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

• Published in: Oncoimmunology Vol. 9; no. 1; p. 1824323
• Main Authors: Hendriks, Mark A. J. M., Ploeg, Emily M., Koopmans, Iris, Britsch, Isabel, Ke, Xiurong, Samplonius, Douwe F., Helfrich, Wijnand
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01-01-2020; Taylor & Francis Group
• Subjects: ADCP; Bispecific antibody; cancer immunotherapy; CD47-blockade; cross-presentation; EGFR; Original Research; trogoptosis; cross-presentation; cancer immunotherapy; trogoptosis; Bispecific antibody; ADCP; EGFR; CD47-blockade
• ISSN: 2162-402X; 2162-4011; 2162-402X
• 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
pos
/CD47
pos
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
pos
/CD47
pos
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.