Abstract SY35-01: The next generation of ADCs

Abstract

Abstract The concept of an antibody-drug conjugate (ADC) is deceptively simple: a monoclonal antibody against a tumor-specific antigen delivers a potent cytotoxic payload directly to the malignant cells, resulting in targeted killing. However, this apparent simplicity belies a complex product with multiple interacting components. Working to optimize these components, we have identified three important concepts that impact the therapeutic potential of ADCs. First, we have learned that stability of an ADC can vary according to the specific conjugation site on the antibody. During the development of engineered cysteine antibodies (EC-mAbs), we evaluated various cysteine substitutions and found that S239C on the IgG heavy chain is particularly stable when conjugated using standard maleimide chemistry. Alternatively, we have devised a method for producing stable conjugation to native cysteine residues by designing maleimides that catalyze their own ring-opening after coupling to the antibody. These modifications in ADC stability appear to result in both improved activity and decreased toxicity in preclinical models. Second, we have observed that modulation of ADC hydrophobicity results in profound changes in both biodistribution and antitumor activity. When utilizing typical drug-linkers, ADCs with a high drug-to-antibody ratio (DAR >4) appear to be cleared from circulation more rapidly by reticuloendothelial cells. By reducing drug-linker hydrophobicity, we can circumvent this clearance pathway and it becomes possible to increase the DAR, resulting in more potent ADCs that retain desirable pharmacokinetic properties. We have achieved a similar result with the use of short, discrete PEG oligomers to mask the drug linker, thereby reducing the apparent hydrophobicity of the ADC. Finally, the chemical properties of the released payload have a major impact on both efficacy and toxicity. The difference between polar and nonpolar payloads will be discussed, including bystander activity, potential mechanisms of resistance, and adverse events observed in clinical trials. A new class of DNA crosslinking payloads is represented by the pyrrolobenzodiazepines (PBD) dimer, which is several logs more potent than auristatins and has the ability to overcome multi-drug resistance phenotypes. These examples demonstrate how rapidly the ADC field is evolving and provide hope that the next generation of ADCs will be even more effective and well-tolerated in the fight against cancer. Citation Format: Jonathan G. Drachman. The next generation of ADCs. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY35-01. doi:10.1158/1538-7445.AM2015-SY35-01