Pharmacokinetics and Systems Pharmacology of Anti-CD47 Macrophage Immune Checkpoint Inhibitor Hu5F9-G4

Abstract

Background: Hu5F9-G4, a human immunoglobulin G4 (IgG4) monoclonal antibody (mAb) has recently been granted fast-track designation by the FDA for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. Hu5F9-G4 has the ability to block CD47-SIRPα signaling along with anti- EGFR and anti-PD-L1 immune checkpoint activity that is involved in a variety of cancers like solid tumors, Non-Hodgkin’s Lymphoma (NHL), colorectal cancer (CRC), breast, ovarian and bladder cancers, and hematological malignancies. Thus, Hu5F9-G4 is an important biologic that has increasing clinical relevance in cancer care. Methods: We queried PubMed, Web of Science, Google Scholar, Science Direct and Scopus databases with keywords pertaining to Hu5F9-G4. In addition, we have included the Hu5F9-G4 data presented at the 60th American Society of Hematology (ASH) Annual Meeting, the American Society of Clinical Oncology (ASCO) Annual Meeting and 23rd Congress of the European Hematology Association (EHA). Results: We discuss the mechanistic basis and preclinical evidence for the anticancer activity of Hu5F9-G4. Further, we delineate clinical studies, alone and in combination with anti-CD20 mAb rituximab, anti-EGFR mAb cetuximab, PD-L1 checkpoint inhibitors avelumab and atezolizumab, and anti-HER2 mAb trastuzumab. Moreover, the potential adverse effects, pharmacokinetics, and pharmacodynamics of Hu5F9-G4 with emphasis on the role of CD47-SIRPα signaling in phagocytosis are presented. Conclusions: Taken together, we review the pharmacokinetics and systems pharmacology of Hu5F9-G4 which appears to hold great promise for the future of cancer care.