Emerging Potential of Anti-CD47 Monoclonal Antibodies
Anti-CD47 drugs have emerged as a promising new class of cancer immunotherapy. CD47 is a "don't eat me" signal that is overexpressed on many cancer cells and prevents macrophages from phagocytosing and clearing them. By blocking the CD47-SIRPα interaction, anti-CD47 therapies can enable macrophages to recognize and eliminate cancer cells. Several pharmaceutical companies are developing humanized anti-CD47 monoclonal antibodies (mAbs) that are showing encouraging results in early clinical trials.
Magrolimab was the first anti-CD47 drug to enter clinical testing. Phase I trials showed magrolimab, developed by Five Prime Therapeutics, had an acceptable safety profile and encouraging signs of anti-tumor activity in solid tumors and myelodoma. Based on these results, magrolimab is now being studied in several phase II trials in combination with azacitidine for myelodysplastic syndrome and in combination with pembrolizumab for solid tumors.
ALX148 is another leading anti-CD47 candidate being developed by ALX Oncology. In 2021, phase Ib data demonstrated that ALX148 combined with Rituximab or Trastuzumab had manageable safety and encouraging responses in lymphoma and HER2+ advanced solid tumors respectively. ALX Oncology is now conducting phase II trials evaluating ALX148 plus standard therapies in myeloma, gastric cancer and head and neck cancer.
Other anti-CD47 mAbs in clinical development include TTI-622 by Trillium Therapeutics, Bemarituzumab by Forty Seven Inc, and OSE-172 by OSE Immunotherapeutics. Preliminary data indicates these drugs also have a reasonable safety profile and some early signs of efficacy against tumors. The results so far suggest anti-CD47 therapy may be broadly applicable across both hematological malignancies and solid tumors.
Challenges in Balancing Anti-Tumor Effects and Anemia Issues
While anti-CD47 therapies show promise, developing these drugs requires carefully balancing their anti-tumor effects and potential anemia-related toxicity. CD47 is expressed on red blood cells and blocking it can cause phagocytosis of red blood cells or hemolysis, potentially leading to anemia. Most anti-CD47 mAbs in development have caused mild to moderate anemia as an on-target effect.
Dose optimization and identification of the appropriate therapeutic window is critical. Combining anti-CD47 drugs with other cancer therapies aims to maximize anti-tumor response rates while minimizing the necessary anti-CD47 dose and risk of anemia. Ongoing clinical trials are evaluating various dosing schedules and combinations to establish the safest approaches. Biomarkers are also being explored to select patients most likely to benefit from anti-CD47 treatment without unacceptable anemia.
Overall, clinical experience with first-generation anti-CD47 mAbs suggests their side effect profiles can be managed sustainably using dose adjustments or combining with other drugs. Next-generation anti-CD47 therapies are being designed to reduce hemagglutination risk through increased selectivity for tumor-associated CD47 or mechanisms independent of CD47 binding on red blood cells. Such refinements may help circumvent dose-limiting anemia issues altogether.
Growing Evidence Supports Clinical Efficacy
With phase I and II trial data continuing to mature, evidence is strengthening that anti-CD47 therapy can achieve meaningful clinical responses in patients with hard-to-treat cancers. Promising efficacy signals have been observed for magrolimab in myeloid malignancies and ALX148 in lymphoma and solid tumors. The phase II HERALD trial demonstrated ALX148 plus trastuzumab yielded an objective response rate of 40% in trastuzumab-resistant HER2+ breast cancer.
Additionally, initial combination studies show potential for anti-CD47 drugs to enhance the activity of standard therapies. In a phase Ib trial, ALX148 in combination with azacitidine led to partial or complete remission in 50% of AML/MDS patients, a superior outcome to the historical response rate of azacitidine alone. Such results validate the concept of using anti-CD47 therapies to sensitize tumor cells to other approved drugs.
With numerous ongoing or planned phase II and III registration studies, substantial efficacy data will become available over the next 2-3 years. This is expected to provide greater clarity around which clinical settings anti-CD47 treatments work best and may lead to initial regulatory approvals. If positive results continue in late-stage trials, anti-CD47 monoclonal antibodies could transform treatment options for several hematological and solid tumor malignancies.
Outlook
The anti-CD47 drug pipeline has advanced remarkably quickly, from early research to multiple therapeutic candidates now in mid-late phase clinical testing. While anemia management remains an area of focus, clinical experience to date supports that anti-CD47 therapy's side effects can be managed with sophisticated dosing and combination strategies. Robust efficacy signals being seen in phase Ib/II trials underscores their
Published Date: Nov 2024
