Advanced cancers often develop resistance to treatment, making them highly aggressive, resulting in unsuccessful therapies. This may leave patients with limited treatment options. According to the National Cancer Institute (NCI), aggressive cancers are cancers that spread rapidly, despite severe treatment.
In some cancers, including lung cancer, pancreatic cancer, and prostate tumors, a key driver of treatment resistance and metastasis is a protein called integrin αvβ3, which is absent in normal tissues but enriched in aggressive tumors. It has emerged as both a marker and a driver of tumor stemness and drug resistance in epithelial cancers. This makes integrin αvβ3 an attractive therapeutic target.
The humanized IgG1 anti-alphavbeta3 antibody (anti-αvβ3) etaracizumab (also known as MEDI-522 and Abegrin®; MedImmune/AstraZeneca) was initially developed to exploit a specific type of cell in the immune system called natural killer (NK-) cells. Despite a favorable safety profile after systemic long-term αvβ3 blockade, demonstrating clinical efficacy in Phase 2 clinical trials for metastatic castration-resistant prostate cancer (CRPC) and metastatic melanoma, its impact was insufficient for further development. NK cell-mediated cytotoxicity against αvβ3-positive tumors ultimately failed to significantly improve patient survival in clinical trials because the tumors didn’t have enough natural killer cells to mount a strong immune response.
A new approach
Now, researchers at the University of California, San Diego School of Medicine have developed a new approach that overcomes this barrier by taking advantage of the tumor’s own immune landscape. By engineering a new anti-αvβ3 antibody that activates macrophages — a type of immune cell already abundant in advanced αvβ3+ tumors — the researchers were able to trigger robust anti-tumor responses in both patient tumor samples and in mouse models.
The study, funded in part by the National Institutes of Health (NIH), Alpha Beta Therapeutics, San Diego Digestive Diseases Research Center, and California Institute for Regenerative Medicine and published in Molecular Cancer Therapeutics, was led by Hiromi I. Wettersten, M.D., Ph.D., assistant professor in the Department of Pathology at UC San Diego School of Medicine and member of UC San Diego Moores Cancer Center. [1]
Key findings
- In both patient tumor samples and mouse models, the new antibody killed cancer cells more effectively than the older version, leading to increased tumor cell death and reduced tumor growth.
- The antibody reprogrammed macrophages to attack tumors by increasing levels of inducible nitric oxide synthase (iNOS), a critical enzyme that helps the immune system kill cells that are infected or cancerous.
- The anti-tumor effect depended entirely on macrophages; when macrophages were depleted, the therapy lost its effectiveness, while depletion of natural killer cells had no impact.
The results suggest that customizing antibody therapies to target the dominant immune cells present in a given tumor could dramatically improve outcomes for patients with aggressive, drug-resistant cancers. Further, because integrin αvβ3 is absent from healthy tissues, the new antibody is highly selective. It will have no negative impact on surrounding cells, making it a potentially safer alternative to conventional therapies.
The researchers believe that their antibody optimization strategy could serve as a blueprint for treating other treatment-resistant tumors, potentially improving a wide range of existing immunotherapies and offering new hope for patients with advanced cancers.
Clinical trials
MEDI-522 in the Treatment of Patients With Metastatic Androgen-Independent Prostate Cancer – ClinicalTrials.gov ID NCT00072930
Monoclonal Antibody Therapy in Treating Patients With Advanced Colorectal Cancer -ClinicalTrials.gov ID NCT00027729
Evaluating The Antitumor Activity Of MEDI-522 With Or Without Dacarbazine In Patients With Metastatic Melanoma – ClinicalTrials.gov ID NCT00066196
Reference
[1] Reddy JP, Yu Z, Shepard RM, Von Schalscha T, Clague RA, Peixoto BP, McCormack SJ, Onaitis MW, Weis SM, Cheresh DA, Wettersten HI. Macrophage-Engaging IgG4 Antibody Triggers Cytotoxicity Against Integrin αvβ3+ Cancers. Mol Cancer Ther. 2025 Oct 13. doi: 10.1158/1535-7163.MCT-25-0300. Epub ahead of print. PMID: 41081633.
Featured image laboratory at AstraZeneca. Used with permission.
DOI
