Bispecific Antibodies: From Cancer Immunotherapy to Next-Generation Precision Medicine

 

Bispecific antibody therapy uses engineered antibodies designed to bind two different targets simultaneously. This dual-targeting ability opens up treatment strategies that arenot possible with regular monoclonal antibodies.

How they work

The most common application is in cancer treatment, where one arm of the antibody binds a tumor cell surface antigen while the other arm binds a receptor on an immune cell (often CD3 on T cells). This physically bridges the two cells, activating the T cell and directing it to kill the tumor cell, essentially redirecting the immune system to attack cancer it might otherwise ignore.

Other bispecific designs:

  • Block two disease-relevant pathways at once (useful when a disease can escape by switching signaling routes)
  • Bind two different sites on the same target protein for stronger inhibition
  • Cross biological barriers by using one arm to “shuttle” the other arm across (e.g., the blood-brain barrier)

Approved examples

  • Blinatumomab — targets CD19 (on B-cell leukemia cells) and CD3 (on T cells); used for acute lymphoblastic leukemia
  • Faricimab — targets two pathways involved in abnormal blood vessel growth; used for macular degeneration
  • Emicizumab — bridges clotting factors IXa and X, mimicking the function of factor VIII; used for hemophilia A
  • Teclistamab, elranatamab, talquetzumab-type BCMAxCD3 agents — used in multiple myeloma
  • Amivantamab — targets EGFR and MET in certain lung cancers

Challenges

  • Manufacturing is more complex than standard antibodies since two different binding arms need to be produced correctly and consistently
  • T-cell engagers can cause cytokine release syndrome, requiring careful dosing and monitoring
  • Tumor cells can sometimes downregulate the target antigen, leading to resistance

Disease areas

Oncology (the largest area by far)

This is where bispecifics have had the most impact, mainly through T-cell engagers (BiTEs) and NK-cell engagers, but also through different anti-tumor mechanisms.

  • Hematologic cancers: Blinatumomab (CD19xCD3) for acute lymphoblastic leukemia was the first major success. BCMAxCD3 bispecifics (teclistamab, elranatamab) now treat multiple myeloma. CD20xCD3 agents (mosunetuzumab, epcoritamab, glofitamab) treat lymphomas, offering an alternative to CAR-T therapy without the need for cell manufacturing.
  • Solid tumors: Harder to crack because solid tumors lack the clean, uniform surface antigens blood cancers have, and the tumor microenvironment suppresses T-cell activity. An example of a BiTE is Tebentafusp, which bridges a melanoma-associated peptide and CD3, is approved for uveal melanoma. Amivantamab (EGFRxMET) is approved for certain non-small cell lung cancers, and is not a BiTE. It works by blocking oncogenic cancer signaling.

Ophthalmology

Faricimab (targeting VEGF-A and Ang-2) treats wet age-related macular degeneration and diabetic macular edema. Blocking two pathways involved in abnormal blood vessel growth and vascular leakage gives more durable control than anti-VEGF therapy alone, meaning fewer injections for patients.

Hematology (non-cancer)

Emicizumab treats hemophilia A by bridging factors IXa and X, substituting for missing factor VIII. It’s given as a subcutaneous injection rather than IV infusions of factor VIII, and works even in patients who’ve developed antibody inhibitors against factor VIII, which is a major advantage.

Autoimmune and inflammatory disease

This area is an earlier stage of development, but advancing toward the clinic. The strategy here is usually blocking two inflammatory cytokines or pathways at once (rather than the immune-bridging approach used in cancer), since autoimmune diseases are often driven by redundant, overlapping signaling. Examples in development target combinations like immune signaling pathways,  IL-4/IL-13 or TNF/IL-17, for conditions like atopic dermatitis, psoriasis, and inflammatory bowel disease. None have reached the blockbuster status of oncology bispecifics yet, but it’s an active research area.

Neurology (emerging)

A newer application uses one arm as a “molecular shuttle”, binding the transferrin receptor to hitch a ride across the blood-brain barrier,  while the other arm delivers a therapeutic payload (like an amyloid-targeting antibody for Alzheimer’s). This is still largely experimental but addresses a huge limitation of antibody drugs, which normally can’t cross into the brain.

Where the field is heading next

Bispecific antibody-drug conjugates (BsADCs) — the biggest new frontier

This is the most notable shift: combining the dual-targeting of bispecifics with the “smart bomb” payload delivery of antibody-drug conjugates. Bispecific antibody drug conjugates are emerging as the next generation of antibody-based therapies, evolving from ADCs with the added advantage of dual targeting, aimed at addressing tumor heterogeneity that limits conventional monoclonal antibodies and ADCs. As of April 2026 the field is early but rapidly advancing, with a strong expanding pipeline. An example is the bispecific ADC izalontamab brengitecan, which carries a toxic payload  and binds two targets commonly overexpressed in epithelial cancers. Izalontamab brengitecan, is among the molecules currently in regulatory review. Market analysts project the first approved BsADC by 2028. GlobeNewswire + 3

PD-1×VEGF bispecifics — a major new immuno-oncology mechanism

Rather than pairing a tumor antigen with CD3, this approach pairs a checkpoint inhibitor target with an angiogenesis target in one molecule. Ivonescimab simultaneously blocks PD-1 from binding its ligand while also inhibiting VEGF-A, restoring immune response and preventing tumor blood vessel growth at once. It was approved in China in May 2024 as the first PD-1×VEGF bispecific globally and was licensed to Summit Therapeutics for global rights. Notably, its Phase 3 head-to-head trial against pembrolizumab (Keytruda) in China showed superiority in progression-free survival.

Differentiated T-cell engager designs

Beyond the classic CD3-engager format, newer molecules are diversifying the co-stimulatory arm: linvoseltamab pairs BCMA with a CD28 arm instead of CD3, a differentiated mechanism approved for relapsed/refractory multiple myeloma.

China’s rise as a bispecific innovation hub

Approximately 500bispecific antibody patents were filed in China between 2016 and 2025, growing from just 81 in 2023, a 7-fold increase.  Akeso’s licensing partnership with Summit Therapeutics for ivonescimab, valued at up to US$5 billion, was a landmark deal that gave a Chinese-developed bispecific antibody a clear path into major Western markets, including the United States, Europe, Canada, and Japan. The agreement signaled that Chinese biotech companies could not only innovate at a global level but also produce high-value biologic therapies capable of competing with leading multinational pharmaceutical companies.

Solid tumors remain the harder frontier, but momentum is building

Approximately 700 clinical trials evaluating 183 distinct bispecific antibodies are now registered, double the number since 2019, with trial counts rising from just 1 in 2014 to 167 in 2024. Combination strategies are also gaining traction: there’s increased focus on pairing bispecifics with checkpoint inhibitors( like anti-PD-1) and chemotherapy.

Expansion beyond oncology continues

Mim8 (denecimig), a bispecific from Novo Nordisk, is in development for prophylactic treatment of hemophilia A, following in emicizumab’s footsteps but as a next-generation option.

Bottom line: the field is moving from “one bispecific format” (tumor antigen × CD3) toward a much more diverse toolkit — dual-payload ADCs, dual-checkpoint/angiogenesis blockers, alternative co-stimulatory arms, and a genuinely global competitive landscape rather than one dominated by a handful of Western biotechs.  This diversification is expected to expand therapeutic opportunities, enable more tailored treatment strategies, and intensify competition as next-generation multispecific therapies continue to advance into the clinic.

Image credit: Portions of the figure in this article were generated using ChatGPT (OpenAI) or Google Gemini.

Disclaimer: This blog post is intended solely for educational and scientific informational purposes. Any mention of therapeutic drug names, including FDA-approved medications, is for the purpose of accurate reporting and discussion of biomedical research and does not constitute medical advice, endorsement, or promotion. Readers should not interpret the content as a recommendation for any specific treatment. Always consult a qualified healthcare professional for medical advice or treatment decisions.

About Marin Biologic Laboratories

Our Recent Publication/Meeting Presentation on Gene Therapy

1. Development of VNX-101, an Adeno-Associated Virus with Less Immunogenicity and Efficient Long-Term Expression of a CD19 T-Cell Engager. Molecular Therapy Methods & Clinical Development, published online July 24, 2025.

2. Cell-Based Potency Assay for Anti-CD3-Anti-CD19 Diabody. Journal of Immunological Methods. 2025. 545-114004.

3. Development of a Pharmacokinetic (PK) Mouse Serum GLP ELISA for an Anti–CD19–AntiCD3 Diabody
bioRxiv 2025.03.19.644217; doi: https://doi.org/10.1101/2025.03.19.644217.

4. American Society of Hematology (ASH) Annual Meeting 2024.
Abstract link: Using Gene Therapy to Solve Challenges with CAR-T Cell Immunotherapy: Lead Selection and Preclinical Development of an Adeno-Associated Virus with Reduced Immunogenicity Exhibiting Efficient and Long-Term Expression of an Anti-CD19 T-Cell Engager.

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