Antibody-Drug Conjugates for the Treatment of Non-Hodgkin's Lymphoma: Target and Linker-Drug Selection

March 4, 2009

Published online first on March 3, 2009

[Cancer Research, 10.1158/0008-5472.CAN-08-2250]

Antibody-Drug Conjugates for the Treatment of Non-Hodgkin's Lymphoma: Target and

Linker-Drug Selection

G. Polson *, Jill Calemine-Fenaux , Pamela Chan , Wesley Chang ,

Christensen , Suzanna , Frederic J. de Sauvage , Dan Eaton , Kristi Elkins

, J. Elliott , Gretchen Frantz , Reina N. Fuji , Alane Gray ,

Harden , Gladys S. Ingle , Noelyn M. Kljavin , Hartmut Koeppen ,

, Saileta Prabhu , Helga Raab , Sarajane Ross , Jean-Philippe Stephan ,

Suzie J. Scales , D. Spencer , Vandlen , Bernd Wranik , Shang-Fan

Yu , Bing Zheng , Ebens

Genentech, Inc., South San Francisco, California

* To whom correspondence should be addressed. E-mail: polson@... .

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. [Cancer Res

2009;69(6):2358-64]

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