A novel anti-CD37 antibody-drug conjugate with multiple anti-tumor mechanisms for the treatment of B-cell malignancies
Menée sur des lignées cellulaires de lymphome non hodgkinien et de leucémie lymphocytaire chronique, ainsi qu'à l'aide de xénogreffes, cette étude évalue l'activité antitumorale d'un conjugué associant un anticorps (anti CD37) et un agent cytotoxique (DM1)
CD37 has gathered renewed interest as a therapeutic target in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL); however, CD37-directed antibody-drug conjugates (ADCs) have not been explored. Here, we identified a novel anti-CD37 antibody, K7153A, with potent in vitro activity against B-cell lines through multiple mechanisms including apoptosis induction, antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and complement-dependent cytotoxicity (CDC). The antibody was conjugated to the maytansinoid, DM1, a potent anti-microtubule agent, via the thioether linker, SMCC, and the resulting conjugate, IMGN529, retained the intrinsic antibody activities and showed enhanced cytotoxic activity from targeted payload delivery. In lymphoma cell lines, IMGN529 induced G2/M cell cycle arrest following internalization and lysosomal processing to lysine-Nϵ-SMCC-DM1 as the sole intracellular maytansinoid metabolite. IMGN529 was highly active against subcutaneous B-cell tumor xenografts in SCID mice with comparable or better activity than rituximab, CVP or bendamustine. In human blood cells, CD37 is expressed in B cells at similar levels as CD20, and IMGN529 resulted in potent and specific depletion of normal and CLL B cells. These results support evaluation of the CD37-targeted ADC, IMGN529, in clinical trials in patients with B-cell malignancies including NHL and CLL.
Blood 2013