title: Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma.
abstract: Monoclonal antibodies are standard therapeutics for several cancers including the anti-CD20 antibody rituximab for B cell non-Hodgkin lymphoma (NHL). Rituximab and other antibodies are not curative and must be combined with cytotoxic chemotherapy for clinical benefit. Here we report the eradication of human NHL solely with a monoclonal antibody therapy combining rituximab with a blocking anti-CD47 antibody. We identified increased expression of CD47 on human NHL cells and determined that higher CD47 expression independently predicted adverse clinical outcomes in multiple NHL subtypes. Blocking anti-CD47 antibodies preferentially enabled phagocytosis of NHL cells and synergized with rituximab. Treatment of human NHL-engrafted mice with anti-CD47 antibody reduced lymphoma burden and improved survival, while combination treatment with rituximab led to elimination of lymphoma and cure. These antibodies synergized through a mechanism combining Fc receptor (FcR)-dependent and FcR-independent stimulation of phagocytosis that might be applicable to many other cancers.
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford Cancer Center, and Ludwig Center at Stanford, Stanford University, Palo Alto, CA 94304, USA. mpchao@stanford.edu
authors.forename: Mark P
authors.initials: MP
authors.lastname: Chao
authors.forename: Ash A
authors.initials: AA
authors.lastname: Alizadeh
authors.forename: Chad
authors.initials: C
authors.lastname: Tang
authors.forename: June H
authors.initials: JH
authors.lastname: Myklebust
authors.forename: Bindu
authors.initials: B
authors.lastname: Varghese
authors.forename: Saar
authors.initials: S
authors.lastname: Gill
authors.forename: Max
authors.initials: M
authors.lastname: Jan
authors.forename: Adriel C
authors.initials: AC
authors.lastname: Cha
authors.forename: Charles K
authors.initials: CK
authors.lastname: Chan
authors.forename: Brent T
authors.initials: BT
authors.lastname: Tan
authors.forename: Christopher Y
authors.initials: CY
authors.lastname: Park
authors.forename: Feifei
authors.initials: F
authors.lastname: Zhao
authors.forename: Holbrook E
authors.initials: HE
authors.lastname: Kohrt
authors.forename: Raquel
authors.initials: R
authors.lastname: Malumbres
authors.forename: Javier
authors.initials: J
authors.lastname: Briones
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
authors.forename: Izidore S
authors.initials: IS
authors.lastname: Lossos
authors.forename: Ronald
authors.initials: R
authors.lastname: Levy
authors.forename: Irving L
authors.initials: IL
authors.lastname: Weissman
authors.forename: Ravindra
authors.initials: R
authors.lastname: Majeti
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D001402:B-Lymphocytes / Q000276:immunology; D051928:CD47 Antigen / Q000276:immunology*; D045744:Cell Line, Tumor; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000175:diagnosis / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D010587:Phagocytosis; D011961:Receptors, Fc / Q000276:immunology; D000069283:Rituximab; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D051928:CD47 Antigen; D011961:Receptors, Fc; D000069283:Rituximab
references.citation: Trends Immunol. 2010 Jun;31(6):212-9
references.pmid: 20452821
references.citation: J Pharmacol Exp Ther. 2006 Oct;319(1):1-7
references.pmid: 16670349
references.citation: Oncogene. 2003 Oct 20;22(47):7359-68
references.pmid: 14576843
references.citation: Blood. 2002 Aug 15;100(4):1177-84
references.pmid: 12149195
references.citation: Nat Med. 2002 Jan;8(1):68-74
references.pmid: 11786909
references.citation: Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):14016-21
references.pmid: 19666525
references.citation: Cell. 2009 Jul 23;138(2):286-99
references.pmid: 19632179
references.citation: Cell. 2009 Jul 23;138(2):271-85
references.pmid: 19632178
references.citation: Leuk Lymphoma. 2008 Nov;49(11):2059-80
references.pmid: 19021049
references.citation: Nature. 2000 Feb 3;403(6769):503-11
references.pmid: 10676951
references.citation: N Engl J Med. 2002 Jun 20;346(25):1937-47
references.pmid: 12075054
references.citation: Leuk Res. 2005 Apr;29(4):445-50
references.pmid: 15725479
references.citation: Blood. 2009 Nov 26;114(23):4823-31
references.pmid: 19805616
references.citation: Curr Opin Immunol. 2008 Aug;20(4):444-9
references.pmid: 18585457
references.citation: Blood. 2007 Dec 1;110(12):4037-46
references.pmid: 17724141
references.citation: Br J Haematol. 2001 Sep;114(4):881-3
references.pmid: 11564080
references.citation: Oncol Rep. 2007 May;17(5):1189-94
references.pmid: 17390064
references.citation: Clin Cancer Res. 2007 Aug 1;13(15 Pt 1):4556-64
references.pmid: 17671142
references.citation: Curr Opin Immunol. 2007 Apr;19(2):239-45
references.pmid: 17291742
references.citation: J Immunol. 2005 May 15;174(10):6477-89
references.pmid: 15879151
references.citation: Blood. 2004 Nov 1;104(9):2635-42
references.pmid: 15226177
references.citation: Cancer Cell. 2003 Feb;3(2):185-97
references.pmid: 12620412
references.citation: N Engl J Med. 2008 Jun 19;358(25):2704-15
references.pmid: 18565863
references.citation: Nat Med. 1999 Nov;5(11):1277-84
references.pmid: 10545994
references.citation: Cancer. 2008 Nov 15;113(10):2714-23
references.pmid: 18853418
references.citation: Ann Oncol. 2007 Jul;18(7):1216-23
references.pmid: 17470451
references.citation: J Clin Oncol. 2005 Aug 1;23(22):5044-51
references.pmid: 15955901
references.citation: Blood. 2009 May 14;113(20):4885-93
references.pmid: 19246561
references.citation: Biochem Biophys Res Commun. 2004 Mar 19;315(4):912-8
references.pmid: 14985099
references.citation: Cell. 1994 Feb 11;76(3):519-29
references.pmid: 8313472
references.citation: Tumour Biol. 2008;29(1):28-34
references.pmid: 18497546
references.citation: Nat Biotechnol. 2005 Sep;23(9):1147-57
references.pmid: 16151408
references.citation: Mol Immunol. 2007 Sep;44(16):3823-37
references.pmid: 17768100
references.citation: Blood. 2006 Apr 15;107(8):3407
references.pmid: 16597597
references.citation: Trends Cell Biol. 2001 Mar;11(3):130-5
references.pmid: 11306274
references.citation: N Engl J Med. 2008 Aug 7;359(6):613-26
references.pmid: 18687642
references.citation: N Engl J Med. 1993 Sep 30;329(14):987-94
references.pmid: 8141877
references.citation: J Immunol. 2004 Mar 1;172(5):3280-8
references.pmid: 14978136