On April 3, 2024 Asher Biotherapeutics, a biotechnology company developing precisely-targeted immunotherapies for cancer, autoimmune, and infectious diseases, reported the publication of two manuscripts in Cancer Discovery, a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper), detailing the design of AB248 and reviewing preclinical data supporting its development as a potentially best-in-class interleukin-2 (IL-2) therapy (Press release, Asher Biotherapeutics, APR 3, 2024, View Source [SID1234641759]). The papers were authored by Asher Bio scientists and collaborators at The Netherlands Cancer Institute (NKI), respectively, and published online in Cancer Discovery on April 2, 2024.
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"We are delighted to announce the publication of preclinical data on AB248, our lead product candidate for the treatment of solid tumors, in a prestigious cancer research and medicine journal", said Andy Yeung, Chief Technology Officer of Asher Bio. "These co-published manuscripts are the culmination of several years of great collaboration between Asher Bio scientists and our academic co-founders, Dr. Ton Schumacher, of NKI, and Dr. Robert Schreiber, of Washington University School of Medicine, alongside our collaborator, Dr. Daniela Thommen, of NKI."
"With AB248, we set out to solve a major limitation of existing immune-based medicines – namely, the significant off-target effects that come from acting on multiple cell types simultaneously", commented Ivana Djuretic, Chief Scientific Officer of Asher Bio. "AB248 was designed to potently and selectively activate CD8+ T cells, which are responsible for driving anti-tumor activity, while avoiding NK cells and Tregs, which can act as a pharmacological sink, contribute to toxicities, and suppress the immune system more broadly. Preclinical data from the Asher Bio, Schreiber and Thommen labs together reinforce the power of AB248’s highly differentiated profile, showing an unprecedented level of selectivity for CD8+ T cells, as well as enhanced anti-tumor activity and improved tolerability, and further support the evaluation of AB248 in our ongoing Phase 1a/1b trial."
Preclinical Data Suggest AB248 Offers Improved Therapeutic Index and CD8+ T Cell Selectivity
In the first publication entitled, "CD8+ T cell-targeted IL-2 promotes robust effector T cell responses to mediate potent anti-tumor immunity," lead author Dr. Kelly Moynihan, Ph.D., Senior Director and Project Team Leader at Asher Bio, described the rationale for, and the design of, AB248, and reviewed nonclinical data suggesting AB248 offers an improved therapeutic index compared to broadly acting IL-2-based therapies.
While high dose IL-2 therapy is approved for the treatment of certain cancers, its clinical use is limited due to life-threatening toxicities. A next generation of IL-2 therapies, "not-α" IL-2s, were subsequently introduced to mitigate some of the liabilities associated with high dose IL-2 through binding the IL-2 α receptor, such as potent regulatory T cell (Treg) stimulation and vascular leak syndrome (VLS). To-date, however, these "not-α" IL-2 have not demonstrated a meaningful improvement in clinical efficacy and, while VLS appears mitigated, significant toxicities still occur. In preclinical studies, natural killer (NK) cells were responsible for toxicities following treatment with a not-α IL-2 therapy but did not contribute to anti-tumor activity. Asher Bio hypothesized that the therapeutic index of an IL-2 therapy could be improved by selectively targeting CD8+ T cells – which are critical effectors of antitumor immunity – while avoiding other cell types, such as non-specific, innate NK cells and immunosuppressive Treg cells.
Asher Bio systematically evaluated the properties needed for effective cis-targeting to CD8+ T cells and generated AB248, a CD8+ T cell selective IL-2. AB248 recapitulates key features of IL-2 biology, including induction of proliferation and enhancement of effector function, but does so selectively in CD8+ T cells across a wide range of concentrations in vitro and in vivo, with over 500-fold preference for CD8+ T cells compared to other cell types. Preclinical data demonstrate the potential of a CD8+ T cell selective IL-2 to improve the therapeutic index of IL-2 and support the advancement of AB248 into the clinic:
– In preclinical mouse models, a single dose of AB248’s murine surrogate (CD8-mIL2) demonstrated strongly improved anti-tumor activity and reduced toxicity compared to untargeted not-α IL-2 variants.
– Further, CD8-mIL2 drastically increased the number and function of tumor antigen specific T cells and induced a "better effector" population, with a signature consistent with high polyfunctionality and low exhaustion.
– Activity depended both on tumor-resident as well as newly infiltrating T cells on therapy.
– In non-human primates, treatment with AB248 induced potent and selective CD8+ T cell expansion. Treatment was generally well tolerated despite expansion of CD8+ T cells by 20-fold or more.
In summary, AB248 achieved substantial improvements in IL-2’s therapeutic index by selectively targeting all CD8+ T cells without the need to restrict signaling to the tumor site or a single CD8+ T cell subset.
Preclinical Data Support Evaluation of AB248 in Combination with Anti-PD-1 Therapy
In a paper entitled, "CD8-targeted IL-2 unleashes tumor-specific immunity in human cancer tissue by reviving the dysfunctional T cell pool," lead author Paulien Kaptein, Division of Molecular Oncology and Immunology at the NKI, reported new preclinical data supporting the evaluation of AB248 in combination with an immune checkpoint inhibitor in models utilizing ex vivo human tumor tissues from patients.
T cell-based immunotherapies are a groundbreaking approach to treating some cancers. However, a considerable portion of tumors characterized by T cell infiltration remain unresponsive to immune checkpoint blockade (ICB), suggesting a need for novel strategies to restore effector activity in tumor specific T cells. IL-2-based therapies have been identified as a promising strategy for enhancing T cell responses in ICB-resistant tumors. To evaluate this hypothesis, Asher Bio’s collaborators at the NKI performed a comprehensive analysis of T cell reinvigoration following treatment with AB248. Data show:
– Treatment with AB248 broadly armed human intratumoral CD8+ T cells with enhanced effector capacity, specifically enabling reinvigoration of the dysfunctional T cell pool to elicit potent immune activity.
– Tumor-specific T cells underwent broader and qualitatively superior activation with AB248 treatment compared to programmed death-1 (PD-1) blockade.
– AB248 generated an immunological response in tumors that did not show an immunological response to anti-PD-1, suggesting the presence of a tumor-reactive T cell pool targetable by AB248 that is not responsive to PD-1 blockade alone.
– Treatment with AB248 in combination with anti-PD-1 resulted in greater ex vivo responses, supporting the combination of AB248 and anti-PD-1 clinically.
"While immune checkpoint inhibitors are an incredibly powerful tool for treating certain cancers, many tumors don’t respond, underscoring the need for new agents that can reinvigorate exhausted T cells and make them susceptible to PD-1 blockade," said Daniela Thommen, M.D., Ph.D., Group Leader, Department of Molecular Oncology and Immunology at the Netherlands Cancer Institute and senior author on the NKI publication. "New preclinical data published today suggest that treatment with AB248 may stimulate T cells within tumors otherwise resistant to PD-1 therapy, offering a combination strategy that may extend the reach of immuno-oncology regimens across a range of solid tumors. I look forward to initial clinical data from Asher Bio’s ongoing Phase 1a/1b clinical trial, which includes a cohort evaluating AB248 in combination with an anti-PD-1 therapy."
Both publications are now available online through Cancer Discovery: View Source
About AB248
AB248 is a novel CD8+ T cell selective IL-2, generated by fusing a reduced potency IL-2 mutein to an anti-CD8β antibody. It was specifically engineered to selectively and potently activate CD8+ T-cells, while avoiding natural killer (NK) cells, which can act as a pharmacological sink and contribute to toxicity, and regulatory T (Treg) cells, which are immunosuppressive. In preclinical studies, AB248 exhibited an approximately 1,000-fold preference for the activation of CD8+ T cells over NK cells and Tregs. In preclinical murine tumor studies, AB248 demonstrated potent anti-tumor activity both alone and in combination with PD-1 checkpoint blockade in a wide variety of murine tumor models.
Asher Bio is currently evaluating AB248 in a Phase 1a/1b clinical trial, AB248-101. The trial consists of a dose escalation and expansion phase to investigate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of AB248 alone and in combination with pembrolizumab in subjects with locally advanced/metastatic solid tumors who failed prior therapies. Please refer to www.clinicaltrials.gov (NCT05653882) for additional details related to this Phase 1a/1b clinical trial.