[Beginner-Friendly | Bispecific Antibody Drugs] Vol.6: Evolution of Bispecific Antibody Technologies — A Historical Overview of Engineering Breakthroughs

2025-08-13

In this final deep-dive of our beginner-friendly bispecific antibody series, we explore the historical trajectory of bispecific antibody (BsAb) technology. From early-stage instability to today’s modular, multifunctional platforms, the evolution of BsAbs reveals not only scientific ingenuity but also the critical role of technological innovation in expanding therapeutic applications. We’ll trace the timeline of key developments, breakthroughs in structural engineering, and the co-evolution of manufacturing and bioinformatics that made modern BsAbs a clinical reality.

■ The First-Generation Struggles: Instability and Heterogeneity

In the 1980s–1990s, bispecific antibodies were initially created by chemically linking two monoclonal antibodies or fusing two hybridomas (quadromas). However, these early prototypes suffered from poor stability, aggregation, and inconsistent targeting due to uncontrolled chain pairing. Their limited clinical utility at the time slowed broader development.

■ Turning Point in the 2000s: Recombinant Engineering and Domain Swapping

The 2000s saw a turning point in BsAb development, thanks to advances in recombinant protein engineering. Notable milestones include:

Knob-into-Hole (KiH) Technology: Developed to solve heavy chain pairing issues by creating complementary structures.
CrossMab: A Roche innovation for avoiding light chain mispairing via domain exchange.
DART and TandAb: Novel scFv-based formats optimized for T-cell redirection and enhanced stability.

■ 2010s: Emergence of Clinical-Grade BsAbs and First Approvals

With stable formats in hand, the 2010s marked the clinical breakthrough of BsAbs. Key milestones:

Blincyto (2014): First FDA-approved BsAb (BiTE format), targeting CD3 × CD19 in ALL.
Amivantamab, Teclistamab, Mosunetuzumab: Several IgG-like and T-cell redirecting BsAbs entered clinical pipelines and received approval for solid and hematologic malignancies.

Platform technologies became more sophisticated, including “2:1 binding” formats to increase target avidity and reduce off-target effects.

■ 2020s: AI Integration and Multifunctional Modules

Recent advances in AI and synthetic biology have further accelerated BsAb development. Innovations include:

Machine-learning-guided affinity prediction
Modular platform designs for plug-and-play antibody development
Bispecific + immune checkpoint fusion formats

Examples include dual targeting of PD-L1 × TGF-β, or combining antigen binding with costimulatory receptor engagement (e.g., CD28).

■ Manufacturing Innovation and Regulatory Frameworks

Manufacturing of BsAbs was once a bottleneck due to structural complexity and yield issues. But the integration of high-throughput screening, cell line engineering, and next-gen purification methods has significantly increased productivity. Regulatory pathways have also matured, with the FDA and EMA now offering specific guidance for BsAb development.

■ Global Pipeline Expansion and Licensing Booms

The 2020s have seen a surge in pipeline expansion, particularly in China, the U.S., and Europe. Licensing deals for BsAb platforms now regularly exceed hundreds of millions in upfront payments. Notable deals include:

Sanofi × Innovent: $2B collaboration on oncology BsAbs
Genmab × AbbVie: Multiple BsAb co-developments
Zymeworks, Xencor, IGM Biosciences: Platform licensing leaders

■ Summary

Bispecific antibody technology has evolved from unstable, exploratory formats to highly-engineered, multifunctional therapeutics. Future innovation will likely be shaped by continued AI integration, new target discovery, and modular biologic engineering. The rapid pace of clinical approvals and deals signals a paradigm shift in biologic therapy.

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This article was produced by the Morningglorysciences editorial team.

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Author of this article

Morning Glory Sciences

After completing graduate school, I studied at a Top tier research hospital in the U.S., where I was involved in the creation of treatments and therapeutics in earnest. I have worked for several major pharmaceutical companies, focusing on research, business, venture creation, and investment in the U.S. During this time, I also serve as a faculty member of graduate program at the university.