On April 8, 2022 Asher Biotherapeutics (Asher Bio), a biotechnology company developing precisely-targeted immunotherapies for cancer, autoimmune, and infectious diseases, reported preclinical data for AB821, its CD8+ T cell cis-targeted interleukin-21 (IL-21) cytokine, which was designed to promote the function, survival, and reduced exhaustion of CD8+ T cells, and for its cis-targeted interleukin-2 (IL-2) fusion molecules, which were developed to specifically target engineered cells such as CAR-T cells, while exhibiting minimal effects on non-engineered or endogenous cells (Press release, Asher Biotherapeutics, APR 8, 2022, View Source [SID1234611743]). The data will be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2022, being held in New Orleans, Louisiana, April 8-13, 2022.
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"We are pleased to announce two new development programs today, reflecting the versatility and broad applicability of our cis-targeting technology, as well as its ability to rapidly produce highly selective molecules that target two different cytokines to two different cell types," said Ivana Djuretic, Ph.D., Chief Scientific Officer and Co-founder of Asher Bio. "Including AB248, we have now validated in nonclinical studies three distinct programs in under three years since our founding, each of which has demonstrated over 100 to 1000x selectivity for its intended immune cell target. Importantly, and consistent with our foundational hypothesis that cis-targeted immunotherapies might overcome the clinical limitations of existing immune-based medicines, this selectivity has translated into improved activity and tolerability across an array of preclinical models. We look forward to advancing each of these programs, while further leveraging the modularity of our platform, with the goal of building a differentiated portfolio of product candidates for the treatment of cancers, autoimmune and infectious diseases."
AB821: a CD8+ T Cell Targeted IL-21
Asher Bio designed AB821 to overcome the historical challenges of IL-21, including pleiotropic activation of multiple lymphoid and myeloid immune cell subsets, by focusing the IL-21 activity of AB821 to only CD8+ T cells – the immune cell type primarily responsible for anti-tumor efficacy – while avoiding activation of non-CD8 cells which may dampen overall anti-tumor efficacy and contribute to adverse effects. IL-21 can have beneficial effects on anti-tumor immune responses due to its ability to activate STAT3, a master transcription factor involved in a broad spectrum of adaptive and innate immune functions. Previously, wild-type IL-21 has demonstrated promising signs of efficacy in early clinical studies, but its utility has been hindered by toxicities and pleiotropic effects, such as suppression of antigen presentation in myeloid cells.
Asher Bio’s presentation at AACR (Free AACR Whitepaper) provides an overview of AB821, a cis-targeted and charge-modified IL-21. In a poster titled "Selective activation of CD8+ T cells by a CD8-targeted IL-21 results in enhanced anti-tumor efficacy and safety," Renee Greer, Ph.D., Senior Scientist, Immunology at Asher Bio, shared foundational nonclinical proof-of-concept data, demonstrating that AB821 exhibits greater than 1000-fold selectivity for CD8+ T cells over other cell types. In addition, a single dose of murine CD8-IL21 surrogate demonstrated activity in multiple syngeneic tumor models without inducing body weight loss. In the MC38 tumor model, for example, treatment with a single dose of CD8-IL21 as low as 0.1 mg/kg induced complete regression of established tumors without toxicity and, in cynomolgus monkeys, treatment with CD8-IL21 demonstrated improved exposure and tolerability over untargeted IL-21.
"We are excited to share the first preclinical data for AB821, our CD8+ T cell targeted IL-21 and the second product candidate in our pipeline," said Andy Yeung, Ph.D., Chief Technology Officer and Co-founder of Asher Bio. "Though early, these data buoy our confidence that AB821 fits our desired product profile as an IL-21 therapy that can selectively activate STAT3 signaling in CD8+ T cells to promote functionality, memory cell differentiation, and survival, all of which are complementary to the proliferation signal provided by IL-2 induced STAT5 activation. We believe AB821 could address unmet needs across tumor types that may have sub-optimal responsiveness to IL-2 and/or PD-1 therapies, and we look forward to advancing this program toward our planned IND filing in the second half of 2023."
In addition to exploring AB821 as a monotherapy, Asher Bio intends to evaluate AB821 with AB248, its engineered interleukin-2 (IL-2) immunotherapy. Asher Bio believes the combination of AB248 and AB821 could enhance efficacy by combining AB248’s proliferation signal with AB821’s non-overlapping and complementary mechanism of action, which optimizes functionality and prevents T cell exhaustion.
Cis-Targeted IL-2 for Cell Therapy Augmentation
Asher Bio designed its highly selective cis-targeted IL-2 fusion molecules to specifically target engineered cells such as CAR-T cells, while exhibiting minimal effects on non-engineered or endogenous cells, enabling superior activity and durability. Positive clinical outcomes of commercially available CAR-T cell therapies in the treatment of some hematological malignancies, as well as the promising results with T cell therapies observed in solid tumors, have stimulated further interest in these treatment approaches. Building on these findings, important efforts in T cell engineering are underway to improve key properties including engraftment, persistence, and expansion in the tumor microenvironment. Preclinical studies have demonstrated that the co-administration of an IL-2 therapy can enhance engineered T cell engraftment, persistence, and functionality. However, the clinical potential of utilizing IL-2 in combination with engineered T cell therapies is limited using current molecules due to the severe toxicity of high-dose IL-2 and the inadequate selectivity of existing engineered IL-2 variants, which expand multiple endogenous cell types in addition to transferred T cells.
Asher Bio will present new data at AACR (Free AACR Whitepaper) characterizing two IL-2 fusions, CAR-IL2 and EGFRt-IL2, and detailed their in vivo activity in tumor-bearing NSG mice infused with human CAR-Ts. CAR-IL2 and EGFRt-IL2 are distinct fusion molecules, both of which leverage cis-targeting to enable CAR-T cell restricted IL-2 signaling. CAR-IL2 targets the FMC63 CAR directly without blocking CD19 antigen recognition, enabling targeting of approved anti-CD19 CAR-T products. EGFRt-IL2 targets an EGFR tag co-expressed with the CAR.
In a poster titled, "CAR-targeted IL-2 drives selective CAR-T cell expansion and improves anti-tumor efficacy," Nathan Mathewson, Ph.D., Senior Scientist at Asher Bio, will demonstrate the specificity of CAR-IL2 and EGFRt-IL2. Both fusion molecules selectively induce phospo-STAT5 signaling resulting in greater than 100-fold preferential STAT5 activity in CAR-expressing cells, compared to CAR-negative cells. The ability of the fusion molecules to selectively expand CAR-Ts in vitro and in vivo was shown through a substantial and specific expansion of the infused CAR-Ts, with the CAR-T fraction increasing from approximately 50% of infused T cells to over 93% of T cells. Re-dosing with either CAR-IL2 or EGFRt-IL2 resulted in a significant re-expansion of CAR-T cells by over 500-fold after a long rest period in vivo. In addition, treatment with the CAR-IL2 molecule augmented the anti-tumor activity of CAR-T therapy in a preclinical model of leukemia, converting a suboptimal dose of CAR-T cells into a curative therapy by meaningfully expanding the low number of transferred CAR-T cells.
"Durable complete responses and survival in CAR-T-treated patients is correlated with CAR-T engraftment and expansion. The new data that will be presented at AACR (Free AACR Whitepaper) provide foundational proof-of-concept for our strategy of selectively boosting CAR-T cells post-adoptive transfer, in order to drive significantly better CAR-T expansion and, therefore, improved activity and durability," said Dr. Djuretic. "In addition, selective support of CAR-T cells and other engineered T cells may provide other benefits, such as decreasing the number of engineered T cells required at infusion, reducing the need for preconditioning, and allowing temporal control over cell activation. We are eager to advance our program forward, as we aim to deliver bespoke cis-targeted cytokines that can augment existing cell therapies without requiring the retrofitting of a novel receptor or other construct, and ultimately optimize therapeutic outcomes."