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A novel anti-CD37 antibody-drug conjugate with multiple anti-tumor mechanisms for the treatment of B-cell malignancies

Jutta Deckert, Peter U. Park, Sharon Chicklas, Yong Yi, Min Li, Katharine C. Lai, Michele F. Mayo, Christina N. Carrigan, Hans K. Erickson, Jan Pinkas, Robert J. Lutz, Thomas Chittenden and John M. Lambert

Key points

  • An anti-CD37 antibody-drug conjugate can kill B-lymphoma cells via direct inhibition, effector function and payload delivery

  • Targeting CD37 with an antibody-drug conjugate results in selective depletion of malignant human B cells

Abstract

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.

  • Submitted May 29, 2013.
  • Accepted August 3, 2013.