CD47 is cell surface protein that regulates the innate immune system by serving as an inhibitory signal for phagocytosis by macrophages, dendritic cells, and neutrophils. We originally identified increased expression of CD47 on AML stem cells, and subsequently identified high expression on many solid tumors including carcinomas, lymphomas, sarcomas, melanomas, and central nervous system tumors. These observations suggested that CD47 inhibits the phagocytosis of cancer cells resulting in immune evasion. Building on this hypothesis, we demonstrated that blocking monoclonal antibodies directed against CD47 enabled the phagocytosis and elimination of AML stem cells and solid tumor cells in mouse pre-clinical models, while having no effect on normal cells and tissues.
On the basis of these studies, together with Irv Weissman, we embarked on a program to develop a humanized anti-CD47 antibody, and with funding from the California Institute for Regenerative Medicine (CIRM) conducted the full pre-clinical development of our own clinical therapeutic including manufacturing, pharmacology, toxicology, clinical protocol design, and regulatory strategy. In summer 2014, we successfully filed an IND with FDA and opened our phase 1 clinical trial in the Stanford Cancer Institute. In fall 2015, we successfully filed an IMPD with MHRA in the UK and opened a second phase 1 clinical trial in the UK. In spring 2016, the CD47 program was licensed to a newly formed biotech company, Forty Seven Inc., who are continuing the clinical development in multiple cancer indications.
Model for CD47 Regulation of Cancer Cell Phagocytosis
(Left) Cancer cells express increased levels of CD47 that contribute to pathogenesis by binding phagocyte/macrophage SIRP, which delivers a potent inhibitory “don’t eat me” signal that predominates over a pro-phagocytic “eat me” stimulus. Normal cells express low levels of CD47, but do not exhibit pro-phagocytic stimuli. (Right) A blocking monoclonal antibody directed against CD47 disrupts the dominant inhibitory SIRP signal in phagocytes, which unmasks the pro-phagocytic stimulus on cancer cells resulting in their phagocytic elimination. Normal cells lack pro-phagocytic stimuli, and thus are unaffected by the blocking anti-CD47 antibody.
Selected CD47 Publications
- Piccione EC, Juarez S, Tseng S, Liu J, Stafford M, Narayanan C, Wang L, Weiskopf K, and Majeti R. SIRP-a antibody fusion proteins selectively bind and eliminate dual antigen-expressing tumor cells. Clinical Cancer Research, epub (2016)
- Liu J, Wang L, Zhao F, Tseng S, Narayanan C, Shura L, Willingham S, Howard M, Prohaska S, Volkmer J, Chao M, Weissman IL*, and Majeti R*. Pre-clinical development of a humanized anti-CD47 antibody with anti-cancer therapeutic potential. PLoS One, 10: e0137345 (2015)
- Piccione EC, Juarez S, Liu J, Tseng S, Ryan C, Narayanan C, Wang L, Weiskopf K, and Majeti R. A bispecific antibody targeting CD47 and CD20 selectively binds and eliminates dual antigen expressing lymphoma cells. MAbs, 7: 946-956 (2015)
- Willingham SB, Volkmer JP, Gentles AJ, Sahoo D, Dalerba P, Mitra SS, Wang J, Contreras-Trujillo H, Martin R, Cohen JD, Lovelace P, Scheeren FA, Chao MP, Weiskopf K, Tang C, Volkmer AK, Naik TJ, Storm TA, Mosley AR, Edris B, Schmid SM, Sun CK, Chua MS, Murillo O, Rajendran P, Cha AC, Chin RK, Kim D, Adorno M, Raveh T, Tseng D, Jaiswal S, Enger PO, Steinberg GK, Li G, So SK, Majeti R, Harsh GR van de Rijn M, Teng NN, Sunwoo JB, Alizadeh AA, Clarke MF, and Weissman IL. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. P.N.A.S., 109: 6662-6667 (2012)
- Chao MP, Jaiswal S, Weissman-Tsukamoto R, Alizadeh AA, Gentles AJ, Volkmer J, Weiskopf K, Willingham SB, Raveh T, Park CY, Majeti R*, and Weissman IL*. Calreticulin Is the Dominant Pro-Phagocytic Signal on Multiple Human Cancers and Is Counterbalanced by CD47. Sci Transl Med, 2: 63ra94 (2010)
- Chao MP, Alizadeh AA, Tang C, Myklebust JH, Varghese B, Gill S, Jan M, Cha AC, Chan CK, Tan BT, Park CY, Zhao F, Kohrt HE, Malumbres R, Briones J, Gascoyne RD, Lossos IS, Levy R, Weissman IL*, and Majeti R*. Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin Lymphoma. Cell, 142: 699-713 (2010)
- Majeti R*, Chao MP*, Alizadeh AA, Pang WW, Jaiswal S, Gibbs KD, van Rooijen N, and Weissman IL. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell, 138: 286-299 (2009)
- Jaiswal S, Jamieson CHM, Pang WW, Park, CY, Chao MP, Majeti R, Traver D, van Rooijen N, and Weissman IL. CD47 is up-regulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell, 138: 271-285 (2009)