Sato et al. investigated whether Fc-independent functions contribute to anti-CTLA-4’s antitumor efficacy. Although treatment with H11, a non-Fc-containing, single-domain CTLA-4 blocking antibody (VHH) had previously been shown to lack efficacy in vivo, a half-life-extended version (>10-fold increase in plasma and tumor) of H11 (H11-HLE) had potent antitumor efficacy in syngeneic tumor models. Moreover, eliminating Fc-receptor binding in ipilimumab (LALAPG-Fc) resulted in antitumor efficacy against H22 tumors without depleting Tregs, but not against MC38 tumors, indicating that Treg depletion may not be required for all anti-CTLA-4 activity.
Contributed by Katherine Turner
ABSTRACT: Ipilimumab, a monoclonal antibody that recognizes cytotoxic T-lymphocyte associated protein 4 (CTLA-4), was the first immune checkpoint inhibitor approved by the FDA to treat metastatic melanoma patients. Multiple preclinical studies have proposed that Fc effector functions of anti-CTLA-4 therapy are required for anti-tumor efficacy, in part, through the depletion of intratumoral regulatory T cells (Tregs). However, the contribution of the Fc-independent functions of anti-CTLA-4 antibodies to the observed efficacy is not fully understood. H11, a non-Fc-containing single-domain antibody (VHH) against CTLA-4, has previously been demonstrated to block CTLA-4-ligand interaction. However, in vivo studies demonstrated lack of anti-tumor efficacy with H11 treatment. Here, we show that a half-life extended H11 (H11-HLE), despite the lack of Fc effector functions, induced potent anti-tumor efficacy in mouse syngeneic tumor models. In addition, a non-Fc receptor binding version of ipilimumab (Ipi-LALAPG) also demonstrated anti-tumor activity in the absence of Treg depletion. Thus, we demonstrate that Fc-independent functions of anti-CTLA-4 antibodies contributed to anti-tumor efficacy, which may indicate that non-Treg depleting activity of anti-CTLA-4 therapy could benefit cancer patients in the clinic.
Author Info: (1) Takeda Pharmaceuticals International Co., Cambridge, MA, USA. (2) Takeda Pharmaceuticals International Co., Cambridge, MA, USA. (3) Takeda Pharmaceuticals International Co., Ca
Author Info: (1) Takeda Pharmaceuticals International Co., Cambridge, MA, USA. (2) Takeda Pharmaceuticals International Co., Cambridge, MA, USA. (3) Takeda Pharmaceuticals International Co., Cambridge, MA, USA. (4) Takeda Pharmaceuticals International Co., Cambridge, MA, USA. (5) Takeda Pharmaceuticals International Co., Cambridge, MA, USA. (6) Takeda Pharmaceuticals International Co., Cambridge, MA, USA. (7) Takeda Pharmaceuticals International Co., Cambridge, MA, USA. (8) Takeda Pharmaceuticals International Co., Cambridge, MA, USA. (9) Takeda Pharmaceuticals International Co., Cambridge, MA, USA. (10) Takeda Pharmaceuticals International Co., Cambridge, MA, USA. Mediar Therapeutics, Cambridge, MA, USA. (11) Takeda Pharmaceuticals International Co., Cambridge, MA, USA. (12) Takeda Pharmaceuticals International Co., Cambridge, MA, USA. (13) Takeda Pharmaceuticals International Co., Cambridge, MA, USA. (14) Takeda Pharmaceuticals International Co., Cambridge, MA, USA. Dragonfly Therapeutics, Waltham, MA, USA. (15) Takeda Pharmaceuticals International Co., Cambridge, MA, USA. Curia, Hopkinton, MA, USA. (16) Takeda Pharmaceuticals International Co., Cambridge, MA, USA. (17) Takeda Pharmaceuticals International Co., Cambridge, MA, USA. michael.shaw2@takeda.com.
