Abstract
A novel disulfide linker was designed to enable a direct connection between cytotoxic pyrrolobenzodiazepine (PBD) drugs and the cysteine on a targeting antibody for use in antibody-drug conjugates (ADCs). ADCs composed of a cysteine-engineered antibody were armed with a PBD using a self-immolative disulfide linker. Both the chemical linker and the antibody site were optimized for this new bioconjugation strategy to provide a highly stable and efficacious ADC. This novel disulfide ADC was compared with a conjugate containing the same PBD drug, but attached to the antibody via a peptide linker. Both ADCs had similar efficacy in mice bearing human tumor xenografts. Safety studies in rats revealed that the disulfide-linked ADC had a higher MTD than the peptide-linked ADC. Overall, these data suggest that the novel self-immolative disulfide linker represents a valuable way to construct ADCs with equivalent efficacy and improved safety. Mol Cancer Ther; 16(5); 871-8. ©2017 AACR.
Highlights
Antibody–drug conjugates (ADCs) have proven to be an effective method of selectively delivering a small cytotoxic payload to a targeted cell
There are over 55 ADCs currently in human clinical testing and the approval of ADCETRIS and KADCYLA has spurred interest in expanding the utility and scope of these powerful agents [1,2,3]
We selected the unhindered disulfide linker (SG3231) for the preliminary evaluation of PBD ADCs. This linker-drug was connected to a cysteine-engineered antibody at either V205C or K149C of the light chain (LC)
Summary
Antibody–drug conjugates (ADCs) have proven to be an effective method of selectively delivering a small cytotoxic payload to a targeted cell. The antibody, linker, and payload of an ADC all play a large and synergistic role in modulating the efficacy and toxicity of the conjugate. A variety of different cytotoxic payloads have been effectively attached to an antibody to produce potent conjugates. These include microtubule-disrupting drugs such as maytansines [4] and auristatins [5], as well as DNA damaging agents such as duocarmycins [6], calicheamicins [7], pyrrolobenzodiazepines (PBDs) [8], and indolinobenzodiazepines (IGNs) [9].
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