Effects of Drug–Antibody Ratio on Pharmacokinetics, Biodistribution, Efficacy, and Tolerability of Antibody–Maytansinoid Conjugates

Published on Apr 13, 2017in Bioconjugate Chemistry4.031
· DOI :10.1021/ACS.BIOCONJCHEM.7B00062
Xiuxia Sun6
Estimated H-index: 6
(ImmunoGen, Inc.),
Jose F. Ponte10
Estimated H-index: 10
(ImmunoGen, Inc.)
+ 18 AuthorsJohn M. Lambert52
Estimated H-index: 52
Antibody–drug conjugates (ADCs) are being actively pursued as a treatment option for cancer following the regulatory approval of brentuximab vedotin (Adcetris) and ado-trastuzumab emtansine (Kadcyla). ADCs consist of a cytotoxic agent conjugated to a targeting antibody through a linker. The two approved ADCs (and most ADCs now in the clinic that use a microtubule disrupting agent as the payload) are heterogeneous conjugates with an average drug-to-antibody ratio (DAR) of 3–4 (potentially ranging from 0 to 8 for individual species). Ado-trastuzumab emtansine employs DM1, a semisynthetic cytotoxic payload of the maytansinoid class, which is conjugated via lysine residues of the antibody to an average DAR of 3.5. To understand the effect of DAR on the preclinical properties of ADCs using maytansinoid cytotoxic agents, we prepared a series of conjugates with a cleavable linker (M9346A–sulfo-SPDB–DM4 targeting folate receptor α (FRα)) or an uncleavable linker (J2898A–SMCC–DM1 targeting the epidermal growth fac...
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