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

• DOI: 10.1073/pnas.1801524115
• Publication Date: 2018-03-26T19:15:12Z
• Authors: Jessica R. Ingram; Olga S. Blomberg; Mohammad Rashidian; Lestat Ali; Scott Garforth; Elena Fedorov; Alexander A. Fedorov; Jeffrey B. Bonanno; Camille Le Gall; Stephanie Crowley; Camilo Espinosa; Tamara Biary; Edmund J. Keliher; Ralph Weissleder; Steven C. Almo; Stephanie K. Dougan; Hidde L. Ploegh; Michael Dougan
• Keywords: CTLA-4; Single-domain antibody; Blocking antibody; Tremelimumab

Ipilimumab, a monoclonal antibody that recognizes cytotoxic T lymphocyte antigen (CTLA)-4, was the first approved "checkpoint"-blocking anticancer therapy. In mouse tumor models, response to antibodies against CTLA-4 depends entirely on expression of Fcγ receptor (FcγR), which may facilitate antibody-dependent cellular phagocytosis, but contribution simple blockade remains unknown. To understand role in complete absence Fc-dependent functions, we developed H11, high-affinity alpaca heavy chain-only fragment (VHH) CTLA-4. The VHH H11 lacks an Fc portion, binds monovalently CTLA-4, and inhibits interactions between its ligand by occluding ligand-binding motif as shown crystallographically. We used visualize vivo using whole-animal immuno-PET, finding surface-accessible is largely confined microenvironment. Despite this, H11-mediated has minimal effects antitumor responses. Installation murine IgG2a constant region dramatically enhances response. Coadministration monovalent blocks efficacy full-sized therapeutic antibody. were thus able demonstrate CTLA-4-binding require domain for effect.