Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity, De Boelelaan 1117, Amsterdam, Netherlands.
Sanquin Research and Landsteiner Laboratory, Department of Experimental Immunohematology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
J Clin Invest. 2021 Mar 15;131(6). doi: 10.1172/JCI134680.
Most clinically used anticancer mAbs are of the IgG isotype, which can eliminate tumor cells through NK cell-mediated antibody-dependent cellular cytotoxicity and macrophage-mediated antibody-dependent phagocytosis. IgG, however, ineffectively recruits neutrophils as effector cells. IgA mAbs induce migration and activation of neutrophils through the IgA Fc receptor (FcαRI) but are unable to activate NK cells and have poorer half-life. Here, we combined the agonistic activity of IgG mAbs and FcαRI targeting in a therapeutic bispecific antibody format. The resulting TrisomAb molecules recruited NK cells, macrophages, and neutrophils as effector cells for eradication of tumor cells in vitro and in vivo. Moreover, TrisomAb had long in vivo half-life and strongly decreased B16F10gp75 tumor outgrowth in mice. Importantly, neutrophils of colorectal cancer patients effectively eliminated tumor cells in the presence of anti-EGFR TrisomAb but were less efficient in mediating killing in the presence of IgG anti-EGFR mAb (cetuximab). The clinical application of TrisomAb may provide potential alternatives for cancer patients who do not benefit from current IgG mAb therapy.
大多数临床应用的抗癌单克隆抗体为 IgG 同种型，可通过 NK 细胞介导的抗体依赖的细胞毒性和巨噬细胞介导的抗体依赖的吞噬作用来消除肿瘤细胞。然而，IgG 并不能有效地招募中性粒细胞作为效应细胞。IgA 单克隆抗体通过 IgA Fc 受体（FcαRI）诱导中性粒细胞的迁移和激活，但不能激活 NK 细胞，且半衰期更短。在这里，我们将 IgG 单克隆抗体的激动活性和 FcαRI 靶向作用结合在一种治疗性双特异性抗体形式中。所得的 TrisomAb 分子招募 NK 细胞、巨噬细胞和中性粒细胞作为效应细胞，在体外和体内清除肿瘤细胞。此外，TrisomAb 在体内具有较长的半衰期，并强烈降低了小鼠中 B16F10gp75 肿瘤的生长。重要的是，结直肠癌患者的中性粒细胞在存在抗 EGFR TrisomAb 的情况下能有效消除肿瘤细胞，但在存在 IgG 抗 EGFR 单克隆抗体（西妥昔单抗）时介导杀伤的效率较低。TrisomAb 的临床应用可能为那些不能从当前 IgG 单克隆抗体治疗中获益的癌症患者提供潜在的替代方案。
