Bispecific antibodies (bsAbs) have emerged as a groundbreaking advancement in the field of therapeutic biotechnology, offering novel approaches to treat a variety of complex diseases. However, with their innovative mechanisms come potential side effects that need to be carefully understood and managed to ensure patient safety and optimal therapeutic outcomes.
In this article, we will provide an overview of the side effects reported with bsAb therapies. We will also discuss strategies for prevention and management, highlighting the importance of continuous monitoring and personalized approaches to treatment. As a CHO specialist, evitria supports these programs through its bispecific antibody production service, delivering well-characterized material for preclinical research.
The most common side effects of bispecific antibodies include cytokine release syndrome (CRS), neurotoxicity such as immune effector cell-associated neurotoxicity syndrome (ICANS), infusion-related reactions, cytopenias (low blood cell counts), and organ-specific effects. Most are manageable with close monitoring, step-up dosing, and supportive care.
| Category | Examples | Typical management |
|---|---|---|
| Infusion-related | Fever, chills, rash during administration | Premedication, slower infusion |
| Immune-related | Cytokine release syndrome (CRS), ICANS | Step-up dosing, monitoring, supportive care |
| Hematologic | Neutropenia, anemia, thrombocytopenia | Blood count monitoring, dose adjustment |
| Organ-specific | Hepatic, cardiac, or neurologic effects | Monitoring of organ function |
General side effects of bispecific antibodies
Side effects can vary depending on the specific bsAb, its target antigen(s), and the patient population. Generally, the side effects of bsAbs can be categorized into infusion-related reactions, immune-related side effects, hematologic side effects, and organ-specific side effects.
Infusion-related reactions
Infusion-related reactions are typically acute reactions that occur during or shortly after the administration of the antibody.
Symptoms can include:
- Fever
- Chills
- Nausea
- Headache
- Rash
- Hypotension (low blood pressure)
- Tachycardia (rapid heart rate)
- Shortness of breath1
Immune-related side effects
Immune-related side effects are a significant concern with bsAb therapies due to their mechanism of action, which often involves engaging the immune system to target and destroy diseased cells. These side effects can vary widely in severity and type, depending on the specific bsAb and the patient’s immune response. Most of the clinical experience with these reactions comes from the FDA-approved bispecific antibodies currently in use.
Cytokine Release Syndrome (CRS) is one of the most common and serious immune-related side effects. CRS occurs when the activation of immune cells leads to a rapid release of cytokines into the bloodstream, causing widespread inflammation.2
Symptoms of CRS can range from mild to severe and include:
- Fever
- Fatigue
- Headache
- Hypotension (low blood pressure)
- Tachycardia (rapid heart rate)
- Respiratory distress
- Multi-organ failure (in severe cases)2
BsAbs can cause both activation and suppression of the immune system, leading to various side effects. Enhanced immune activation can result in autoimmune reactions where the immune system attacks healthy tissues, potentially causing conditions such as myocarditis, hepatitis, or pneumonitis.3 In some cases, immune suppression can occur, increasing the risk of infections by impairing the body’s ability to fight off pathogens.4
Hematologic Side Effects
Hematologic side effects primarily affect the blood and bone marrow, leading to changes in blood cell counts that can impact a patient’s overall health and ability to tolerate treatment. BsAbs can influence the production and function of various blood cells, leading to:
- Anemia: A reduction in red blood cells, which can cause fatigue, weakness, and shortness of breath.
- Thrombocytopenia: A decrease in platelets, which are essential for blood clotting. This can increase the risk of bleeding and bruising.
- Leukopenia: A reduction in white blood cells, which can impair the immune system’s ability to fight infections, making patients more susceptible to illness.5
Organ-specific side effects
One of the common hepatic side effects of bsAbs is the elevation of liver enzymes, which can indicate liver inflammation or damage. Elevated liver enzymes such as alanine transaminase (ALT) and aspartate transaminase (AST) can occur due to the immune system’s reaction to the therapy.6
Symptoms of hepatic side effects may include:
- Fatigue
- Jaundice (yellowing of the skin and eyes)
- Abdominal pain
- Dark urine7
BsAbs can also affect kidney function, leading to conditions such as acute kidney injury (AKI). This can be due to immune-mediated damage or other mechanisms related to the therapy.8
Symptoms of AKI may include:
- Reduced urine output
- Swelling in the legs and ankles
- Fatigue
- Confusion9
Factors influencing the occurrence of side effects
Several factors can influence the occurrence and severity of side effects associated with bsAbs:
- Dosage and administration schedule: Higher doses and more frequent administration can increase the risk and severity of side effects.
- Patient-specific factors: Individual patient characteristics, such as underlying health conditions, age, and genetic factors, can affect how a patient responds to bsAb therapy.
- Antibody design and format: The specific design and format of the bsAb, including the types of antigens targeted, can influence the likelihood of side effects.
Strategies for prevention and management of side effects
Effectively preventing and managing the side effects of bsAb therapies is crucial for maximizing their therapeutic benefits while minimizing risks to patients. Key strategies include thorough patient selection and screening to identify individuals most likely to benefit from treatment, along with baseline testing to establish a reference point.
Regular monitoring and early intervention are essential, enabling healthcare providers to detect and address side effects promptly. Symptom management through supportive care measures and specific medications for targeted side effects can alleviate discomfort and enhance patient well-being.10
Personalized treatment adjustments, including dose modifications and, if necessary, pausing or discontinuing therapy, help balance efficacy and safety. A multidisciplinary approach, involving collaboration among various specialists and thorough patient education, ensures comprehensive care tailored to each patient’s needs.
Future perspectives and advancements
Researchers are continuously exploring and developing new bispecific antibody formats to improve therapeutic outcomes. Furthermore, advanced genetic and protein engineering techniques are being utilized to create bsAbs with superior characteristics.11
While bsAbs are primarily used in oncology, their application is expanding into other therapeutic areas, including autoimmune diseases, infectious diseases or neurological disorders.12
evitria is dedicated to supporting the future of bispecific antibody therapy with its expertise in bispecific antibody production services. We offer comprehensive services, including the expression of all common formats such as the Duobody system and innovative designs like IgG-scFvs, enabling researchers and therapeutic companies to develop high-quality antibody therapeutics efficiently.
By partnering with evitria, clients gain access to cutting-edge technologies and extensive experience to drive forward the development of novel bispecific drug candidates.
How evitria supports bispecific antibody production
evitria supports researchers by producing high-quality recombinant bispecific antibodies for preclinical work. Well-characterized, pure material helps generate reliable data in early development. Please note that this article is not a guide for patients; it summarizes reported side effects from the scientific literature.
Please note that this article is not intended as a guide for patients. It is a summary of known side effects from various sources, and we are not liable for the accuracy of the information. For more detailed information, please contact a doctor.
FAQs on side effects of bispecific antibodies
The most frequently reported are cytokine release syndrome (CRS), neurotoxicity (including ICANS), infusion-related reactions, cytopenias, and organ-specific effects. Their frequency and severity vary by target, format, and patient.
CRS is an over-activation of the immune system that can cause fever, low blood pressure, and, in severe cases, multi-organ effects. It is the most characteristic side effect of T-cell-engaging bispecific antibodies and is typically managed with monitoring, step-up dosing, and supportive care.
Yes. Common strategies include premedication, priming or step-up dosing, close monitoring during administration, and supportive treatment. Many reactions are manageable and reversible when addressed early.
Because bispecific antibodies engage two targets at once, often bridging immune and tumor cells, they can trigger stronger immune-related effects such as CRS that are less common with conventional monoclonal antibodies. See how bispecific antibodies differ from monoclonal antibodies for the full comparison.
Sources
- Infusion or immune reactions. American Cancer Society. https://www.cancer.org/cancer/managing-cancer/side-effects/infusion-immune-reactions.html. Published June 4, 2024. Accessed July 11, 2024. ↩︎
- Cytokine Release Syndrome (CRS) After Immunotherapy. St. Jude Together. https://together.stjude.org/en-us/diagnosis-treatment/side-effects/cytokine-release-syndrome-crs.html. Published March 2019. Accessed July 11, 2024. ↩︎
- Immunotherapy Side Effects. Cancer Research Institute. https://www.cancerresearch.org/immunotherapy-side-effects#:~:text=While%20most%20side%20effects%20from,and%20hepatitis%20(liver%20inflammation). Published November 2019. Accessed July 11, 2024. ↩︎
- Mazahreh F, Mazahreh L, Schinke C, et al. Risk of infections associated with the use of bispecific antibodies in multiple myeloma: a pooled analysis. Blood Advances. 2023;7(13):3069-3074. doi:10.1182/bloodadvances.2022009435 ↩︎
- Golmohammadi M, Dima D, Albayyadhi M, Moradi A, Raza S, Jaberi-Douraki M. Pooled analysis on bispecific Antibody-Related toxicities in multiple myeloma. Blood. 2023;142(Supplement 1):1953. doi:10.1182/blood-2023-191305 ↩︎
- Hoofnagle JH, Serrano J, Knoben JE, Navarro VJ. LiverTox: a website on drug-induced liver injury. Hepatology. 2013;57:873–4. ↩︎
- Liver disease. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/liver-problems/symptoms-causes/syc-20374502. Published February 13, 2024. Accessed July 11, 2024.
↩︎ - Wen X, Xu G. Nephrotoxicity in Bispecific Antibodies recipients: Focus on T-Cell-Engaging Bispecific Antibodies. OncoTargets and Therapy. 2024;Volume 17:545-556. doi:10.2147/ott.s465679 ↩︎
- Acute kidney injury. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/kidney-failure/symptoms-causes/syc-20369048. Published July 10, 2024. Accessed July 11, 2024. ↩︎
- Managing Side Effects of Immunotherapy. Cancer Council NSW. https://www.cancercouncil.com.au/cancer-information/cancer-treatment/immunotherapy/side-effects-of-immunotherapy/managing-side-effects/#:~:text=Grades%201%E2%80%932%3A%20Your%20doctor,steroid%20tablets%2C%20such%20as%20prednisolone. Published July 2021. Accessed July 11, 2024.
↩︎ - Klein C, Brinkmann U, Reichert JM, Kontermann RE. The present and future of bispecific antibodies for cancer therapy. Nature Reviews Drug Discover/Nature Reviews Drug Discovery. 2024;23(4):301-319. doi:10.1038/s41573-024-00896-6 ↩︎
- U.S. Food And Drug Administration. Bispecific Antibodies: an area of research and clinical applications. Published February 14, 2024. Accessed June 14, 2024. https://www.fda.gov/drugs/spotlight-cder-science/bispecific-antibodies-area-research-and-clinical-applications. ↩︎