Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma.
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.
Chao
Mark P
MP
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
Alizadeh
Ash A
AA
Tang
Chad
C
Myklebust
June H
JH
Varghese
Bindu
B
Gill
Saar
S
Jan
Max
M
Cha
Adriel C
AC
Chan
Charles K
CK
Tan
Brent T
BT
Park
Christopher Y
CY
Zhao
Feifei
F
Kohrt
Holbrook E
HE
Malumbres
Raquel
R
Briones
Javier
J
Gascoyne
Randy D
RD
Lossos
Izidore S
IS
Levy
Ronald
R
Weissman
Irving L
IL
Majeti
Ravindra
R
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
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D051928:CD47 Antigen; D011961:Receptors, Fc; D000069283:Rituximab
Trends Immunol. 2010 Jun;31(6):212-9
20452821
J Pharmacol Exp Ther. 2006 Oct;319(1):1-7
16670349
Oncogene. 2003 Oct 20;22(47):7359-68
14576843
Blood. 2002 Aug 15;100(4):1177-84
12149195
Nat Med. 2002 Jan;8(1):68-74
11786909
Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):14016-21
19666525
Cell. 2009 Jul 23;138(2):286-99
19632179
Cell. 2009 Jul 23;138(2):271-85
19632178
Leuk Lymphoma. 2008 Nov;49(11):2059-80
19021049
Nature. 2000 Feb 3;403(6769):503-11
10676951
N Engl J Med. 2002 Jun 20;346(25):1937-47
12075054
Leuk Res. 2005 Apr;29(4):445-50
15725479
Blood. 2009 Nov 26;114(23):4823-31
19805616
Curr Opin Immunol. 2008 Aug;20(4):444-9
18585457
Blood. 2007 Dec 1;110(12):4037-46
17724141
Br J Haematol. 2001 Sep;114(4):881-3
11564080
Oncol Rep. 2007 May;17(5):1189-94
17390064
Clin Cancer Res. 2007 Aug 1;13(15 Pt 1):4556-64
17671142
Curr Opin Immunol. 2007 Apr;19(2):239-45
17291742
J Immunol. 2005 May 15;174(10):6477-89
15879151
Blood. 2004 Nov 1;104(9):2635-42
15226177
Cancer Cell. 2003 Feb;3(2):185-97
12620412
N Engl J Med. 2008 Jun 19;358(25):2704-15
18565863
Nat Med. 1999 Nov;5(11):1277-84
10545994
Cancer. 2008 Nov 15;113(10):2714-23
18853418
Ann Oncol. 2007 Jul;18(7):1216-23
17470451
J Clin Oncol. 2005 Aug 1;23(22):5044-51
15955901
Blood. 2009 May 14;113(20):4885-93
19246561
Biochem Biophys Res Commun. 2004 Mar 19;315(4):912-8
14985099
Cell. 1994 Feb 11;76(3):519-29
8313472
Tumour Biol. 2008;29(1):28-34
18497546
Nat Biotechnol. 2005 Sep;23(9):1147-57
16151408
Mol Immunol. 2007 Sep;44(16):3823-37
17768100
Blood. 2006 Apr 15;107(8):3407
16597597
Trends Cell Biol. 2001 Mar;11(3):130-5
11306274
N Engl J Med. 2008 Aug 7;359(6):613-26
18687642
N Engl J Med. 1993 Sep 30;329(14):987-94
8141877
J Immunol. 2004 Mar 1;172(5):3280-8
14978136