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