Blocking "don't eat me" signal of CD47-SIRPα in hematological malignancies, an in-depth review

Atlantis Russ; Anh B Hua; William R Montfort; Bushra Rahman; Irbaz Bin Riaz; Muhammad Umar Khalid; Jennifer S Carew; Steffan T Nawrocki; Daniel Persky; Faiz Anwer

doi:10.1016/j.blre.2018.04.005

Blocking "don't eat me" signal of CD47-SIRPα in hematological malignancies, an in-depth review

Blood Rev. 2018 Nov;32(6):480-489. doi: 10.1016/j.blre.2018.04.005. Epub 2018 Apr 14.

Authors

Affiliations

¹ Department of Medicine, University of Arizona, Tucson, AZ, USA. Electronic address: aruss@deptofmed.arizona.edu.
² Pharmacology and Toxicology, University of Arizona, Tucson, AZ, USA. Electronic address: anhhua@email.arizona.edu.
³ Chemistry and Biochemistry, University of Arizona, Tucson, AZ, USA. Electronic address: montfort@email.arizona.edu.
⁴ Department of Medicine, University of Arizona, Tucson, AZ, USA. Electronic address: bushra.rahman@bannerhealth.com.
⁵ Department of Medicine, Hematology Oncology, Mayo Clinic, Rochester, MN, USA. Electronic address: riaz.dr@mayo.edu.
⁶ Department of Medicine, Division of Hematology, Oncology, Arizona Cancer Center, The University of Arizona, Tucson, AZ, USA. Electronic address: umarkhalid1990@gmail.com.
⁷ Department of Medicine, Division of Hematology, Oncology, Arizona Cancer Center, The University of Arizona, Tucson, AZ, USA. Electronic address: jcarew@email.arizona.edu.
⁸ Department of Medicine, Division of Hematology, Oncology, Arizona Cancer Center, The University of Arizona, Tucson, AZ, USA. Electronic address: snawrocki@email.arizona.edu.
⁹ Department of Medicine, Division of Hematology, Oncology, Arizona Cancer Center, The University of Arizona, Tucson, AZ, USA. Electronic address: dpersky@email.arizona.edu.
¹⁰ Department of Medicine, Division of Hematology, Oncology, Arizona Cancer Center, The University of Arizona, Tucson, AZ, USA. Electronic address: anwerf@email.arizona.edu.

Abstract

Hematological malignancies express high levels of CD47 as a mechanism of immune evasion. CD47-SIRPα triggers a cascade of events that inhibit phagocytosis. Preclinical research supports several models of antibody-mediated blockade of CD47-SIRPα resulting in cell death signaling, phagocytosis of cells bearing stress signals, and priming of tumor-specific T cell responses. Four different antibody molecules designed to target the CD47-SIRPα interaction in malignancy are currently being studied in clinical trials: Hu5F9-G4, CC-90002, TTI-621, and ALX-148. Hu5F9-G4, a humanized anti-CD47 blocking antibody is currently being studied in four different Phase I trials. These studies may lay the groundwork for therapeutic bispecific antibodies. Bispecific antibody (CD20-CD47SL) fusion of anti-CD20 (Rituximab) and anti-CD47 also demonstrated a synergistic effect against lymphoma in preclinical models. This review summarizes the large body of preclinical evidence and emerging clinical data supporting the use of antibodies designed to target the CD47-SIRPα interaction in leukemia, lymphoma and multiple myeloma.

Keywords: Apoptosis; CD47; Hematologic malignancy; Immunotherapy; Leukemic stem cell; Monoclonal antibody; Phagocytosis.

Publication types

Research Support, N.I.H., Extramural
Review

MeSH terms

Animals
Antigens, Differentiation / metabolism*
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Apoptosis
CD47 Antigen / metabolism*
Hematologic Neoplasms / diagnosis
Hematologic Neoplasms / drug therapy
Hematologic Neoplasms / etiology
Hematologic Neoplasms / metabolism*
Humans
Immunotherapy / methods
Molecular Targeted Therapy
Phagocytosis
Receptors, Immunologic / metabolism*
Signal Transduction* / drug effects

Substances

Antigens, Differentiation
Antineoplastic Agents
CD47 Antigen
Receptors, Immunologic
SIRPA protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding