Research abstract
Article abstract
Nature Biotechnology 26, 925 - 932 (2008)
Published online: 20 July 2008 | doi:10.1038/nbt.1480
Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index
Jagath R Junutula1, Helga Raab1, Suzanna Clark1, Sunil Bhakta1, Douglas D Leipold1, Sylvia Weir1, Yvonne Chen1, Michelle Simpson1, Siao Ping Tsai1, Mark S Dennis1, Yanmei Lu1, Y Gloria Meng1, Carl Ng1, Jihong Yang1, Chien C Lee1, Eileen Duenas1, Jeffrey Gorrell1, Viswanatham Katta1, Amy Kim1, Kevin McDorman1,2, Kelly Flagella1, Rayna Venook1, Sarajane Ross1, Susan D Spencer1, Wai Lee Wong1, Henry B Lowman1, Richard Vandlen1, Mark X Sliwkowski1, Richard H Scheller1, Paul Polakis1 & William Mallet1
Abstract
Antibody-drug conjugates enhance the antitumor effects of antibodies and reduce adverse systemic effects of potent cytotoxic drugs. However, conventional drug conjugation strategies yield heterogenous conjugates with relatively narrow therapeutic index (maximum tolerated dose/curative dose). Using leads from our previously described phage display–based method to predict suitable conjugation sites, we engineered cysteine substitutions at positions on light and heavy chains that provide reactive thiol groups and do not perturb immunoglobulin folding and assembly, or alter antigen binding. When conjugated to monomethyl auristatin E, an antibody against the ovarian cancer antigen MUC16 is as efficacious as a conventional conjugate in mouse xenograft models. Moreover, it is tolerated at higher doses in rats and cynomolgus monkeys than the same conjugate prepared by conventional approaches. The favorable in vivo properties of the near-homogenous composition of this conjugate suggest that our strategy offers a general approach to retaining the antitumor efficacy of antibody-drug conjugates, while minimizing their systemic toxicity.
- Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
- Present address: Division of Pathology, Charles River Preclinical Services, Nevada, 6995 Longley Lane, Reno, Nevada 89511, USA.
Correspondence to: William Mallet1 e-mail: wmallet@gene.com
Correspondence to: Jagath R Junutula1 e-mail: jagath@gene.com
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