Abstract 4424: Preclinical efficacy of a first-in-class anti-Integrin α/β ADC in hard-to-treat solid tumors

Abstract Integrin (ITG) α/β is a heterodimeric type I transmembrane glycoprotein composed of one α and one β integrin subunit. It mediates cell-cell and cell-extracellular matrix (ECM) interactions and elicits subsequent signaling cascades that regulate cell adhesion, motility, proliferation, survival, and gene expression. The aberrant overexpression of ITGα/β has been observed across a variety of solid tumors, and it supports cancer progression and metastasis, suggesting that it may serve as a potential therapeutic target. Using our proprietary live-cell immunization (LC-I) and high-throughput screening (LC-HTS) platforms, we generated and developed MAb51-31, an anti-ITGα/β monoclonal antibody (mAb), which selectively recognizes a tumor-restricted conformational epitope of ITGα/β. MAb51-31 exhibited no cross-reactivity with normal cells or tissues. Both the chimeric and humanized versions of MAb51-31 displayed high binding affinity to recombinant ITGα/β (KD ≈ 1.4 nM). MAb51-31-cAb, engineered with two point-mutations in each Fc region, was conjugated to MMAE via an MC-Vc-PAB linker to generate MAb51-31-ADC (DAR4). MAb51-31-ADC demonstrated potent antiproliferative effects in vitro, with cytotoxicity correlating with its internalization efficiency across various solid tumor cell lines. In cell line-derived xenograft (CDX) models of triple-negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), gastric cancer (GC), and other solid tumors, a single intraperitoneal (i.p.) dose of MAb51-31-ADC at 4, 7, or 10 mg/kg effectively inhibited tumor growth, resulting in complete tumor regression within 24∼30 days post-treatment. Initial toxicology assessments indicated that MAb51-31-ADC was well tolerated, with no notable safety concerns observed. MAb51-31-ADC is a promising therapeutic candidate for treating solid tumors, with selective recognition of a tumor-specific ITGα/β epitope potentially enabling strong antitumor efficacy and reduced off-target effects. Ongoing studies include evaluation of MAb51-31-ADC in patient-derived xenograft (PDX) models of gastrointestinal (GI) cancers, as well as retrospective analyses of target expression in tumor samples, to further support its clinical development. Citation Format: Qinhong Ma, Daizong Li, Kewei Zhao, Mary Q. Xu, Mason Lu. Preclinical efficacy of a first-in-class anti-Integrin α/β ADC in hard-to-treat solid tumors [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 4424.