Anti–CTLA-4 therapy requires an Fc domain for efficacy

Significance Ipilimumab, an antibody that recognizes cytotoxic T lymphocyte antigen (CTLA)-4, was the first approved “checkpoint”-blocking anticancer therapy. In mice, the response to antibodies against CTLA-4 depends entirely on expression of the Fcγ receptor. We developed H11, an alpaca heavy chain-only antibody fragment against CTLA-4 that lacks an Fc portion and inhibits interactions between CTLA-4 and its ligand. By using H11 to visualize CTLA-4 expression in the whole animal, we found that accessible CTLA-4 is largely confined to the tumor; however, H11 treatment has minimal effects on antitumor responses. Installing the murine IgG2a constant region on H11 greatly enhances antitumor response. We were thus able to dissociate CTLA-4 blockade from CTLA-4–dependent receptor engagement as an explanation for the antitumor effect.