Generic placeholder image

Current Pharmacogenomics and Personalized Medicine


ISSN (Print): 1875-6921
ISSN (Online): 1875-6913

Review Article

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

Author(s): Adarsh Mishra, Ishant Kataria and Sujit Nair*

Volume 17 , Issue 1 , 2020

Page: [14 - 24] Pages: 11

DOI: 10.2174/1875692117666190820105134


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.

Conclusion: Taken together, we review the pharmacokinetics and systems pharmacology of Hu5F9-G4 which appears to hold great promise for the future of cancer care.

Keywords: Hu5F9-G4, cancer, immunotherapy, CD47-SIRPα signalling, phagocytosis, biologic.

Graphical Abstract
Wong RS. Apoptosis in cancer: From pathogenesis to treatment. J Exp Clin Cancer Res 2011; 30: 87.
[] [PMID: 21943236]
Verhoef J. Phagocytosis in encyclopedia of immunology. 2nd ed. London: Elsevier 1998.
Arandjelovic S, Ravichandran KS. Phagocytosis of apoptotic cells in homeostasis. Nat Immunol 2015; 16(9): 907-17.
[] [PMID: 26287597]
Varol C, Mildner A, Jung S. Macrophages: development and tissue specialization. Annu Rev Immunol 2015; 33: 643-75.
[] [PMID: 25861979]
Dorrington KJ. Properties of the Fc receptor on macrophages. Immunol Commun 1976; 5(4): 263-80.
[] [PMID: 786861]
National Institutes of Health Fc-dependent mechanisms of antibody-mediated killing Available from:. https:// grantsnihgov/ grants/guide/pa-files/PA-19-020.
Siveen KS, Kuttan G. Role of macrophages in tumour progression. Immunol Lett 2009; 123(2): 97-102.
[] [PMID: 19428556]
Bashyam H. Retraining macrophages to kill tumors. J Exp Med 2008; 6: 1247-57.
Brown E, Hooper L, Ho T, Gresham H. Integrin-associated protein: a 50-kD plasma membrane antigen physically and functionally associated with integrins. J Cell Biol 1990; 111(6 Pt 1): 2785-94.
[] [PMID: 2277087]
Matozaki T, Murata Y, Okazawa H, Ohnishi H. Functions and molecular mechanisms of the CD47-SIRPalpha signalling pathway. Trends Cell Biol 2009; 19(2): 72-80.
[] [PMID: 19144521]
Xiang YR. “Eating” Cancer cells by blocking CD47 signaling: Cancer therapy by targeting the innate immune checkpoints. Cancer Transl Med 2017; 3: 6.
Vernon-Wilson EF, Kee WJ, Willis AC, Barclay AN, Simmons DL, Brown MH. CD47 is a ligand for rat macrophage membrane signal regulatory protein SIRP (OX41) and human SIRPalpha 1. Eur J Immunol 2000; 30(8): 2130-7.
[<2130:AID-IMMU2130>3.0.CO;2-8] [PMID: 10940903]
Saginario C, Sterling H, Beckers C, et al. MFR, a putative receptor mediating the fusion of macrophages. Mol Cell Biol 1998; 18(11): 6213-23.
[] [PMID: 9774638]
Seiffert M, Brossart P, Cant C, et al. Signal-regulatory protein alpha (SIRPalpha) but not SIRPbeta is involved in T-cell activation, binds to CD47 with high affinity, and is expressed on immature CD34(+)CD38(-) hematopoietic cells. Blood 2001; 97(9): 2741-9.
[] [PMID: 11313266]
Fukunaga A, Nagai H, Noguchi T, et al. Src homology 2 domain-containing protein tyrosine phosphatase substrate 1 regulates the migration of Langerhans cells from the epidermis to draining lymph nodes. J Immunol 2004; 172(7): 4091-9.
de Vries HE, Hendriks JJ, Honing H, et al. Signalregulatory protein alpha-CD47 interactions are required for the transmigration of monocytes across cerebral endothelium. J Immunol (Baltimore, Md : 1950) 2002; 168(11): 5832-9.
Liu Y, Bühring HJ, Zen K, et al. Signal regulatory protein (SIRPalpha), a cellular ligand for CD47, regulates neutrophil transmigration. J Biol Chem 2002; 277(12): 10028-36.
[] [PMID: 11792697]
Bouguermouh S, Van VQ, Martel J, Gautier P, Rubio M, Sarfati M. CD47 expression on T cell is a self-control negative regulator of type 1 immune response. J Immunol (Baltimore, Md:1950) 2008; 180(12): 8073-2.
National cancer institute. Anti-CD47 monoclonal antibody Hu5F9-G4. Available from:. https://wwwcancergov/ publications/ dictionaries/cancer-drug/def/anti-cd47-monoclonalantibody- hu5f9-g4.
Forty Seven Inc. Why CD47 matters. Available from:. https://wwwfortyseveninccom/science.
Advani R, Flinn I, Popplewell L, et al. CD47 Blockade by Hu5F9-G4 and Rituximab in Non-Hodgkin’s Lymphoma. N Engl J Med 2018; 379(18): 1711-21.
[] [PMID: 30380386]
US national library of medicine. Trial of Hu5F9-G4 in combination with cetuximab in patients with solid tumors and advanced colorectal cancer. Available from:. https://clinicaltrialsgov/ct2/show/NCT02953782?term=Hu5 F9-G4+and+cetuximab&rank=1.
Forty seven Inc. Combination treatment with 5F9 and Azacitidine enhances phagocytic elimination of acute myeloid leukemia. Available From:. https://www. fortyseveninccom/ application/files/6115/4388/0741/ASH_2018_-_Forty_ Seven_AZA_5F9_Combo_Poster_FINALpdf.
Kinchen JM, Ravichandran KS. Phagocytic signaling: you can touch, but you can’t eat. Curr Biol 2008; 18(12): R521-4.
[] [PMID: 18579095]
Rosales C, Uribe-Querol E. Phagocytosis: A fundamental process in immunity. BioMed Res Int 2017; 2017 9042851
[] [PMID: 28691037]
Oldenborg PA, Zheleznyak A, Fang YF, Lagenaur CF, Gresham HD, Lindberg FP. Role of CD47 as a marker of self on red blood cells. Science 2000; 288(5473): 2051-4.
[] [PMID: 10856220]
Bian Z, Shi L, Guo YL, et al. Cd47-Sirpα interaction and IL-10 constrain inflammation-induced macrophage phagocytosis of healthy self-cells. Proc Natl Acad Sci USA 2016; 113(37): E5434-43.
[] [PMID: 27578867]
Barclay AN, Van den Berg TK. The interaction between signal regulatory protein alpha (SIRPα) and CD47: structure, function, and therapeutic target. Annu Rev Immunol 2014; 32: 25-50.
[] [PMID: 24215318]
Matlung HL, Szilagyi K, Barclay NA, van den Berg TK. The CD47-SIRPα signaling axis as an innate immune checkpoint in cancer. Immunol Rev 2017; 276(1): 145-64.
[] [PMID: 28258703]
Tsai RK, Rodriguez PL, Discher DE. Self inhibition of phagocytosis: the affinity of ‘marker of self’ CD47 for SIRPalpha dictates potency of inhibition but only at low expression levels. Blood Cells Mol Dis 2010; 45(1): 67-74.
[] [PMID: 20299253]
Stanford medicine. Anti-CD47 cancer therapy safe, shows promise in small clinical trial. Available From:. https://medstanfordedu/news/all-news/2018/10/anti-cd47- cancer-therapy-safe-shows-promise-in-small-trial.
Creative biolabs. CD47. Available From:. https://www. creative-biolabscom/car-t/target-cd47-24.
Oldenborg PA. CD47: A cell surface glycoprotein which regulates multiple functions of hematopoietic cells in health and disease. ISRN Hematol 2013; 2013 614619
[] [PMID: 23401787]
Xiang YRLL. “Eating” cancer cells by blocking CD47 signaling: Cancer therapy by targeting the innate immune checkpoint. Cancer Transl Med 2017; 3(6): 200-8.
Takahashi S. Molecular functions of SIRPα and its role in cancer. Biomed Rep 2018; 9(1): 3-7.
[] [PMID: 29930800]
Russ A, Hua AB, Montfort WR, et al. Blocking “don’t eat me” signal of CD47-SIRPα in hematological malignancies, an in-depth review. Blood Rev 2018; 32(6): 480-9.
[] [PMID: 29709247]
Feng D, Gip P, McKenna KM, et al. Combination treatment with 5F9 and Azacitidine enhances phagocytic elimination of acute myeloid leukemia. Blood 2018; 132: 2729. [DOI: 10.1182/blood-2018-99-120170].
Hatherley D, Harlos K, Dunlop DC, Stuart DI, Barclay AN. The structure of the macrophage signal regulatory protein alpha (SIRPalpha) inhibitory receptor reveals a binding face reminiscent of that used by T cell receptors. J Biol Chem 2007; 282(19): 14567-75.
[] [PMID: 17369261]
Fujioka Y, Matozaki T, Noguchi T, et al. A novel membrane glycoprotein, SHPS-1, that binds the SH2-domain-containing protein tyrosine phosphatase SHP-2 in response to mitogens and cell adhesion. Mol Cell Biol 1996.
Barrera L, Servín E, Hernandez-Martinez JM, et al. Levels of peripheral blood polymorphonuclear myeloid-derived suppressor cells and selected cytokines are potentially prognostic of disease progression for patients with non-small cell lung cancer. Cancer Immunol Immunother 2018; 67: 1393-406.
Lee WY, Weber DA, Laur O, et al. The role of cis dimerization of signal regulatory protein alpha (SIRPalpha) in binding to CD47. J Biol Chem 2010; 285(49): 37953-63.
[] [PMID: 20826801]
Liu J, Wang L, Zhao F, et al. Pre-clinical development of a humanized anti-CD47 antibody with anti-cancer therapeutic potential. PLoS One 2015; 10(9) e0137345
[] [PMID: 26390038]
Chao MP, Jaiswal S, Weissman-Tsukamoto R, et al. Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47. Sci Transl Med 2010; 2(63) 63ra94
[] [PMID: 21178137]
Weiskopf K, Jahchan NS, Schnorr PJ, et al. CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer. J Clin Invest 2016; 126(7): 2610-20.
[] [PMID: 27294525]
Liu X, Pu Y, Cron K, et al. CD47 blockade triggers T cell-mediated destruction of immunogenic tumors. Nat Med 2015; 21(10): 1209-15.
[] [PMID: 26322579]
Forty Seven Inc. Planned trials: 5F9 combinations with checkpoint inhibitors. Available From:. https://irforty seveninccom/static-files/10304fc3-c692-4e02-995e- 2d9eecbec022.
Takeda K, Nakayama M, Hayakawa Y, et al. IFN-γ is required for cytotoxic T cell-dependent cancer genome immunoediting. Nat Commun 2017; 8: 14607.
[] [PMID: 28233863]
Liu X, Kwon H, Li Z, Fu YX. Is CD47 an innate immune checkpoint for tumor evasion? J Hematol Oncol 2017; 10(1): 12.
[] [PMID: 28077173]
Gholamin S, Mitra SS, Feroze AH, et al. Disrupting the CD47-SIRPα anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors. Sci Transl Med 2017; 9(381) pii:eaaf2968
Krampitz GW, George BM, Willingham SB, et al. Identification of tumorigenic cells and therapeutic targets in pancreatic neuroendocrine tumors. Proc Natl Acad Sci USA 2016; 113(16): 4464-9.
[] [PMID: 27035983]
Nagy A, Neubauer A. Acute myeloid leukemia with myelodysplasia related changes. Atlas Genet Cytogenet Oncol Haematol 2017; 21(11): 404-8.
Forty Seven Inc. Importance of 5F9 in a multipronged approach to treating cancer. Available From:. https:// irfortyseveninccom/ node/6646/html.
Moynihan TJ. HER2-positive breast cancer: What is it? Mayo Clinic. Available From:. breast-cancer/expert-answers/faq-20058066.
Vu T, Claret FX. Trastuzumab: updated mechanisms of action and resistance in breast cancer. Front Oncol 2012; 2: 62.
[] [PMID: 22720269]
Hudis CA. Trastuzumab--mechanism of action and use in clinical practice. N Engl J Med 2007; 357(1): 39-51.
[] [PMID: 17611206]
Agoram B, Wang B, Sikic IB. Pharmacokinetics of Hu5F9-G4, a first-in-class anti-CD47 antibody, in patients with solid tumors and lymphomas. American Society of Clinical Oncology. J Clin Oncol 2018; 36(15): 2525-5.
Sikic B, Lakhani NJ, Patnaik A, et al. A first-in-class, first-in-human phase 1 pharmacokinetic (PK) and pharmacodynamic (PD) study of Hu5F9-G4, an anti-CD47 monoclonal antibody (mAb), in patients with advanced solid tumors. J Clin Oncol 2018; 36(15): 3002-2.
US national library of medicine. Phase 1 trial of Hu5F9-G4, a CD47-targeting antibody. Available From:. https:// clinicaltrialsgov/ ct2/show/NCT02216409.
Vyas P, Knapper S, Kelly R. Initial phase 1 results of the first-in-class anti-cd47 antibody hu5f9-g4 in relapsed/ refractory acute myeloid leukemia patients. Hemasphere. Available From:. eha/ 2018/stockholm/214718/paresh.vyas.initial.phase.1.results. of.the.first-in-class.anti-cd47.antibody.html.
Klepin HD. Myelodysplastic syndromes and acute myeloid leukemia in the elderly. Clin Geriatr Med 2016; 32(1): 155-73.
[] [PMID: 26614866]
Chao MP, Alizadeh AA, Tang C, et al. Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell 2010; 142(5): 699-713.
[] [PMID: 20813259]
Piccione EC, Juarez S, Liu J, et al. A bispecific antibody targeting CD47 and CD20 selectively binds and eliminates dual antigen expressing lymphoma cells. MAbs 2015; 7(5): 946-56.
[] [PMID: 26083076]
Li S, Schmitz KR, Jeffrey PD, Wiltzius JJ, Kussie P, Ferguson KM. Structural basis for inhibition of the epidermal growth factor receptor by cetuximab. Cancer Cell 2005; 7(4): 301-11.
[] [PMID: 15837620]
US National Library of Medicine. A trial of Hu5F9-G4 with avelumab in ovarian cancer. Available From:. https:// clinicaltrialsgov/ ct2/show/ NCT03558139?term=Hu5F9-G4+ and+avelumab &cond=ovarian+ cancer&rank=1.
[65] A study evaluating the safety and pharmacokinetics of atezolizumab administered in combination with Hu5F9-G4 to patients with relapsed and/or refractory acute myeloid leukemia. Available From:. https:// clinicaltrials. gov/ct2/show/NCT03922477?term=5F9&rank=2.
Forty seven Inc. Granted fast track designation for 5F9 for the treatment of diffuse large B-Cell lymphoma and Follicular lymphoma. Available From. https://www. biospacecom/ article/releases/ forty-seven-inc-granted-fasttrack- designation-for-5f9-for-the-treatment-of-diffuselarge- b-cell-lymphoma-and-follicular-lymphoma.
[67] Trial of Hu5F9-G4 in combination with cetuximab in patients with solid tumors and advanced colorectal cancer. Available From:. show/NCT02953782?term=5F9&rank=3.

© 2022 Bentham Science Publishers | Privacy Policy