The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors

Abstract

CD47, a "don't eat me" signal for phagocytic cells, is expressed on the surface of all human solid tumor cells. Analysis of patient tumor and matched adjacent normal (nontumor) tissue revealed that CD47 is overexpressed on cancer cells. CD47 mRNA expression levels correlated with a decreased probability of survival for multiple types of cancer. CD47 is a ligand for SIRPα, a protein expressed on macrophages and dendritic cells. In vitro, blockade of CD47 signaling using targeted monoclonal antibodies enabled macrophage phagocytosis of tumor cells that were otherwise protected. Administration of anti-CD47 antibodies inhibited tumor growth in orthotopic immunodeficient mouse xenotransplantation models established with patient tumor cells and increased the survival of the mice over time. Anti-CD47 antibody therapy initiated on larger tumors inhibited tumor growth and prevented or treated metastasis, but initiation of the therapy on smaller tumors was potentially curative. The safety and efficacy of targeting CD47 was further tested and validated in immune competent hosts using an orthotopic mouse breast cancer model. These results suggest all human solid tumor cells require CD47 expression to suppress phagocytic innate immune surveillance and elimination. These data, taken together with similar findings with other human neoplasms, show that CD47 is a commonly expressed molecule on all cancers, its function to block phagocytosis is known, and blockade of its function leads to tumor cell phagocytosis and elimination. CD47 is therefore a validated target for cancer therapies.

Extracellular vesicles as a platform for membrane‐associated therapeutic protein delivery

“…For example, Koh et al developed exosomes harbouring signal-regulatory protein alpha (SIRPα), and found that they exhibited augmented antagonizing activity against CD47–SIRPα interactions [121]. Emerging data suggest that the binding of tumour cell-surface CD47 to SIRPα on phagocytic cells can inhibit their phagocytic function [122]. Because CD47 is expressed on most cancer cell types, it represents a potentially tractable and widely applicable target for therapeutic blockade in cancer patients.…”

Anti-CD47 antibodies promote phagocytosis and inhibit the growth of human myeloma cells

“…For in vivo bioluminescence imaging, RPMI 8226 cells were transduced with pCDH-CMV-MCSEF1-puro HIV-based lentiviral vector (Systems Biosciences, Mountain View, CA, USA) encoding eGFP and luciferase as described previously. 16 All human myeloma cell lines were cultured in RPMI 1640 medium (Invitrogen, Carlsbad, CA, USA) supplemented with 10% fetal bovine serum (FBS), Pen/ Strep (Invitrogen), GlutaMax (Invitrogen), sodium pyruvate (Invitrogen), non-essential amino acids (Invitrogen) and b-mercaptoethanol (Sigma, St Louis, MO, USA).…”

“…16 Mice were imaged 18 min after luciferin injection and total flux (photons/second) values were calculated within a region of interest corresponding to the anatomic region of tumor engraftment when peak radiance was achieved. Mice exhibiting comparable total flux values were then randomized into treatment groups and imaged weekly.…”

“…Anti-CD47 monoclonal antibodies inhibiting the interaction of CD47 and SIRPa promote the phagocytosis of tumor cells by macrophages, and also by monocytes and neutrophils. [9][10][11] Cancer cells including acute myelogenous leukemias, 11,12 lymphomas, 13,14 and various solid cancers [15][16][17] express CD47 at a high level, and can be phagocytosed by macrophages in the presence of blocking antibodies to CD47. [11][12][13][14][15][16][17] In those cases where the tumor-initiating cells (or cancer stem cells) are known, for example, from acute myelogenous leukemias and bladder cancers, the tumor-initiating cells also upregulate CD47 expression, possibly to avoid phagocytosis.…”

“…12,15,16 Blocking the CD47-SIRPa interaction with anti-CD47 monoclonal antibodies has proven effective in inducing the phagocytosis of tumor cells in vitro and inhibiting the growth of the various hematological and solid tumors in vivo. 12,13,15,16 A previous microarray analysis indicated that CD47 is among the highly expressed genes by malignant myeloma cells compared with healthy plasma cells. 18 Here, we examined the expression of CD47 on the surface of patient myeloma cells, the therapeutic potential of an anti-CD47 monoclonal antibody (B6H12) in vitro and in xenotransplantation models.…”