Agenus Inc., Lexington, MA 02421, USA.
Agenus Inc., Lexington, MA 02421, USA; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Cancer Cell. 2018 Jun 11;33(6):1033-1047.e5. doi: 10.1016/j.ccell.2018.05.005.
The co-engagement of fragment crystallizable (Fc) gamma receptors (FcγRs) with the Fc region of recombinant immunoglobulin monoclonal antibodies (mAbs) and its contribution to therapeutic activity has been extensively studied. For example, Fc-FcγR interactions have been shown to be important for mAb-directed effector cell activities, as well as mAb-dependent forward signaling into target cells via receptor clustering. Here we identify a function of mAbs targeting T cell-expressed antigens that involves FcγR co-engagement on antigen-presenting cells (APCs). In the case of mAbs targeting CTLA-4 and TIGIT, the interaction with FcγR on APCs enhanced antigen-specific T cell responses and tumoricidal activity. This mechanism extended to an anti-CD45RB mAb, which led to FcγR-dependent regulatory T cell expansion in mice.
片段可结晶 (Fc) γ 受体 (FcγRs) 与重组免疫球蛋白单克隆抗体 (mAbs) 的 Fc 区域的共同结合及其对治疗活性的贡献已得到广泛研究。例如，Fc-FcγR 相互作用对于 mAb 定向效应细胞活性以及 mAb 通过受体聚集对靶细胞的依赖性正向信号传导非常重要。在这里，我们确定了靶向 T 细胞表达抗原的 mAbs 的一种功能，该功能涉及抗原呈递细胞 (APC) 上的 FcγR 共同结合。在针对 CTLA-4 和 TIGIT 的 mAbs 的情况下，与 APC 上的 FcγR 的相互作用增强了抗原特异性 T 细胞反应和杀肿瘤活性。这种机制扩展到抗 CD45RB mAb，它导致了小鼠中 FcγR 依赖性调节性 T 细胞扩增。
