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Dolores Mruk, PhD
Cancer treatments have come a long way since the early 1900s, evolving from chemotherapy and radiotherapy to more targeted interventions. One promising approach involves the use of bispecific antibodies (bsAbs)—engineered molecules that help in fighting cancer. Today, these immunotherapies are being studied across different malignancies, with a particular focus on blood cancers and solid tumors, thereby offering a new option where conventional treatments have fallen short.
Role of Bispecific Antibodies in Cancer Treatment
Antibodies are proteins produced by B cells, a type of immune cell, that help defend the body against infections by finding and attacking harmful invaders such as bacteria and viruses. Researchers have long harnessed the power of monoclonal antibodies to develop cancer therapies. Monoclonal antibodies (mAbs) bind to specific targets, such as a single protein or antigen, on cancer cells and engage immune cells, particularly T cells, to block critical signals that promote uncontrolled cell division and rapid tumor growth. These antibodies can even deliver drugs, radioisotopes, and other therapeutic agents to tumors, thereby aiding in the destruction of cancer cells. The limitation of this approach, however, is that cancer cells can modify or lose expression of the target in a process known as resistance, making the treatment less effective or even ineffective.
This is where bsAbs come in. Unlike mAbs that target only one protein, bsAbs bind to two different antigens or epitopes at the same time.1 This approach makes bsAbs highly effective in treating cancer because they bring immune cells even closer to cancer cells than mAbs. Other bsAbs block multiple signaling pathways that cancer cells need to survive, divide, and evade the immune system.2 Thus, they offer greater treatment precision, reducing harm to healthy cells and minimizing side effects. They can also enhance the immune system’s ability to fight cancer, even in patients with severely weakened immune systems, and improve the effectiveness of other therapies, such as immune checkpoint inhibitors.3 As such, their adaptability to various targets makes bsAbs a promising immunotherapy for treating different malignancies.
Current FDA-Approved Bispecific Antibody Therapies
The FDA has approved several bsAbs, mainly for blood cancers such as leukemia and lymphoma. For instance, catumaxomab, the first FDA-approved bsAb, showed effectiveness in treating malignant ascites,4 a condition in which fluid builds up in the abdomen of patients with advanced cancer. It works by binding to EpCAM, a protein found on the surface of cancer cells, and CD3, a protein found on the surface of T cells. In addition, the Fc region of this antibody binds to Fcγ receptors on immune cells, such as natural killer cells and macrophages, which aid in antibody-dependent cellular cytotoxicity. This helps the immune system destroy tumors more efficiently. Other bsAbs, such as mosunetuzumab, have also been approved for blood cancers.5 In particular, this treatment is intended for patients who failed to respond after undergoing at least two other types of systemic therapy or whose cancer has recurred.
While most FDA-approved bsAbs are designed to treat blood cancer, researchers are also developing these immunotherapies for solid tumors, including lung and breast cancers. Fewer of these therapies have received FDA authorization, but a recent wave of approvals shows positive progress and hope for further advancements in the field. For instance, in May 2021, the FDA approved amivantamab, a bsAb that targets EGFR and MET for non-small cell lung cancer (NSCLC).6 Later, in December 2024, zenocutuzumab, a HER2/HER3 targeting bsAb, was approved for NSCLC and pancreatic cancer.7 These approvals highlight the growing impact of bsAbs in treating solid tumors, particularly in patients who do not respond to conventional therapies.
Current Challenges and Future Directions in Bispecific Antibody Development
Developing bsAbs is challenging––from selecting compatible targets and optimizing binding affinity to minimizing side effects and ensuring safety. Stability-related issues, such as aggregation, can reduce therapeutic efficacy and cause serious side effects, including cytokine release syndrome and neurotoxicity. Manufacturing is also complex, requiring precise pairing of heavy and light chains, rigorous quality control, and sophisticated production methods. Regulatory approval is another challenge, owing to the newness of these therapies.
Future investigations aim to improve the selective targeting ability, stability, and production of bsAbs. Currently, researchers are studying novel scaffold designs with the goal of reducing aggregation and enhancing stability. Improved protein expression systems and bioprocessing techniques are also streamlining manufacturing, and this can lead to faster regulatory reviews and approvals. Lastly, tumor characteristics, such as tumor mutational burden and immune cell infiltration, are helping to guide patient selection, ensuring bsAbs are used more effectively.
Conclusion
Bispecific antibodies are a promising approach to cancer treatment. Although challenges in development, stability, and regulatory approval remain, these therapies will continue to improve with ongoing research. With continued innovation, bsAbs have the potential to expand therapeutic options and improve patient outcomes.
Header Image Source: Created by author, using Canva.com
Edited by Anamika Bandyopadhyay
References
1. Bispecific antibodies: an area of research and clinical applications. Accessed March 1, 2025. https://www.fda.gov/drugs/spotlight-cder-science/bispecific-antibodies-area-research-and-clinical-applications
2. Klein C, Brinkmann U, Reichert JM, Kontermann RE. The present and future of bispecific antibodies for cancer therapy. Nat Rev Drug Discov. 2024;23(4):301-319. https://www.nature.com/articles/s41573-024-00896-6
3. Li T, Niu M, Zhou J, Wu K, Yi M. The enhanced antitumor activity of bispecific antibody targeting PD-1/PD-L1 signaling. Cell Commun Signal. 2024;22(1):179. https://biosignaling.biomedcentral.com/articles/10.1186/s12964-024-01562-5
4. Sebastian M, Kuemmel A, Schmidt M, Schmittel A. Catumaxomab: a bispecific trifunctional antibody. Drugs Today (Barc). 2009;45(8):589-597.
5. FDA grants accelerated approval to mosunetuzumab-axgb for relapsed or refractory follicular lymphoma. U.S. Food and Drug Administration. Published online December 22, 2022. Accessed March 4, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-mosunetuzumab-axgb-relapsed-or-refractory-follicular-lymphoma
6. FDA grants accelerated approval to amivantamab-vmjw for metastaic non-small cell lung cancer. U.S. Food and Drug Administration. Published online May 21, 2021. Accessed March 4, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-amivantamab-vmjw-metastatic-non-small-cell-lung-cancer
7. FDA grants accelerated approval to zenocutuzumab-zbco for non-small cell lung cancer and pancreatic cancer. U.S. Food and Drug Administration. Published online December 4, 2024. Accessed March 4, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zenocutuzumab-zbco-non-small-cell-lung-cancer-and-pancreatic
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