Abstract 1767: Preclinical efficacy of a first-in-class anti-SLC3A2 ADC in hard-to-treat solid and hematologic malignancies

Abstract SLC3A2 (CD98 heavy chain, CD98hc, or 4F2hc) is a type II transmembrane glycoprotein that functions primarily as the heavy chain component of heterodimeric amino acid transporters (HATs). The aberrant overexpression of SLC3A2 has been linked to many types of cancer, such as lung cancer, breast cancer, colorectal cancer (CRC), pancreatic cancer (PDAC), and various types of hematologic malignancies. Using our proprietary live-cell immunization (LC-I) and high-throughput screening (LC-HTS) platforms, we developed MAb52-4.2, an anti-SLC3A2 monoclonal antibody that selectively recognizes a tumor-associated conformational epitope of SLC3A2, which significantly elevated expression levels in cancer cell lines, and exhibits minimal or no cross-reactivity with normal cells or tissues. Both the chimeric and humanized versions of MAb52-4.2 bound to recombinant SLC3A2-ECD with high affinities in the low single-digit nanomolar range. MAb52-4.2 cAb, containing two Fc point-mutations, was conjugated to MMAE through an MC-Vc-PAB linker to produce MAb52-4.2-ADC (DAR4). MAb52-4.2-ADC demonstrated potent antiproliferative effects in vitro, with cytotoxicity correlating with the target abundance and antibody internalization efficiency across a variety of cancer cell lines. A single intraperitoneal (i.p.) dose of MAb52-4.2-ADC at 4, 7, or 10 mg/kg effectively inhibited tumor growth in cell line-derived xenograft (CDX) mouse models of triple-negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), gastric cancer (GC), and other tumor types, with subcutaneously inoculated tumors completely regressing within 24∼30 days post-treatment. Preliminary toxicology studies indicated that MAb52-4.2-ADC did not raise any safety concerns. These findings support MAb52-4.2-ADC as a promising therapeutic candidate for treating solid and hematologic malignancies, and potentially mitigating toxicity concerns. Ongoing studies aiming to support further clinical investigation include MAb52-4.2-ADC in patient-derived xenograft (PDX) gastrointestinal (GI) cancer models, along with retrospective analyses of its target expression in clinical tumor samples. Citation Format: Qinhong Ma, Daizong Li, Kewei Zhao, Mary Q. Xu, Mason Lu. Preclinical efficacy of a first-in-class anti-SLC3A2 ADC in hard-to-treat solid and hematologic malignancies 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 1767.