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Abstract CD33, is a transmembrane receptor expressed on cells of myeloid lineage. It is therapeutically targeted in cancer due to overexpression broadly among hematopoietic malignancies including AML. To develop a promising therapeutic anti-tumor agent, we generated BL-M11D1, a CD33-Ed-04 ADC. It is built on gemtuzumab, a specific monoclonal antibody against CD33, having a wt Fc that can mediate ADCC in vitro. BL-M11D1 is composed of gemtuzumab, a cathepsin B cleavable linker, and a novel topoisomerase I inhibitor agent (Ed-04). The novel Ed-04 is a derivative of the alkaloid camptothecin and mediates cell cycle arrest at the S phase and subsequent apoptosis. BL-M11D1 achieves a high drug-to-antibody-ratio (DAR=10) with a highly stable linker and is readily internalized and trafficked to lysosomal cellular compartments. The antitumor efficacy of BL-M11D1 was evaluated in xenograft tumor models. BL-M11D1 exhibited strong tumor inhibition capacity toward the human hematopoietic malignancies engrafted xenograft models. In summary, these studies suggest BL-M11D1, a novel CD33-targeting ADC, is potentially efficacious in the treatment of CD33-expressing disease. The clinical phase I trial is being undertaken to evaluate safety, dosing and observations of preliminary signs of efficacy. Citation Format: Weili Wan, Shuwen Zhao, Shi Zhuo, Yong Zhang, Lan Chen, Ruigang Li, Jahan Salar Khalili, Xiao Sa, Yongqi Yan, Xuejiao Shen, Yi Zhu. BL-M11D1, a novel CD33-targeting ADC, demonstrates robust anti-tumor efficacy in preclinical evaluation abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 3139.
Wan et al. (Fri,) studied this question.