Abstract 4746: PLB-001, a novel anti-dll3 ADC with topoisomerase 1 inhibitor-based linker-payload for treatment of SCLC

Abstract Delta-like ligand 3 (DLL3) is a promising target for antibody-drug conjugates (ADCs) in the treatment of small cell lung cancer (SCLC) due to its high expression on the cell surface of SCLC cells and minimal expression in normal tissues. With highly specific, fast internalized mAbs from antibody screening, various types of payloads including tubulin and TOPI inhibitors were conjugated with different platforms, linkers, conjugation methods available from our linker-payload arsenal to obtain the optimal ADC. Here, we present a novel DLL3 targeted ADC, PLB-001, which using a highly potent topoisomerase I inhibitor exatecan, conjugated to a humanized IgG1 antibody, through a highly hydrophilic, enzyme-cleavable linker with a DAR of 8. PLB-001 demonstrated strong in vitro efficacy in several different SCLC cell lines correlating with DLL3 expression levels. This ADC also exhibited potent and durable antitumor effects in cell line-derived and patient-derived xenograft models, and exhibited favorable pharmacokinetic profiles. These preclinical result support PLB-001 as a potential candidate for the treatment of DLL3-positive SCLC Citation Format: Yingdong Lu, xin li, Ganyuan Xiao, Kia J. Puan, Ling xu, Mao Yin. PLB-001, a novel anti-dll3 ADC with topoisomerase 1 inhibitor-based linker-payload for treatment of SCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4746.