A Fully‐Human Antibody Specifically Targeting a Membrane‐Bound Fragment of CADM1 Potentiates the T Cell‐Mediated Death of Human Small‐Cell Lung Cancer Cells

Abstract

Small‐cell lung cancer (SCLC) is the most aggressive form of lung cancer and the leading cause of global cancer‐related mortality. Despite the earlier identification of membrane‐proximal cleavage of cell adhesion molecule 1 (CADM1) in cancers, the role of the membrane‐bound fragment of CAMD1 (MF‐CADM1) is yet to be clearly identified. In this study, we first isolated MF‐CADM1‐ specific fully human single‐chain variable fragments (scFvs) from the human synthetic scFv antibody library using the phage display technology. Following the selected scFv conversion to human immunoglobulin G1 (IgG1) scFv‐Fc antibodies (K103.1–4), multiple characterization studies, including antibody cross‐species reactivity, purity, production yield, and binding affinity, were verified. Finally, via intensive in vitro efficacy and toxicity evaluation studies, we identified K103.3 as a lead antibody that potently promotes the death of human SCLC cell lines, including NCI‐H69, NCI‐ H146, and NCI‐H187, by activated Jurkat T cells without severe endothelial toxicity. Taken together, these findings suggest that antibody‐based targeting of MF‐CADM1 may be an effective strategy to potentiate T cell‐mediated SCLC death, and MF‐CADM1 may be a novel potential therapeutic target in SCLC for antibody therapy.