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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. 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