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.

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 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.

• Authors: Mark A J M Hendriks, Emily M Ploeg, Iris Koopmans, Isabel Britsch, Xiurong Ke, Douwe F Samplonius, Wijnand Helfrich
• Journal: Oncoimmunology (Oncoimmunology) Vol. 9 Issue 1 Pg. 1824323 (09 29 2020) ISSN: 2162-402X [Electronic] United States
• PMID: 33299654 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.

Chemical References

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

Topics

• Antibodies, Bispecific (pharmacology)
• Antigens, Differentiation
• CD47 Antigen
• Cross-Priming
• ErbB Receptors
• Neutrophils
• Receptors, Immunologic