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Nature Biotechnology 26, 925–932 (1 August 2008) | doi:10.1038/nbt.1480

Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index

Jagath R Junutula , Helga Raab , Suzanna Clark , Sunil Bhakta , Douglas D Leipold , Sylvia Weir , Yvonne Chen , Michelle Simpson , Siao Ping Tsai , Mark S Dennis , Yanmei Lu , Y Gloria Meng , Carl Ng , Jihong Yang , Chien C Lee , Eileen Duenas , Jeffrey Gorrell , Viswanatham Katta , Amy Kim , Kevin McDorman , Kelly Flagella , Rayna Venook , Sarajane Ross , Susan D Spencer , Wai Lee Wong , Henry B Lowman , Richard Vandlen , Mark X Sliwkowski , Richard H Scheller , Paul Polakis & William Mallet

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.