ADC Surrogates for Process Development

Performance Period: 8/1/2020 to 5/31/2022

The segment of the ADC Surrogates for Process Development project is led by Rensselaer Polytechnic Institute (PI: Todd Przybycien) and includes Carnegie Mellon University (Co-PI: James Schneider), MilliporeSigma (Co-PI: Lisa McDermott), and MedImmune-AstraZeneca (Co-PI: Dan Pappas) as partners. Antibody-drug conjugates (ADCs) are an important, growing class of anti-cancer drugs consisting of a highly toxic killing molecule, the “warhead”, attached via a linking group to an antibody that can bind specifically to cancer cells. The warheads make ADCs extremely dangerous to handle during manufacture, requiring elaborate containment facilities, personnel protection devices and cleaning protocols. This makes process development efforts expensive and limited in scope, giving fast rather than optimal solutions. Vendor companies and small and medium manufacturers generally lack these specialized facilities and may be effectively excluded from accessing the ADC processing market. And, there are no safe alternatives for training new personnel and students to handle ADCs.

We will develop and characterize non-toxic molecules that mimic the physicochemical properties and processing behaviors of ADCs. These surrogate ADCs (“sADCs”) comprise antibodies with less toxic, chemically similar fluorescent dyes (“fluorheads”) attached in place of warheads and will ultimately be made at scales which support ADC process development for commercialization. In this first segment of the project, we will demonstrate the physicochemical similarity of candidate fluorhead-linker conjugates to two warhead-linker conjugates in current use in ADCs: an auristatin-based conjugate (MMAE-SMCC) and a pyrrolobenzodiazepine-based conjugate (PBD-SMCC).