anti-CLL1-PBD ADC DCLL9718S

An antibody-drug conjugate (ADC) consisting of MCLL0517A , an anti-C-type lectin-like molecule-1 (CLL-1; CLL1; C-type lectin domain family 12 member A; CLEC12A) humanized immunoglobulin G1 (IgG1) monoclonal antibody, conjugated, via a cleavable disulfide linker, to two cytotoxic, DNA minor-groove crosslinking agent pyrrolobenzodiazepine (PBD) dimers, with potential antineoplastic activity. Upon administration of anti-CLL1-PBD ADC DCLL9718S, the antibody moiety targets the cell surface tumor-associated antigen (TAA) CLL1. Upon antibody/antigen binding, internalization, and lysosome uptake, the cytotoxic PBD moiety is released. The imine groups of the PBD moiety covalently bind to the N2 positions of guanines on opposite strands in the minor groove of DNA. This induces DNA strand breaks, inhibits DNA replication, leads to G2/M cell cycle arrest, induces cell death, and inhibits the proliferation of CLL1-overexpressing tumor cells. CLL1, a transmembrane glycoprotein and member of the C-type lectin/C-type lectin-like domain (CTL/CTLD) superfamily, is overexpressed in leukemic stem cells (LSCs) while absent on normal hematopoietic stem cells (HSCs). It plays an important role in disease progression and relapse of myeloid malignancies.