Hendriks Mark A J M, Ploeg Emily M, Koopmans Iris, Britsch Isabel, Ke Xiurong, Samplonius Douwe F, Helfrich Wijnand
Department of Surgery, Laboratory for Translational Surgical Oncology, University of Groningen, University Medical Center Groningen (UMCG), Groningen, The Netherlands.
Department of Immunotherapy and Gastrointestinal Oncology, Affiliated Cancer Hospital of Shantou University Medical College, Shantou, China.
Oncoimmunology. 2020 Sep 29;9(1):1824323. doi: 10.1080/2162402X.2020.1824323.
Cancer cells overexpress CD47 to subvert phagocytic elimination and evade immunogenic processing of cancer antigens. Moreover, CD47 overexpression inhibits the antibody-dependent cellular phagocytosis (ADCP) and cytotoxicity (ADCC) activities of therapeutic anticancer antibodies. Consequently, CD47-blocking antibodies have been developed to overcome the immunoevasive activities of cancer cell-expressed CD47. However, the wide-spread expression of CD47 on normal cells forms a massive "antigen sink" that potentially limits sufficient tumor accretion of these antibodies. Additionally, a generalized blockade of CD47-SIRPα interaction may ultimately lead to unintended cross-presentation of self-antigens potentially promoting autoimmunity. To address these issues, we constructed a bispecific antibody, designated bsAb CD47xEGFR-IgG1, that blocks cancer cell surface-expressed CD47 in an EGFR-directed manner. BsAb CD47xEGFR-IgG1 selectively induced phagocytic removal of EGFR/CD47 cancer cells and endowed neutrophils with capacity to kill these cancer cells by trogoptosis; an alternate form of ADCC that disrupts the target cell membrane. Importantly, bsAb CD47xEGFR-IgG1 selectively enhanced phagocytosis and immunogenic processing of EGFR/CD47 cancers cells ectopically expressing viral protein CMVpp65. In conclusion, bsAb CD47xEGFR-IgG1 may be useful to reduce on-target/off-tumor effects of CD47-blocking approaches, enhance cancer cell elimination by trogoptosis, and promote adaptive anticancer immune responses.
癌细胞过度表达CD47以颠覆吞噬清除作用并逃避癌症抗原的免疫原性加工。此外，CD47的过度表达会抑制治疗性抗癌抗体的抗体依赖性细胞吞噬作用（ADCP）和细胞毒性（ADCC）活性。因此，已开发出CD47阻断抗体以克服癌细胞表达的CD47的免疫逃逸活性。然而，CD47在正常细胞上的广泛表达形成了一个巨大的“抗原库”，这可能会限制这些抗体在肿瘤中的充分聚集。此外，CD47-SIRPα相互作用的全面阻断最终可能导致自身抗原的意外交叉呈递，从而潜在地促进自身免疫。为了解决这些问题，我们构建了一种双特异性抗体，命名为bsAb CD47xEGFR-IgG1，它以EGFR导向的方式阻断癌细胞表面表达的CD47。BsAb CD47xEGFR-IgG1选择性地诱导对EGFR/CD47癌细胞的吞噬清除，并赋予中性粒细胞通过穿孔凋亡杀死这些癌细胞的能力；穿孔凋亡是一种破坏靶细胞膜的ADCC替代形式。重要的是，bsAb CD47xEGFR-IgG1选择性地增强了异位表达病毒蛋白CMVpp65的EGFR/CD47癌细胞的吞噬作用和免疫原性加工。总之，bsAb CD47xEGFR-IgG1可能有助于减少CD47阻断方法的靶向非肿瘤效应，通过穿孔凋亡增强癌细胞清除，并促进适应性抗癌免疫反应。
