Therapeutic antibodies are widely used to treat diseases like cancer and inflammatory conditions by binding with high specificity to their molecular targets. Masking is a strategy to mitigate undesirable activity in non-target tissues, improving safety and pharmacokinetic (PK) profiles by reducing target-mediated drug disposition (TMDD). In this study, we explored masking an anti-CTLA-4 antibody by conjugating a large PEG molecule to specific sites on the antibody. While anti-CTLA-4 immunotherapy benefits solid tumor treatment, its adverse events limit its utility. We evaluated multiple conjugation sites within the complementarity-determining regions (CDRs) and adjacent framework regions to attenuate CTLA-4 binding. We identified the optimal site for maximizing masking efficiency, allowing for efficient bioconjugation and functional restoration upon exposure to a cleaving enzyme in the tumor microenvironment. The prodrugged antibody exhibited reduced binding to CTLA-4 and Fc gamma receptors (FcgRs), high stability, and an extended half-life in a mouse model. This technology has the potential to improve the PK profile and safety attributes of therapeutic antibodies.