Bispecific antibody approach for EGFR-directed blockade of the CD47-SIRPα "don't eat me" immune checkpoint promotes neutrophil-mediated trogoptosis and enhances antigen cross-presentation.
Bispecific antibody approach for EGFR-directed blockade of the CD47-SIRPα "don't eat me" immune checkpoint promotes neutrophil-mediated trogoptosis and enhances antigen cross-presentation.
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DOI：
10.1080/2162402x.2020.1824323
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发表时间：
2020-09-29
期刊：
影响因子：
7.2
通讯作者：
Helfrich W
中科院分区：
文献类型：
--
作者：
Hendriks MAJM;Ploeg EM;Koopmans I;Britsch I;Ke X;Samplonius DF;Helfrich W
癌细胞过度表达CD 47以破坏吞噬消除并逃避癌抗原的免疫原性加工。此外，CD 47过表达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，已经开发了CD 47阻断抗体以克服癌细胞表达的CD 47的免疫逃避活性。然而，CD 47在正常细胞上的广泛表达形成了大量的“抗原库”，这可能限制这些抗体在肿瘤中的充分增长。此外，CD 47-SIRPα相互作用的全面阻断可能最终导致自身抗原的非预期交叉呈递，可能促进自身免疫。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 CD 47 xEGFR-IgG 1，它以EGFR导向的方式阻断癌细胞表面表达的CD 47。BsAb CD 47 xEGFR-IgG 1选择性诱导EGFRpos/CD 47 pos癌细胞的吞噬清除，并赋予中性粒细胞通过胞吞作用（破坏靶细胞膜的ADCC的替代形式）杀死这些癌细胞的能力。重要的是，bsAb CD 47 xEGFR-IgG 1选择性增强了异位表达病毒蛋白CMVpp 65的EGFR pos/CD 47 pos癌细胞的吞噬作用和免疫原性加工。总之，bsAb CD 47 xEGFR-IgG 1可能有助于降低CD 47阻断方法的靶向/脱瘤效应，增强通过trogoptosis消除癌细胞，并促进适应性抗癌免疫应答。
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 EGFRpos/CD47pos 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 EGFRpos/CD47pos 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.