Abstract 2818: Preclinical Characterization of ALG-094295, a highly potent and orally bioavailable small molecule PD-1/PD-L1 inhibitor targeting dimerization, internalization and degradation of PD-L1

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Abstract Background: PD-1/PD-L1 antibody-based therapies have demonstrated tremendous success in the treatment of a variety of cancers. However, these antibody drugs are associated with several disadvantages, such as weak tumor penetration, immune-related adverse events and emergence of anti-drug antibodies. Here, we report the discovery and characterization of ALG-094295 as a highly potent and orally bioavailable small molecule PD-1/PD-L1 inhibitor that binds to PD-L1 and promotes PD-L1 dimerization, internalization and degradation, offering a different mechanism of action with potential advantages over PD-1/PD-L1 antibody therapeutics. Methods: The interaction of PD-1/PD-L1 and PD-L1 dimerization were assessed by AlphaLISA®. Cellular activity was measured using PD-1 expressing Jurkat NFAT luciferase T cells and CHO-hPD-L1 cells. In vivo PD-L1 target engagement, tumor growth inhibition and tumor infiltration of T-cells were assessed in a humanized-PD-L1 MC38 subcutaneous tumor mouse model. In vitro ADME tox profile was established using standard assays. Pharmacokinetic (PK) studies were performed with rat, dog and cynomolgus monkey. Results: ALG-094295 demonstrated inhibition of PD-1/PD-L1 interaction at sub-nanomolar concentrations and induced PD-L1 dimerization. In vitro studies showed that ALG-094295 activated T cells with approximately ten times greater potency compared to INCB086550, an orally administered small molecule PD-L1 inhibitor that has demonstrated clinical responses in a phase I trial. Furthermore, treatment of CHO-hPD-L1 cells with ALG-094295 resulted in internalization and reduction of PD-L1 protein levels. In ex vivo human PBMC assays, ALG-094295 demonstrated PD-L1 target engagement, T cell activation and immune cell mediated tumor cell killing. In a humanized PD-L1 MC38 mouse model, a single oral dose of ALG-094295 (5 mg/kg) achieved PD-L1 target engagement comparable to INCB086550 (150 mg/kg PO). Daily oral dosing of ALG-094295 (50 or 150 mg/kg) in humanized PD-L1 MC38 mice over 21 days resulted in tumor growth inhibition equivalent to twice-weekly administration of durvalumab (10 mg/kg IV), with tumor size correlating with increased CD8+ T-cell infiltration. ALG-094295 demonstrated no in vitro liabilities for CYP450 inhibition or induction mediated drug-drug interactions, off target toxicity, cardiovascular safety, or genotoxicity. Preclinical in vivo PK data suggests once-daily oral dosing is feasible in humans. Conclusion: ALG-094295 is a highly potent and orally bioavailable small molecule PD-1/PD-L1 inhibitor that promotes PD-L1 dimerization, internalization and degradation. ALG-094295 has the potential to overcome some limitations of antibody-based therapies due to potent PD-L1 blockade, oral delivery and novel mechanism of action. Citation Format: Heleen Roose, Kristina Rekstyte-Matiene, Sarah Stevens, Kusum Gupta, Sandra Chang, Nour Fayyad, Cheng Liu, Vladimir Serebryany, Lillian Adame, Kha Le, Antitsa Stoycheva, Dinah Misner, Lawrence M. Blatt, Sushmita Chanda, David B. Smith, Julian A. Symons, Andreas Jekle, Tongfei Wu. Preclinical Characterization of ALG-094295, a highly potent and orally bioavailable small molecule PD-1/PD-L1 inhibitor targeting dimerization, internalization and degradation of PD-L1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2818.

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