Open AccessGenerating tumor-selective conditionally active biologic anti-CTLA4 antibodies via protein-associated chemical switches
Author(s) -
Hwai Wen Chang,
Gerhard Frey,
Haizhen Liu,
Charles Xing,
Lawrence Steinman,
William J. Boyle,
Jay M. Short
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2020606118
Subject(s) - drug , antibody , drug discovery , computational biology , cancer research , chemistry , bioinformatics , medicine , pharmacology , biology , immunology
Significance On-target, off-tumor toxicity of anti-CTLA4 checkpoint inhibitors leads to severe adverse events, restricting therapeutic efficacy. We engineered anti-CTLA4 antibodies and generated a new class of antibodies referred to as conditionally active biologic (CAB) antibodies using physiological chemicals (bicarbonate, hydrogen sulfide) as protein-associated chemical switches (PaCS) to reduce binding under normal physiological conditions, while maintaining binding in the tumor. PaCS add a new dimension to drug discovery. PaCS can be applied to a variety of targets and drug formats, improving safety, increasing the number of targets, allowing the development of new therapies, and enhancing the tolerability of existing therapeutics. The PaCS mechanism can be used to tune the binding activity for disease-related microenvironments, including cancer, infection, inflammation, and cellular senescence.