By Pushp Ranjan and Nikhil Srivastava
The efficiency and precision of cancer treatments, which may be surgical removal, radiotherapy, chemotherapy, or a combination of second and third depends upon the stage and type of cancer. Targeting CD47 and Signal inhibitory receptor alpha protein interactions (SIRPα) has evolved as one of several such methods of cancer therapy. Both CD47 and SIRPα belong to the Ig superfamily; CD47 is expressed by most cells, whereas SIRPα is restricted to neurons and myeloid lineage phagocytic cells, including macrophages. Interaction of SIRPα with growth factors, chemokines, or even induction from CD47 residing on the cell membrane of other cells results in phosphorylation at two out of four tyrosine residues at cytoplasmic domain. These phosphorylated regions serve as a docking site for the Src homology domain-containing phosphatases (SHP 1/2) that initiates signaling. This interaction has a roles in cell migration, cell proliferation, and, most notably, macrophage-mediated phagocytosis regulation (Figure 1).
Studies have revealed that tumor cells show overexpression of CD47. It is one of the several tactics of immune evasion. Overexpression of CD47 on surface tumor cells blocks the FcꭚR mediated phagocytosis by macrophage. Even after opsonization by Ab (monoclonal Ab prepared against cancer antigen), tumor cells easily bypass macrophage-mediated phagocytosis through signaling phagocytes through CD47-SIRPα interaction. CD47-SIRPα interaction blocks myosin accumulation and FcꭚR aggregation at phagocytic synapse thus generating “do not eat me” signal which allow tumor cells to escape phagocytosis (Figure 2). Thus, this signaling principle has been exploited to block CD47 through anti-CD47 antibodies, thus making tumor cells more prone to macrophage-mediated phagocytosis.
In 2015, successful attempts to block CD47 using Humanized ab was established. Humanized 5F9 antibody (Hu5F9) mediated blocking of CD47 gave a significant positive result in Acute myeloid leukaemia and solid tumour. Phase1 human trial of Hu5F9 monotherapy (NCT02216409 completed in December 2018) two patients with clear ovarian and fallopian tube carcinoma had confirmed partial response with significant decline in target lesion and cancer antigen, moreover it was well tolerated in patients with solid tumor and lymphoma. Results of phase 1b trial of combinational therapy (ClinicalTrials.gov ,NCT02953509 run for combination of Hu5F9 and rituximab) has suggested a significant improvement in half of patients with refractory and relapsing B cell lymphoma. Chemotherapy alone has not very significant in case of refractory and relapsing lymphomas. Hu5F9 synergistic effect with rituximab appeared to be safe and induce durable response against refractory and relapsing follicular lymphoma. RBC was studied to be best protective shield for tumour. Anti-CD47 antibodies quantity was reported to be depleted even before reaching to tumor cells, which was due to interaction with CD47 residing on RBC surface. This resulted to main toxicity that were anaemia and thrombocytopenia. Both these toxicities were predicted and were reported mild. Several attempts have been made in order to generate more effective and safer anti-CD47 antibody capable of escaping RBC and targeting tumor CD47. TTI-621 product by Trillium’s has been generated with the similar principle. It is fusion of SIRPα protein and Fc part of ab to show weak binding affinity for CD47 of RBC surface. Several such attempts have been made to generate more effective anti-CD47 antibody.
Initial results from several clinical trials have supported anti CD47 ab mediated therapy as significantly effective cancer immunotherapy. Still many trials are being run and next 5 to 10 years might provide us with a whole new insight for cancer therapy in form of anti-CD47 antibodies.
About the authors:
Pushp Ranjan is from the Department of Biological Sciences and Bioengineering, IIT Guwahati, India where he is an M.tech. student and is busy finishing his final year dissertation.
Nikhil Srivastava is a student at the Cytogenetics Laboratory, Department of Zoology, Banaras Hindu University, India.