Abstract 4477: Resistance interception: Development of novel immune checkpoint inhibitor as dynamic combination with Anti-PD-1 to overcome resistance.

Abstract Background: Durable benefit from anti-PD1 therapy is limited by adaptive resistance that evolves under therapeutic pressure which is often missed by static pretreatment tumor profiling. We developed Dynamic Precision™ to mine longitudinal plasma proteomic profiling before and on-treatment to identify adaptive immune resistance drivers. With dynamic blood-based biomarkers to detect emerging resistance as early on-treatment, we establish a window before clinical progression to intercept resistance with precision drug and extend anti-PD-1 therapeutic benefit. Methods: We analyzed serial plasma proteomics from melanoma patients on standard-of-care anti-PD1 therapy to define dynamic non-responder signatures and identify actionable immune targets driving resistance, including AH004, a novel B-cell checkpoint. Mining of public multi-omic datasets defined tumor contexts associated with AH004 biology. Results: In this study, we conducted Dynamic Precision™ analysis of 2.7 million plasma proteomic data points from 300+ melanoma patients before and on anti-PD1 standard-of-care treatment. AH004 was found to be differentially regulated in ∼17% of anti-PD1 non-responders after one treatment cycle. Mechanistically, as a checkpoint on B-cells, AH004 inhibits T and NK effector cell function and promotes an immunosuppressive tumor milieu. Analysis of public multi-omic datasets showed that AH004+ tumors exhibit an inflamed-but-ineffective (“pseudohot”) phenotype and have poor ICI response. Utilizing Alloy Therapeutics’ antibody discovery platform, we have generated and characterized 24 antibody clones with high affinity binding to cell-surface human AH004 and inhibition of ligand binding. Functional characterization is ongoing. Conclusions: Resistance Interception represents a paradigm shift from reactive to proactive combination therapy, using blood-based biomarker surveillance to detect emerging immune-mediated resistance and guide targeted intervention before clinical progression. AH004 is a tractable B-cell checkpoint associated with anti-PD1 resistance and pseudo-hot tumor phenotypes. A biomarker-guided “resistance interception” strategy—adding AH004 blockade as the signal emerges—may extend anti-PD1 efficacy and increase durable response rate. Citation Format: Lynda Chin, Ronan O'Hagan, Magali Pederzoli-Ribeil. Resistance interception: Development of novel immune checkpoint inhibitor as dynamic combination with Anti-PD-1 to overcome resistance [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 4477.