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

Mark A J M Hendriks; Emily M Ploeg; Iris Koopmans; Isabel Britsch; Xiurong Ke; Douwe F Samplonius; Wijnand Helfrich

doi:10.1080/2162402X.2020.1824323

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

Oncoimmunology. 2020 Sep 29;9(1):1824323. doi: 10.1080/2162402X.2020.1824323.

Authors

Mark A J M Hendriks¹, Emily M Ploeg¹, Iris Koopmans¹, Isabel Britsch¹, Xiurong Ke^{1

2}, Douwe F Samplonius¹, Wijnand Helfrich¹

Affiliations

¹ Department of Surgery, Laboratory for Translational Surgical Oncology, University of Groningen, University Medical Center Groningen (UMCG), Groningen, The Netherlands.
² Department of Immunotherapy and Gastrointestinal Oncology, Affiliated Cancer Hospital of Shantou University Medical College, Shantou, China.

Abstract

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.

Keywords: ADCP; Bispecific antibody; CD47-blockade; EGFR; cancer immunotherapy; cross-presentation; trogoptosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antibodies, Bispecific* / pharmacology
Antigens, Differentiation
CD47 Antigen*
Cross-Priming
ErbB Receptors
Neutrophils
Receptors, Immunologic

Substances

Antibodies, Bispecific
Antigens, Differentiation
CD47 Antigen
Receptors, Immunologic
ErbB Receptors

Grants and funding

This work was supported by the Dutch Cancer Society [RUG2018-11464]; Dutch Cancer Society [RUG2013-6209]; Abel Tasman Talent Program [ATTP-2017]; Dutch Cancer Society [RUG2014-6986]; GSMS [MPDI-123015].