SIRPα-Fc fusion protein
TTI-621, the SIRP-Fc fusion protein, is an immune checkpoint inhibitor that targets CD47. TTI-621 improves CD47 blockage through attaching to the macrophage Fc receptor (FcR), as well as macrophage phagocytosis of tumor cells. In mice xenografted with B-cell lymphoma, TTI-621 efficiently reduces tumor growth with superior efficiency than rituximab alone. Anemia, thrombocytopenia, and lymphopenia were the most common TTI-621 side effects in the experimental group. TTI-621 has only minor binding to human erythrocytes, according to flow cytometry studies, which is a highlight of immunotherapy against B-cell lymphoma. However, the thrombocytopenia and lymphocytopenia observed in the experimental group with TTI-621 might have more serious consequences. Rare complications such as intracranial hemorrhage may occur with too low platelets, and too few lymphocytes may affect immune function, which requires further study.
Bispecific antibody (bsAb)
Piccione et al. found that CD20-CD47 SL, a bispecific antibody against CD47 and CD20 (encoded by the MS4A1 gene), selectively bound to B-cell chronic lymphocytic leukemia tumor cells expressing the dual antigen and bound less to red blood cells compared to controls. In experiments in mice transplanted with human non-Hodgkin's lymphoma, the CD20-CD47 SL treatment group significantly reduced tumor load and significantly prolonged survival compared with the CD47 antibody treatment group alone and the rituximab treatment group alone.
The bispecific antibody NI-1701 against CD47 and CD19 binds selectively to B cells in whole blood and less to T cells and platelets, while the CD47 mAb binds to B cells, T cells, and platelets. In a mouse xenograft model implanted with Raji cells, the anti-tumor effect of NI-1701 was significantly better than that of the control group using CD47 antibody alone and CD19 antibody alone, and the mice survived longer. In NHP studies, NI-1701 had good pharmacokinetic and safety profiles, with no severe side effects such as anemia or thrombocytopenia. In an in vitro assay of 13 different types of non-Hodgkin's lymphoma tumor cell samples, NI-1701 mediated enhanced phagocytosis of macrophages, eliminated tumor load, and made B cells more amenable to phagocytosis and elimination, thus providing an alternative or adjuvant treatment option for patients resistant to CD20 antibody-targeted therapy.
The mechanism of action between CD47 and tumors has been better understood as a result of the growing number of CD47-related studies, and the existing evidence suggests that CD47 is intimately linked to immune escape in lymphoma. The CD47-SIRP pathway plays an immune escape role in most tumors, but in T-cell lymphoma, the interaction of CD47 with TSP-1 promotes tumor development, which is a novel study of CD47 interaction with non-SIRPα receptors.
CD47 is overexpressed on the membrane of various lymphoma cells, and inhibition of it could help to address many therapeutic challenges in lymphoma. Immunotherapies targeting CD47 are undergoing clinical trials with multiple drugs. bsAbs are an important area of research. CD47 is also abundantly expressed on healthy human cells, making patients more susceptible to negative reactions.
The following are some of the topics that may require further investigation in the future:
(1) Which types of tumors are suited for this immunotherapy, and at what stage of the tumor.
(2) Whether combining this medicine with other drugs can provide greater benefits to patients.
(3) How to prevent side effects such as anemia and thrombocytopenia in clinical studies.
CD47-related lymphoma immunotherapy, in general, has a promising future, and a game-changing anti-tumor drug is hopeful to emerge in no time.
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