2. Academic Validation
  3. Antibody-drug conjugates for the treatment of non-Hodgkin's lymphoma: target and linker-drug selection

Antibody-drug conjugates for the treatment of non-Hodgkin's lymphoma: target and linker-drug selection

  • Cancer Res. 2009 Mar 15;69(6):2358-64. doi: 10.1158/0008-5472.CAN-08-2250.
Andrew G Polson 1,  Jill Calemine-Fenaux,  Pamela Chan,  Wesley Chang,  Erin Christensen,  Suzanna Clark,  Frederic J de Sauvage,  Dan Eaton,  Kristi Elkins,  J Michael Elliott,  Gretchen Frantz,  Reina N Fuji,  Alane Gray,  Kristin Harden,  Gladys S Ingle,  Noelyn M Kljavin,  Hartmut Koeppen,  Christopher Nelson,  Saileta Prabhu,  Helga Raab,  Sarajane Ross,  Dion S Slaga,  Jean-Philippe Stephan,  Suzie J Scales,  Susan D Spencer,  Richard Vandlen,  Bernd Wranik,  Shang-Fan Yu,  Bing Zheng,  Allen Ebens
Affiliations

Affiliation

  • 1 Genentech, Inc., South San Francisco, California, USA. polson@gene.com
PMID: 19258515 DOI: 10.1158/0008-5472.CAN-08-2250
Abstract

Antibody-drug conjugates (ADC), potent cytotoxic drugs covalently linked to Antibodies via chemical linkers, provide a means to increase the effectiveness of chemotherapy by targeting the drug to neoplastic cells while reducing side effects. Here, we systematically examine the potential targets and linker-drug combinations that could provide an optimal ADC for the treatment for non-Hodgkin's lymphoma. We identified seven antigens (CD19, CD20, CD21, CD22, CD72, CD79b, and CD180) for potential treatment of non-Hodgkin's lymphoma with ADCs. ADCs with cleavable linkers mediated in vivo efficacy via all these targets; ADCs with uncleavable linkers were only effective when targeted to CD22 and CD79b. In target-independent safety studies in rats, the uncleavable linker ADCs showed reduced toxicity, presumably due to the reduced release of free drug or other toxic metabolites into the circulation. Thus, our data suggest that ADCs with cleavable linkers work on a broad range of targets, and for specific targets, ADCs with uncleavable linkers provide a promising opportunity to improve the therapeutic window for ADCs in humans.

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