunotherapy Platform to develop ANK-101, a stable complex of a modified IL-12 cytokine with aluminum hydroxide (Alhydrogel). Alhydrogel, an FDA-approved adjuvant for use in human and veterinary vaccines, acts as a scaffold to locally retain the potent activity of IL-12 following intratumoral administration in order to improve its therapeutic window.

"We are excited to present these findings from our ANK-101 program at this year’s SITC (Free SITC Whitepaper) Annual Meeting, which highlight the potential of our Anchored Immunotherapy Platform to enable an expanded therapeutic window for cytokines like IL-12," said Howard Kaufman, M.D., president and chief executive officer. "IL-12 is well known to have the ability to offer a meaningful treatment option for patients with cancer, but that has historically been limited by toxicity and dosing challenges. By leveraging our platform based on Alhydrogel anchoring, we believe we can overcome the shortcomings of systemic IL-12 to deliver a safe and effective treatment option. This is supported by our extensive preclinical work with ANK-101, where we’ve observed potent anti-tumor responses with good tolerability, and we look forward to its continued advancement towards clinical studies."

The data to be presented today are from several preclinical studies in mouse models and non-human primates (NHPs). Findings include:

Administration of mANK-101 (murine surrogate) led to enhanced tumor retention and reduced systemic exposure compared to un-anchored IL-12
Administration of mANK-101 was efficacious in diverse syngeneic tumor models, including large tumors, leading to substantial reductions in tumor volume after one or two injections
mANK-101 treatment induced a profound remodeling of the tumor microenvironment with increased T- and NK-cell infiltration and activation, shifts to pro-inflammatory myeloid cell phenotypes, and increased markers of antigen presentation and co-stimulation as measured by Nanostring, IHC, and scRNA-seq
ANK-101 administration in NHPs was well tolerated across all dose levels evaluated
Ankyra is currently advancing ANK-101 through Investigational New Drug (IND) enabling studies and plans to submit an IND to the U.S. Food and Drug Administration in the second quarter of 2023.

On November 10, 2022 Asher Biotherapeutics, Inc. (Asher Bio), a biotechnology company focused on developing therapies to precisely engage specific immune cells to fight cancer, chronic viral infection, and autoimmune disease, reported new preclinical data for AB248, its CD8-targeted interleukin-2 (IL-2) immunotherapy, and for AB821, its CD8-targeted interleukin-21 (IL-21) immunotherapy (Press release, Asher Biotherapeutics, NOV 10, 2022, View Source [SID1234623771]). The data will be presented at the Society for Immunotherapy in Cancer (SITC) (Free SITC Whitepaper) 37th Annual Meeting, being held in Boston, Massachusetts, on November 8-12, 2022.

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"We are very pleased to share new data for both AB248 and AB821 at SITC (Free SITC Whitepaper), showcasing the power of our platform to efficiently generate product candidates that demonstrate highly selective T cell engagement, as well as differentiated pharmacodynamics, anti-tumor activity and tolerability across a range of in vitro and in vivo models," said Ivana Djuretic, Ph.D., Chief Scientific Officer and Co-Founder of Asher Bio. "These data provide further validation that our cis-targeting approach enables us to activate only the desired immune cell type, potentially overcoming the pleiotropic effects that limited the clinical potential of previous immunotherapies. We look forward to advancing both programs as we aim to deliver on the promise of IL-2 and IL-21 as high-value targets to improve the care and treatment of people living with cancer."

New Preclinical Data for AB248, Asher Bio’s CD8-Targeted IL-2

In a poster presentation entitled, "CD8+ T cell selectivity of AB248 is essential for optimal anti-tumor activity and safety in nonclinical models," lead author Kelly Moynihan, Ph.D., Senior Director and Project Team Leader at Asher Bio, described new preclinical data further differentiating AB248 from "not-α" IL-2 therapies and elucidating the mechanisms by which AB248 achieves enhanced anti-tumor activity and greater tolerability. The data show:

AB248’s murine surrogate, muAB248, delivered strong anti-tumor activity without body weight loss, a general measure of tolerability, while a representative "not-α" IL-2 could not achieve meaningful activity without body weight loss.
Selectivity for CD8+ T cells avoided expansion of other immune cells and, thereby, natural killer (NK) cell-driven toxicity and regulatory T cell (Treg)-mediated immunosuppression, while maximizing pharmacology on CD8+ T cells by avoiding the pharmacological sink comprised of other cells that express IL-2 receptors.
Treatment with muAB248 demonstrated expansion of several CD8+ T cell subsets in the mouse tumor immune infiltrate, including stem-like, effector and memory CD8+ T cell subsets, which are distinct from effects of a representative "not-α" IL-2.
In cynomolgus monkeys, repeat doses of AB248 selectively expanded CD8+ T cells by up to 20-fold, and AB248 was generally well-tolerated up to 1 mg/kg, with no adverse histopathology or clinical pathology findings at any dose level.
"We are particularly encouraged to report new preclinical findings that underscore AB248’s differentiation from broadly acting IL-2-based therapies," said Dr. Moynihan. "In addition to reinforcing the importance of selectively activating only CD8+ T cells for potentially improved safety and tolerability, new analyses presented at SITC (Free SITC Whitepaper) suggest that AB248 may profoundly impact the tumor immune infiltrate, which has not been seen following treatment with ‘not-α’ IL-2 and provides further mechanistic rationale for AB248’s differentiated anti-tumor activity. We look forward to initiating our first Phase 1 trial of AB248 in patients with solid tumors later this year."

New Preclinical Data for AB821, Asher Bio’s CD8-Targeted IL-21

In a poster presentation entitled, "AB821 is a CD8+ T cell selective IL-21 with enhanced bioavailability that mediates potent anti-tumor activity, cytotoxicity, and expansion of memory CD8+ T cells," lead author Renee Greer, Ph.D., Senior Scientist at Asher Bio, described new preclinical data further characterizing AB821 relative to wild-type IL-21 in multiple in vitro and in vivo studies. The data show:

In STAT3 assays with human blood leukocytes, AB821 potently activated CD8+ T cells, with 1000-fold selectivity over other IL-21 target cell types, including B cells, NK cells and CD4+ T cells.
In human CD8+ T cells, AB821 activity synergized with T cell receptor (TCR) stimulation to increase CD8+ T cell cytotoxic functionality and support T cell memory.
AB821’s murine surrogate, muAB821, demonstrated potent single-dose monotherapy activity down to 0.1 mg/kg in MC38 colon cancer and T3 sarcoma tumor models, and showed synergistic anti-tumor activity with anti-PD1 therapy in multiple PD1-resistant tumor models.
"We are pleased to share new data on AB821, which support its continued development for the treatment of solid tumors," said Dr. Greer. "Like IL-2, IL-21 derives its benefit from stimulating CD8+ T cells, but it does so via a distinct, potentially complementary, pathway. Whereas IL-2 agents, like AB248, drive T cell proliferation, AB821, an IL-21-based agent, can provide benefit through optimizing functionality of tumor-reactive CD8+ T cells. We look forward to advancing AB821 towards the clinic."

Both poster presentations will be available in the "Presentations and Posters" section of Asher Bio’s website: View Source