Bispecific antibody approach for EGFR-directed blockade of the CD47-SIRP alpha "don't eat me" immune checkpoint promotes neutrophil-mediated trogoptosis and enhances antigen cross-presentation

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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-SIRP alpha 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.

Original languageEnglish
Article number1824323
Pages (from-to)1-12
Number of pages12
JournalOncoImmunology
Volume9
Issue number1
DOIs
Publication statusPublished - 1-Jan-2020

Keywords

  • Bispecific antibody
  • CD47-blockade
  • EGFR
  • ADCP
  • trogoptosis
  • cross-presentation
  • cancer immunotherapy
  • REGULATORY PROTEIN-ALPHA
  • GROWTH-FACTOR RECEPTOR
  • TARGETING CD47
  • HIGH-AFFINITY
  • CANCER
  • CELLS
  • OVEREXPRESSION
  • PHAGOCYTOSIS
  • ENGRAFTMENT
  • EXPRESSION

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