CD47 is a transmembrane protein that regulates a wide range of physiological and pathological functions in the body. CD47 expressed on tumor cells interacts with signal-regulated protein alpha (SIRP) on macrophages to prevent tumor phagocytosis, and research into the CD47-SIRP pathway suggests that CD47 could be a potential therapeutic target. CD47 antibody drugs have been shown to have considerable anti-tumor effects in various preclinical studies and clinical trials done in recent years. Immunotherapy for lymphoma is quickly evolving, and CD47 has garnered a lot of attention as a factor in lymphoma immunotherapy exploration.
The structure and expression of CD47
CD47 has a molecular weight of 50 kDa and belongs to the immunoglobulin family. It has a single IgV-like structural domain at the N terminus, a transmembrane structural domain made up of five hydrophobic transmembrane segments, and a 3- to 36-amino-acid-long cytoplasmic tail region at the C terminus. Campbell et al. discovered CD47 on ovarian cancer cells in 1992, which was previously thought to be an OA3 antigen. Oldenborg et al. revealed in 2000 that CD47 can work as an autologous erythrocyte marker, preventing macrophages from phagocytosing erythrocytes.
CD47 is expressed on red blood cells and platelets, among other normal cells and tissues in the body. Willingham et al. discovered that CD47 was overexpressed on solid tumor cells in 2012, with expression much greater than normal in ovarian cancer, breast cancer, colon cancer, bladder cancer, glioblastoma, hepatocellular carcinoma, and prostate tumor cells. CD47 has a stronger link to hematological malignancies. In acute myeloid leukemia, non-Hodgkin's lymphoma and acute lymphoblastic leukemia, elevated expression of CD47 has been found, indicating a poor response to treatment.
CD47-SIRPα pathway
SIRP has an N-terminal V-region structural domain and two C1-type structural domains. Unlike CD47, which is expressed on a wide range of cells, SIRP is mostly prevalent in bone marrow cells, including monocytes, macrophages, granulocytes, and dendritic cells, as well as neuronal cells. Macrophages phagocytoze erythrocytes that lack CD47 on their surfaces. The immune escape mechanism for tumors is the direct binding of CD47 on the surface of tumor cells to SIRP on macrophages. CD47-SIRP provides "don't eat me" signals to phagocytes (macrophages and dendritic cells), allowing them to avoid phagocytosis. Majeti et al. demonstrated in 2009 that CD47 monoclonal antibodies (mAbs) can induce anti-tumor responses in T cells by cross-presenting cancer antigens to macrophages, and Tseng et al. indicated in 2013 that CD47 mAbs can also induce anti-tumor responses in T cells by cross-presenting cancer antigens to macrophages.
Antibody drugs targeting CD47
CD47 mAb
CD47 monoclonal antibody can induce macrophages to recognize and engulf tumor cells by blocking CD47 and its ligand SIRPα.
In a trial, Chao et al. found that in diffuse large B-cell lymphoma xenografts, a regimen of CD47 mAb B6H12.2 in combination with rituximab cured 89% of mice. A regimen combining CD47 mAb B6H12.2 and rituximab completely eradicated lymphoma cells from the peripheral blood and bone marrow of mice xenografted with follicular lymphoma, while none of the controls did.
In 2015, Liu et al. found that the combination of Hu5F9-G4, a humanized CD47 mAb, with rituximab cured 75% of mice infected with non-Hodgkin's lymphoma, whereas in the control group, treatment regimens with rituximab or Hu5F9-G4 alone only prolonged the survival of mice and did not cure them. In experiments in non-human primates (NHPs), no serious adverse effects of Hu5F9-G4 were observed, and the experimental group developed temporary anemia that was corrected by compensatory red blood cell regeneration.
Hu5F9-G4 was examined in human clinical trials for the first time in 2018. In phase I clinical trial, a total of 22 patients with refractory/relapsed non-Hodgkin's lymphoma, 15 with diffuse large B-cell lymphoma, and 7 with follicular lymphoma were resistant to rituximab in approximately 95% of patients. Those 22 patients were treated with Hu5F9-G4 in combination with rituximab, and good therapeutic results were achieved.
