Preclinical efficacy of a first-in-class anti-ALCAM ADC in hard-to-treat solid and hematologic malignancies

ALCAM (CD166) is a type I transmembrane glycoprotein that mediates cell-cell adhesion through homophilic ALCAM-ALCAM and heterophilic ALCAM-CD6 interactions. ALCAM is aberrantly overexpressed across a variety of solid and hematologic malignancies. Using our proprietary live-cell immunization (LC-I) and high-throughput screening (LC-HTS) platforms, we developed MAb52-29.1, an anti-ALCAM monoclonal antibody that selectively recognizes a tumor-restricted conformational epitope of ALCAM, exhibiting minimal or no cross-reactivity with normal cells or tissues. Both the chimeric and humanized versions of MAb52-29.1 exhibited high binding affinities to recombinant ALCAM-ECD (K D ≈ 1.1 nM). MAb52-29.1 cAb, containing two point-mutations in each Fc, was conjugated to MMAE through an MC-Vc-PAB linker to produce MAb52-29.1-ADC (DAR4). MAb52-29.1-ADC demonstrated potent antiproliferative effects in vitro , with cytotoxicity correlating with its high antibody internalization efficiency in various cancer cell lines. Anti-tumor efficacy was demonstrated by a single intraperitoneal ( i.p .) dose of MAb52-29.1-ADC at 4, 7, or 10 mg/kg using 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 disappearing within 27~30 days after treatment. Preliminary toxicology studies indicated that MAb52-29.1-ADC did not raise any safety concerns. These findings support MAb52-29.1-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 MAb52-29.1-ADC in patient-derived xenograft (PDX) gastrointestinal (GI) cancer models, along with retrospective analyses of its target expression in clinical tumor samples.