Anti-cd47 Drugs: Targeting Thecd47-sirpα Axis In Cancer Immunotherapy

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CD47 is a transmembrane protein that is expressed on almost all cell types. It functions as a "don't eat me" signal to macrophages and dendritic cells by binding to the signal-regulatory protein alpha (SIRPα) receptor on these immune cells. This interaction delivers an inhibitory "self" signal that prevents phagocytosis of normal healthy cells. However, many cancer cells also overexpress CD47 as a means to evade detection and elimination by the immune system. By hijacking this "self" signal, tumors are able to disguise themselves and avoid phagocytosis. Blocking the CD47-SIRPα interaction removes this cloak of invisibility and allows macrophages to once again recognize and eliminate cancer cells. As a result, inhibiting CD47 has emerged as a promising strategy for cancer immunotherapy.

Mechanism Of Action Of Anti-CD47 Drugs

Antibody-drug work by blocking the interaction between Anti-CD47 Drugs on cancer cells and SIRPα on macrophages and dendritic cells. This prevents the transmission of the "don't eat me" signal, thereby converting the tumor cells into targets that can be phagocytosed. Some key ...
... aspects of their mechanism include:

- Binding of the anti-CD47 antibody to CD47 competitively inhibits its natural binding to SIRPα. This disables the inhibitory signal and allows the immune cells to recognize the cancer cells as "foreign".

- Without the CD47 shield, macrophages and dendritic cells are free to engage their recognition receptors like FcγR and TLR4 that identify cancer cell markers.

- Upon binding to cancer cells, these immune cells initiate phagocytosis through actin cytoskeleton rearrangement and cellular engulfment.

- The ingested cancer material is then processed and tumor antigens are presented on MHC molecules. This stimulates an adaptive anti-tumor immune response.

- Antibody-drug may also induce direct killing of cancer cells through antibody-dependent cellular phagocytosis or complement-dependent cytotoxicity.

Clinical Development Of Leading Anti-CD47 Candidates

Several antibody-drug have already entered clinical trials, demonstrating promising efficacy with acceptable safety profiles:

- Magrolimab (Hu5F9-G4, Five Prime Therapeutics): A humanized IgG4 monoclonal antibody in Phase 1 trials across multiple solid tumors and hematologic malignancies. Showed signs of clinical activity as monotherapy and in combinations.

- VIB7734 (Vir Biotechnology/GlaxoSmithKline): A humanized IgG4 antibody being tested in Phase 1/2 trials for various hematologic and solid tumors. Demonstrated an acceptable safety profile with preliminary responses.

- TTI-621 (Trillium Therapeutics): A SIRPα-Fc fusion protein designed to mimic the CD47-blocking effects of antibodies. Presented interim Phase 1 results in hematologic malignancies with no dose-limiting toxicities reported.

- ALX148 (ALX Oncology): A fusion protein combining an CD47 blocking domain with an albumin-binding domain to enhance half-life. Ongoing Phase 1/2 clinical studies focus on solid tumors and myeloid malignancies.

Beyond monotherapy, combining antibody-drug with other agents like chemotherapy, radiation therapy, immune checkpoint inhibitors or other targeted therapies holds significant promise to boost anti-tumor immune responses.

Safety Considerations And Future Directions

Key potential toxicities of targeting CD47 include on-target, off-tumor effects like anemia due to interference with red blood cell homeostasis. However, the leading clinical candidates have thus far shown acceptable safety profiles when dosed carefully and combined rationally. Further investigation should help define optimal biophysical properties, dosing schedules as well as biomarker-guided combinations that maximize therapeutic index.

Longer term follow up of ongoing studies will provide more insights into the full scope of efficacy and safety of various anti-CD47 approaches. Combination strategies remain an area of intense focus, with studies pairing antibody-drug with other immunotherapy regimens or targeted agents. Overall, targeting the CD47-SIRPα checkpoint demonstrates tremendous potential to transform cancer treatment by unleashing the immune system against tumors.

Get more insights on this topic:  https: https://dailygram.com/blog/1316542/anti-cd47-drugs-a-promising-new-class-of-cancer-immunotherapy-in-globally/

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Ravina Pandya, Content Writer, has a strong foothold in the market research industry. She specializes in writing well-researched articles from different industries, including food and beverages, information and technology, healthcare, chemical and materials, etc. (https://www.linkedin.com/in/ravina-pandya-1a3984191)

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1. Source: Coherent Market Insights, Public sources, Desk research
2. We have leveraged AI tools to mine information and compile it