On October 31, 2023 Asher Biotherapeutics, a biotechnology company developing precisely-targeted immunotherapies for cancer, autoimmune, and infectious diseases, reported new preclinical data for AB821, its CD8-targeted interleukin-21 (IL-21) immunotherapy (Press release, Asher Biotherapeutics, OCT 31, 2023, View Source [SID1234636595]). The data will be presented at the Society for Immunotherapy in Cancer (SITC) (Free SITC Whitepaper) 38th Annual Meeting, being held in San Diego, CA on November 1-5, 2023.
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"We are pleased to share new preclinical data for AB821 at SITC (Free SITC Whitepaper), further illustrating the potential of our highly differentiated cis-targeted immunotherapies for the treatment of cancer," said Andy Yeung, Ph.D., Chief Technology Officer and Co-founder of Asher Bio. "IL-21 has historically demonstrated promising antitumor activity, but its clinical use has been limited due to toxicities and pleiotropic effects. We designed AB821 to activate only CD8+ T cells, the immune cell type driving the antitumor response, potentially maximizing the efficacy of IL-21 and limiting off-target activity. The new preclinical data presented at SITC (Free SITC Whitepaper) demonstrate that AB821 can improve the functionality of exhausted CD8+ T cells and promote their function and survival to effectively facilitate potent antitumor activity. Based on these data, we believe AB821 could significantly improve the treatment paradigm for patients with tumor types unresponsive to checkpoint blockade therapies, who typically have highly exhausted CD8+ T cells in their tumors. We look forward to advancing AB821’s clinical development and remain on track to file an IND in the fourth quarter of 2023."
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 reduces CD8+ T cell exhaustion to induce potent antitumor activity," lead author Renee Greer, Ph.D., Principal Scientist at Asher Bio, described new preclinical data further characterizing the mechanisms by which AB821 enhances the functionality of CD8+ T cells and facilitates the antitumor effects of IL-21, further supporting AB821’s development. The data show:
A murine surrogate of AB821 (muAB821) demonstrated potent antitumor activity both as a monotherapy and in combination with anti-PD-1 therapy in anti-PD-1 refractory mouse tumor models.
Exhausted CD8+ T cells are a promising target for AB821 therapy, as supported by the following:
High levels of IL-21R were observed in the exhausted CD8+ T cell subset in mouse tumors and in human tumor-infiltrating lymphocytes (TILs)
Treatment with muAB821 resulted in replacement of exhausted CD8+ T cells with CD8+ T cells with restored cytotoxic potential and expressing memory markers.
In human TILs, exhausted CD8+ T cells were shown to be highly responsive to treatment with AB821 as measured by pSTAT3 sensitivity.
In human TILs cultured with AB821, AB821 acted on exhausted CD8+ T cells to improve their antitumor functionality by increasing expression and secretion of key effector proteins such as Granzyme B and perforin, both of which are essential for antitumor activity.
Clinical Trial in Progress for AB248, Asher Bio’s CD8-Targeted IL-2
Also at SITC (Free SITC Whitepaper), a poster highlighting Asher Bio’s lead immunotherapy candidate, AB248, a CD8+ T cell-selective IL-2, will be featured in a clinical trial in progress poster. The poster, entitled "An open-label, Phase 1a/b study of AB248, a CD8+ T selective IL-2 mutein fusion protein, alone or in combination with pembrolizumab in patients with advanced solid tumors," details the design of the ongoing Phase 1a/1b study of AB248 alone and in combination with pembrolizumab in patients with advanced solid tumors who failed prior standard of care treatments (NCT05653882). Asher Bio initiated this Phase 1a/1b study in January 2023.
Both poster presentations will be available in the "Presentations and Posters" section of Asher Bio’s website: View Source
About AB821
IL-21 is a cytokine that activates STAT3, a master transcription factor involved in a broad spectrum of adaptive and innate immune functions. In oncology, IL-21 has historically demonstrated promising in early clinical studies, but was hindered by toxicities and pleiotropic effects, such as suppression of antigen presentation, which could dampen overall antitumor efficacy. Asher Bio hypothesized that focusing the activity of IL-21 to only the immune cell type primarily responsible for antitumor efficacy, while avoiding activation of other cells, would maximize the efficacy potential of IL-21 and reduce toxicity. Like IL-2, IL-21 derives its benefit from stimulating CD8+ T cells, but it mediates antitumor activity via a distinct, potentially complementary pathway. Asher Bio developed AB821 as a cis-targeted IL-21 activating cytokine that selectively targets CD8+ T cells, the immune cell type driving antitumor response. The IL-21 activating cytokine promotes cytotoxicity, memory cell differentiation, survival and reinvigoration of CD8+ T cells, all of which support antitumor activity. Asher Bio believes that AB821 has the potential to treat tumor types that may not be responsive to IL-2 and/or PD-1 therapy. PD-1-resistant tumors are associated with reduced memory T cell numbers and increased exhausted T cell numbers, suggesting that this molecule may be beneficial in these resistant tumors. AB821 also has the potential to be used in combination with AB248 to enhance efficacy by combining a proliferation signal with one that optimizes functionality and prevents T cell exhaustion.