Bispecific Antibodies: A Medical Revolution of "One Key for Two Locks"
In the battle against cancer and autoimmune diseases, the medical community has been searching for more precise and effective weapons. Traditional antibody drugs act like "one key for one lock," targeting only a single site. In contrast, the emerging bispecific antibodies (BsAbs) function as masterfully designed "master keys," capable of recognizing and binding two different targets simultaneously, bringing revolutionary breakthroughs to disease treatment. This "killing two birds with one stone" strategy is rewriting modern medical paradigms and has become one of the most exciting frontiers in biopharmaceuticals.
I. From Theoretical Concept to Clinical Reality: The Evolution of Bispecific Antibodies
The concept of bispecific antibodies dates back to the 1960s, when immunologists first proposed the idea of artificially constructing bivalent antibodies. French scientists Nisonoff and Rheinhermer created the earliest bispecific molecules by chemically linking fragments of two different antibodies. However, these early attempts were limited by technological constraints, resulting in low purity, poor stability, and challenges for clinical application.
A true turning point came in 1983 when German scientists Milstein and Cuello developed the hybrid-hybridoma (quadroma) technique, fusing two different hybridoma cells to produce bispecific antibodies. While this improved yield, challenges such as product heterogeneity, purification difficulties, and high immunogenicity persisted. In the 1990s, breakthroughs in genetic engineering enabled scientists to construct bispecific antibodies using recombinant DNA technology, laying the foundation for future advancements.
In 2009, the first bispecific antibody drug, Catumaxomab (targeting EpCAM and CD3), was approved in Europe for treating malignant ascites, marking a major milestone. Although it was later withdrawn for commercial reasons, it validated the clinical feasibility of BsAbs. In 2014, the FDA approved Blinatumomab (targeting CD19 and CD3) for B-cell acute lymphoblastic leukemia, becoming the first globally recognized bispecific antibody drug and energizing the field with its remarkable efficacy.
II. Design Revolution: Structural Innovations in Bispecific Antibodies
The core value of bispecific antibodies lies in their sophisticated structural design. Unlike traditional antibodies, BsAbs must bind two distinct epitopes, presenting significant engineering challenges. Scientists have developed over 100 different structural formats, broadly categorized into two classes: IgG-like (with Fc regions) and non-IgG-like (without Fc regions).
IgG-like structures retain the traditional antibody framework while achieving bispecificity through modifications to the Fc or Fab regions. For example, the Knobs-into-Holes (KiH) technique introduces a "knob" on one heavy chain and a complementary "hole" on another to promote heterodimerization. CrossMab technology swaps antibody domains to ensure correct pairing. These structures typically have long half-lives and good stability but larger molecular weights, limiting tissue penetration.
Non-IgG-like structures are more flexible and diverse, including bispecific T-cell engagers (BiTEs), dual-affinity retargeting (DART) antibodies, and tandem single-chain variable fragments (tandem scFvs). Blinatumomab, a BiTE, consists of two linked scFvs—small in size with strong tissue penetration but short half-lives, requiring continuous infusion. Scientists continue to optimize these structures, such as adding albumin-binding domains to extend half-life or incorporating cross-linkers for stability.
Recent years have seen an explosion of novel bispecific platforms, including nanobody-based designs, bispecific antibody-drug conjugates (BsADCs), and conditionally activated BsAbs, expanding their functional possibilities. These innovations enable more complex functions, such as dual-pathway blockade, immune cell-redirecting, and multi-receptor activation.
III. Clinical Breakthroughs: The Therapeutic Revolution of Bispecific Antibodies
The most successful applications of BsAbs are in oncology, particularly hematologic malignancies. Blinatumomab, targeting CD19 (B-cell antigen) and CD3 (T-cell receptor), redirects T cells to leukemia cells, achieving complete remission rates as high as 80%. This led to its accelerated FDA approval for relapsed/refractory B-cell acute lymphoblastic leukemia. In 2022, Teclistamab (targeting BCMA and CD3) was approved for multiple myeloma, further expanding BsAbs' reach in blood cancers.
In solid tumors, BsAbs also show great promise. Amivantamab (targeting EGFR and cMet) gained FDA approval in 2021 for EGFR exon 20 insertion-mutated non-small cell lung cancer, overcoming resistance to traditional EGFR inhibitors. Cadonilimab, a PD-1/CTLA-4 bispecific antibody, demonstrates superior safety and efficacy compared to combination therapy in trials, potentially becoming a next-generation immunotherapy.
Beyond oncology, BsAbs are making strides in autoimmune and infectious diseases. For example, dual IL-4/IL-13 blockade shows synergistic effects in atopic dermatitis and asthma. Anti-COVID-19 BsAbs targeting multiple viral epitopes reduce the risk of escape mutations.
As of 2023, over 10 BsAbs are approved globally, with more than 200 candidates in clinical development. Despite their promise, challenges like cytokine release syndrome (CRS), neurotoxicity, and on/off-target effects persist. Researchers are addressing these through predictive models, dosing optimization, and combination therapies.
IV. Future Directions: The Cutting Edge of Bispecific Antibodies
As technology advances, BsAbs are evolving toward smarter, more precise therapies. Next-generation "conditionally activated" BsAbs will function only in specific microenvironments (e.g., tumors), minimizing systemic toxicity. Examples include pH-sensitive BsAbs activated in acidic tumor conditions or protease-cleavable BsAbs assembled only in the presence of tumor-associated enzymes.
Multispecific antibodies (tri-specific or more) represent the next frontier, integrating additional functions like simultaneous tumor antigen targeting, immune cell engagement, and cytokine modulation. In 2022, the first trispecific antibody (targeting CD3, CD38, and CD28) entered clinical trials for multiple myeloma.
Combining BsAbs with other modalities is also gaining traction. Bispecific antibody-drug conjugates (BsADCs) extend the ADC concept to dual targeting, delivering payloads to cells expressing either antigen. Cell therapies paired with BsAbs enhance immune cell homing and cytotoxicity, creating synergistic effects.
Artificial intelligence is reshaping BsAb development. Deep learning predicts epitopes, optimizes structures, and simulates molecular interactions, accelerating design cycles and improving success rates. Several biotech firms now use AI platforms to engineer BsAbs with ideal properties—highaffinity, low immunogenicity, and superior stability.
V. Conclusion
From laboratory curiosity to clinical breakthrough, bispecific antibodies have traversed over 60 years of scientific progress. This field embodies the power of translational research, merging fundamental discoveries with therapeutic innovation. BsAbs represent the pinnacle of antibody engineering and pioneer a new paradigm of "multi-target intervention."
As designs grow more sophisticated and applications expand, BsAbs are poised to play a central role in precision medicine. Future "smart" BsAbs may autonomously adjust activity based on disease microenvironments, achieving true precision targeting. Meanwhile, advances in manufacturing, delivery, and combination strategies will continue driving progress.