The Bispecific Revolution: How Dual-Targeting Antibodies Are Reshaping Therapy and Creating a Manufacturing Bottleneck

May 27, 2025

The biopharmaceutical industry is in the throes of a revolution, one engineered with atomic precision in the heart of a protein. This is the era of the bispecific antibody (BsAb), a class of therapeutics that has moved decisively from the cutting edge of scientific research to the front lines of clinical practice. With a market that surpassed $12 billion in 2024 and is projected to explode to $50 billion by 2030, the science is no longer in question. The approvals are landing, and the clinical pipeline is overflowing with more than 600 molecules in development as of early 2025.

Unlike traditional monoclonal antibodies (mAbs) which bind to a single target, bispecifics are the Swiss Army knives of modern medicine, designed to engage two different targets simultaneously. This dual-action capability unlocks a host of powerful therapeutic mechanisms. The most prominent of these is T-cell redirection, where one arm of the antibody grabs a tumor cell while the other grabs a T-cell, forcing an introduction that proves fatal for the cancer. Other strategies involve blocking two separate disease-driving pathways at once, a tactic showing immense promise in both oncology and complex autoimmune disorders.

The clinical success has been staggering. Within a single 12-month period, three different T-cell engaging bispecifics were approved for relapsed/refractory multiple myeloma, a testament to their profound efficacy. In May 2024, Amgen’s tarlatamab (Imdelltra™) became the first bispecific T-cell engager approved for a major solid tumor, treating extensive-stage small cell lung cancer and opening a new chapter for this technology.

But this triumph has created a massive, downstream problem – a challenge not of science, but of infrastructure. The bispecific boom is straining the industry’s ability to produce these intricate molecules and find the niche talent required to oversee their complex lifecycle. The central question in biopharma has pivoted from if these drugs work to who can actually make them.

This article will explore the breathtaking scope of the bispecific revolution, from the late-stage clinical programs redefining standards of care to the immense manufacturing and talent bottlenecks that threaten to slow its progress. We will delve into the specific technological hurdles that make these drugs a different league of complex, the infrastructure arms race among the world’s leading Contract Development and Manufacturing Organizations (CDMOs) to meet the demand, and the critical shortage of human expertise that has become the new rate-limiting step in bringing these transformative therapies to patients.

Part 1: The Clinical Triumph – A Pipeline Overflowing with Promise

The late-stage clinical landscape for bispecific antibodies is a testament to years of sophisticated protein engineering finally bearing fruit. The pipeline is not only crowded but is actively reshaping treatment paradigms, demonstrating superiority over established standards of care and offering hope where there was none. This success is most pronounced in hematology but is rapidly expanding to conquer the formidable challenge of solid tumors and complex autoimmune diseases.

The New Standard in Hematology

Nowhere has the impact of bispecifics been more immediate or profound than in hematological malignancies. A trio of target classes has emerged, each with multiple approved drugs and a deep pipeline, creating a fiercely competitive environment.

CD20xCD3: A New Pillar in Lymphoma Treatment

The CD20 antigen on B-cells is a classic, validated target, and bispecifics that tether CD20-positive malignant cells to CD3-positive T-cells have proven remarkably effective. A wave of approvals has established this class as a new standard of care:

Glofitamab (Columvi™) from Roche, featuring a unique 2:1 format with two binding sites for CD20, was approved in 2023 for relapsed/refractory (R/R) Diffuse Large B-cell Lymphoma (DLBCL). In June 2024, a Phase 3 trial showed it significantly improved overall survival when combined with chemotherapy in this setting.

Epcoritamab (Epkinly®), co-developed by Genmab and AbbVie, also gained approval for R/R DLBCL in 2023. It has shown stunningly high response rates in previously untreated follicular lymphoma and high-risk DLBCL when used in combinations.

Mosunetuzumab (Lunsumio®), another Roche product, was a frontrunner, securing approval in 2022 for R/R Follicular Lymphoma (FL). It exemplifies the strategy of moving up the treatment ladder, as it is now being studied in newly diagnosed and lower-tumor burden settings.

Odronextamab, from Regeneron, received EU approval in 2024 for both R/R FL and R/R DLBCL and is currently under review by the FDA.

A key advantage of these therapies is their “off-the-shelf” nature. Unlike complex, individualized CAR T-cell therapies, these bispecifics are readily available biologics, a significant logistical benefit that facilitates their use in community oncology settings.

BCMAxCD3 and GPRC5DxCD3: Transforming the Multiple Myeloma Landscape

The B-Cell Maturation Antigen (BCMA) is expressed on virtually all malignant plasma cells, making it an ideal target in multiple myeloma. The result has been an unprecedented flood of highly effective BCMAxCD3 T-cell engagers, transforming the outlook for patients with this incurable disease.

Teclistamab (Tecvayli®) from Janssen (a Johnson & Johnson company) was the first-in-class, approved in 2022 for heavily pretreated R/R myeloma.

Elranatamab (Elrexfio™) from Pfizer followed in 2023 with an approval for a similar patient population.

Linvoseltamab (Lynozyfic™ in the EU) from Regeneron was approved in the EU in 2024/2025 and is under FDA review. Pivotal trials showed a 71% response rate in heavily pretreated patients, with nearly half achieving a complete response.

The rapid succession of these approvals has created a highly competitive market. Building on this success, Janssen also brought the first GPRC5D-targeted bispecific to market, Talquetamab (Talvey®), approved in 2023. GPRC5D is another antigen highly expressed on myeloma cells, and Talquetamab provides a completely new mechanism of action for patients, including those who may have relapsed after BCMA-targeted therapy.

Notably, many of these leading hematology drugs (epcoritamab, teclistamab, elranatamab, talquetamab) are administered subcutaneously. This method is more convenient for patients and may help mitigate severe side effects like Cytokine Release Syndrome (CRS) by allowing for slower drug absorption compared to intravenous infusion.

Cracking the Solid Tumor Code

Translating the success of bispecifics into solid tumors has been more challenging due to physical barriers like the dense tumor microenvironment (TME). However, recent breakthroughs and a diversification of strategies are proving that this hurdle can be overcome.

The Rise of PD-1xVEGF: A New Immuno-Oncology Power Couple

One of the most exciting trends in solid tumors is the dual blockade of PD-1 and VEGF. This combination is powerfully synergistic: blocking VEGF not only chokes off a tumor’s blood supply but also helps normalize tumor vasculature, allowing immune cells to better penetrate the TME and do their job, which is enhanced by the simultaneous PD-1 blockade.

Ivonescimab (AK112/SMT112), from Akeso Biopharma and Summit Therapeutics, is the undisputed leader in this class. In May 2024, it became the first PD-1xVEGF bispecific approved anywhere in the world, receiving the green light in China. More importantly, it was the first bispecific antibody to demonstrate superiority over a standard PD-1 inhibitor (pembrolizumab) in a head-to-head Phase 3 trial for a major solid tumor indication (NSCLC). Global Phase 3 results are expected by mid-2025.

The intense interest in this target pair is underscored by major business deals. In May 2025, Pfizer inked a massive agreement with Chinese firm 3SBio to license its PD-1xVEGF candidate, SSGJ-707, paying $1.25 billion upfront with a total potential value of over $6 billion.

Compass Therapeutics is also advancing its own tetravalent PD-1xVEGF-A bispecific, CTX-10726, with an IND filing expected in late 2025.

Precision Oncology with Novel Targets

Beyond broad immunotherapies, bispecifics are enabling highly targeted approaches for genetically defined solid tumors.

HER2-Axis Innovation: Zymeworks’ Zanidatamab (Ziihera®), approved in the US in 2024 for HER2+ biliary tract cancer, is a “biparatopic” antibody that binds to two different places on the HER2 receptor, leading to more potent receptor clustering and degradation. Merus N.V.’s Zenocutuzumab (Bizengri®), also approved in 2024, targets HER2 and HER3 to specifically shut down signaling in tumors driven by NRG1 gene fusions.

DLL3 for Small Cell Lung Cancer: Amgen’s Tarlatamab (Imdelltra™), approved in May 2024, was a landmark achievement. It is the first T-cell engager approved for a major solid tumor and the first therapy to successfully target DLL3, an antigen found on the surface of neuroendocrine tumors like SCLC but largely absent from healthy tissue.

Other Key Pairs: Other approved agents are tackling different solid tumor pathways, including Johnson & Johnson’s Amivantamab (Rybrevant®), which targets EGFR and c-Met in NSCLC with specific EGFR exon 20 insertion mutations, and Akeso’s Cadonilimab, which targets the dual checkpoints PD-1 and CTLA-4 and is approved in China for cervical cancer.

Beyond Oncology: A New Frontier in Autoimmunity and Obesity

Perhaps most exciting is the strategic expansion of bispecifics beyond cancer into complex, chronic diseases.

Inflammatory Bowel Disease (IBD): In a landmark deal, Sanofi committed up to $1.8 billion in April 2025 to license two potential first-in-class bispecifics from AI-driven biotech Earendil Labs. HXN-1002 targets α4β7 and TL1A, while HXN-1003 targets TL1A and IL-23, both aiming to provide superior efficacy in diseases like ulcerative colitis and Crohn’s disease.

Obesity: Harbour BioMed recently launched a new company, Élancé Therapeutics, dedicated to creating next-generation obesity treatments using its HCAb-based bispecific antibody technology. The goal is to develop therapies that not only improve weight loss but also preserve muscle mass, a key challenge with current treatments.

Ophthalmology: Innovent Biologics is developing Efdamrofusp alfa, a bispecific fusion protein targeting both VEGF and the Complement pathway for Diabetic Macular Edema (DME), addressing two key pathological drivers of the disease simultaneously.

This diversification is a logical evolution. The technological platforms, once validated in the high-stakes world of oncology, are now being deployed to tackle other complex, multifactorial diseases where dual-targeting offers a clear therapeutic advantage.

Part 2: The Manufacturing Maze – Why Making Bispecifics is a Different League

The elegant complexity that makes bispecific antibodies so potent in the clinic also makes them a formidable challenge in the manufacturing plant. Producing a traditional monoclonal antibody is already a highly controlled, difficult process. Manufacturing a bispecific, which is essentially two different antibodies fused into one, adds layers of complexity that require specialized platforms, processes, and expertise.

The Core CMC Challenge: A Molecular Jigsaw Puzzle

The fundamental problem in Chemistry, Manufacturing, and Controls (CMC) for bispecifics lies in their structure. A typical IgG-like bispecific antibody is composed of two different heavy chains and two different light chains. The primary manufacturing challenge is ensuring these four chains assemble correctly into the desired functional molecule and do not instead form inactive or undesirable byproducts.

The Chain-Pairing Headache: If the two different heavy chains pair with themselves, they form monospecific “homodimers” instead of the desired bispecific “heterodimer”. Likewise, the light chains must pair correctly with their cognate heavy chains. Any mispairing leads to a cocktail of non-functional or potentially immunogenic byproducts that are difficult to separate from the active drug. This issue, known as the “chain association” problem, was a major roadblock in the early days of bispecific development.

Purity, Yield, and Stability: The purification process for bispecifics is inherently more complex. Downstream processing must be designed to effectively remove closely related impurities like homodimers, which may share very similar physicochemical properties with the target molecule. Furthermore, these intricate, engineered proteins can sometimes be less stable or express at lower levels (yield) in cell culture compared to standard antibodies, demanding highly optimized processes to be commercially viable.

To de-risk these programs, the industry has widely adopted the concept of “developability assessment,” where CMC and manufacturing considerations are integrated very early in the discovery process to engineer out potential liabilities before a candidate is selected.

The Engineering Solutions: A Tour of Key Platforms

To solve the chain-pairing problem, scientists have devised a stunning array of sophisticated protein engineering strategies. The vast majority of late-stage programs use IgG-like formats, which retain the antibody’s Fc region to give the molecule a longer half-life in the body, a crucial advantage over smaller fragment-based formats.

Solving the Heavy Chain Problem: The most widely used technology to force heavy chains to pair correctly is the “Knobs-into-Holes” (KiH) platform, pioneered by Genentech (Roche). This involves engineering a bulky amino acid “knob” into one heavy chain and a complementary “hole” in the other, making heterodimer formation far more energetically favorable than homodimer formation. CDMOs have embraced this approach, with Samsung Biologics offering its proprietary S-DUAL™ and S-KiH™ platforms, which are based on the KiH design and boast a 99% chain-pairing success rate. Other strategies include using electrostatic steering, as seen in Merus’s DEKK platform used for Zenocutuzumab. Many T-cell engagers also use a human IgG4 scaffold, which is engineered to be stable and have a “silenced” Fc region to prevent unwanted immune interactions. This is the case for Regeneron’s odronextamab and linvoseltamab, and Janssen’s teclistamab and talquetamab.

Solving the Light Chain Problem: To ensure light chains don’t pair with the wrong heavy chain, companies use technologies like CrossMab (also from Roche) or develop antibodies with a “common light chain” that can pair with both different heavy chains.

Advanced Formats and Fragment Evolution: While IgG-like formats dominate, fragment-based platforms remain important. Amgen’s pioneering BiTE® (Bispecific T-cell Engager) format, which is just two antibody fragments linked together, has a very short half-life requiring continuous infusion. To overcome this, Amgen developed the Half-Life Extended (HLE) BiTE® format by fusing an Fc domain to the fragment, as used for the approved solid tumor drug Tarlatamab. Meanwhile, the field is already moving toward more complex designs like tetravalent antibodies (with four binding sites), such as Ivonescimab, and trispecific antibodies that engage three targets, like Merck’s recently acquired MK-6070.

Innovations in the Manufacturing Process

Beyond the design of the molecule itself, CDMOs and developers are innovating across the manufacturing process to improve efficiency and quality.

Advanced Cell Line Development: The foundation of any biologics process is the cell line that produces it. Thermo Fisher Scientific recently launched an enhanced development platform featuring a new proprietary CHO K-1 cell line capable of producing bispecifics at titers up to a remarkable 8 g/L, significantly boosting productivity. AGC Biologics leverages its proven CHEF1® expression platform, which has a long track record of developing stable cell lines for complex molecules.

Process Intensification and Continuous Manufacturing: To increase yield and improve product quality, especially for less stable molecules, companies are turning to continuous manufacturing. Fujifilm’s “MaruX™” platform is a key example. This continuous production system can achieve up to five times higher productivity than traditional batch methods and can reduce product degradation that occurs during long culture times, thereby improving purity and potentially cutting the cost of goods by up to 50%.

AI and Data Science: The complexity of bispecific manufacturing makes it a perfect candidate for optimization using artificial intelligence. Fujifilm is actively using AI to slash the time it takes to develop culture media recipes and is integrating AI with advanced sensors for real-time process visualization, aiming to eliminate quality variations and ensure consistently high productivity.

Part 3: The Infrastructure Arms Race – How CDMOs Are Responding

The explosive growth of the bispecific pipeline has ignited a veritable arms race among the world’s leading CDMOs. This isn’t just about adding more stainless-steel bioreactors; it’s a strategic shift from providing undifferentiated capacity to building highly specialized, end-to-end technological platforms designed to solve the specific challenges of complex biologics. The winners are positioning themselves not as simple contractors, but as indispensable partners with deep technical know-how.

Profiles in Strategic Expansion

Fujifilm Diosynth Biotechnologies: Fujifilm is in the midst of a multi-billion-dollar global expansion, with a cornerstone being its “KojoX™” initiative—a network of massive, standardized, modular facilities designed for rapid and reliable tech transfer of complex biologics. Major sites in Hillerød, Denmark, and Holly Springs, North Carolina, are being built out with dozens of 20,000L bioreactors explicitly designated for next-generation antibodies, including bispecifics. The validation for this enormous investment came in April 2025, when Regeneron signed a landmark 10-year manufacturing agreement valued at over $3 billion to secure US-based production at the new Holly Springs site. This deal, made with a leader in bispecifics even before the facility was fully operational, was a massive vote of confidence in Fujifilm’s strategy and capabilities.

Samsung Biologics: Samsung has pursued a strategy of achieving both massive scale and technological leadership. Its new Plant 5 in South Korea, which came online in April 2025, added 180,000 liters of capacity, bringing its total to a world-leading 784,000 liters. This physical expansion is coupled with a deep investment in proprietary platforms like the S-DUAL™ and S-KiH™ bispecific antibody technologies, as well as a new, dedicated facility for producing complex Antibody-Drug Conjugates (ADCs), which is highly relevant for the emerging class of bispecific ADCs.

Lonza: Rather than building entirely from scratch, Lonza made a bold strategic move in October 2024 by acquiring one of the world’s largest biologics manufacturing facilities from Roche in Vacaville, California. This immediately added 330,000 liters of existing capacity. Lonza then announced it would invest a further CHF 500 million to upgrade the site specifically to handle the demands of “next-generation mammalian biologics therapies,” a category where bispecifics are a key component. This approach rapidly secured a commanding position in the large-scale US market for complex antibodies.

WuXi Biologics: WuXi Biologics has differentiated itself through deep, accumulated experience and a unique global strategy. The company’s integrated project portfolio includes an astounding 151 bispecific and multispecific antibodies, positioning it as an industry leader in handling these molecules. Acknowledging geopolitical realities, WuXi Biologics is pursuing an aggressive “Global Dual Sourcing” strategy, establishing major, advanced manufacturing hubs in the US (Worcester, MA) and Europe (Dundalk, Ireland) in addition to its sites in China. This offers clients unparalleled supply chain security and manufacturing redundancy, a crucial differentiator for high-value, life-saving therapies.

A New Era of Partnership

These massive CDMO investments are not being made in a vacuum. They are a direct response to, and are often underpinned by, the needs of pharmaceutical innovators. The relationship is shifting from a transactional outsourcing of capacity to one of deeply embedded, collaborative problem-solving. Innovators are not just looking for an empty bioreactor; they are seeking a partner who can help de-risk the entire development and manufacturing journey for their most complex and valuable assets. The potential influence of legislation like the US BIOSECURE Act, which may encourage domestic manufacturing, likely further reinforces the strategic value of the major investments being made by these CDMOs in the US and Europe.

Part 4: The People Problem – A Crisis-Level Demand for Niche Talent

The gleaming new facilities and advanced platforms are only one part of the equation. The other, more pressing bottleneck is human. The bispecific boom has ignited a fierce, industry-wide war for talent, creating a crisis-level demand for a limited pool of professionals with the niche skills required to shepherd these complex molecules from the lab to the patient. This “people problem” may be the ultimate rate-limiting factor in the bispecific revolution.

The Anatomy of a Talent Shortage

The skills needed to develop and manufacture a bispecific antibody are not the same as those for a standard mAb. The increased complexity across the board demands a deeper level of expertise.

CMC & Analytical Development: This is perhaps the most acute pain point. The structural intricacy of bispecifics requires a far more sophisticated and comprehensive analytical strategy to ensure identity, purity, and potency. A 2024 market report already noted a “limited availability of skilled professionals” for general pharmaceutical analytical testing; this shortage is significantly worse for the niche of complex biologics. Companies are desperately seeking PhD-level scientists who can develop novel HPLC and electrophoresis methods to do things like accurately quantify heterodimer purity or characterize unique impurity profiles—tasks that are simply not required for mAbs. Job postings from AbbVie, Regeneron, and Amgen consistently call for specialists with experience in state-of-the-art analytical methods for “novel bispecific constructs” and “complex biologics”.

Specialized Manufacturing (MSAT & Tech Transfer): The process of transferring a bispecific manufacturing process from a development lab to a commercial-scale facility (tech transfer) is fraught with challenges. The teams responsible for this, typically called Manufacturing Sciences and Technology (MSAT), are in high demand. They need a deep understanding of how novel formats and formulations will behave at scale. Job listings from Lonza, WuXi Biologics, and UCB seek MSAT engineers and scientists with subject matter expertise in biologics tech transfer and process validation, roles that are critical for bridging the gap between development and manufacturing.

Bioconjugation Experts: The rise of even more complex formats, particularly bispecific antibody-drug conjugates (BsADCs), has created a new demand for scientists skilled in bioconjugation. These experts must master the delicate chemistry of linking cytotoxic drug payloads to bispecific antibodies, a field requiring interdisciplinary knowledge. The research collaboration between Merus and Biohaven to develop “ADClonics” is a prime example of this trend, and biotech firms like Abzena and Voyager Therapeutics are actively hiring scientists with experience in linker chemistries and the purification of these multi-component drugs.

Quality Assurance (QA) for Sterile Fill-Finish: The final step—aseptically filling vials or pre-filled syringes with the sterile drug product—is a critical control point overseen by Quality Assurance. For sensitive, high-value biologics like bispecifics, this requires QA teams with deep experience in sterile processing and validation. The growing trend toward patient-friendly pre-filled syringes and auto-injectors adds another layer of complexity related to device compatibility and regulation, further increasing the demand for skilled QA professionals.

The Evolving Skillset for the Bispecific Era

The talent crunch is forcing a re-evaluation of required skills. It is no longer enough to be a siloed expert. The most valuable professionals are those with a holistic, cross-functional understanding of the entire drug development lifecycle, from discovery to regulatory approval. Furthermore, the increasing integration of data science and AI into process development and manufacturing means the workforce of the future must be more digitally literate, comfortable interpreting large datasets, and capable of working alongside automated systems.

Conclusion

The bispecific revolution is undeniably real, and its impact on medicine will be profound. The science has delivered, producing a wave of therapies that are demonstrating transformative efficacy in oncology and are now poised to tackle a host of other complex diseases. The clinical pipeline is robust, and the market is expanding at a staggering pace.

However, this very success has revealed the industry’s new frontier of challenges. The central battleground has shifted from the laboratory to the factory floor and the human resources department. The intricate nature of these dual-targeting molecules has created an unprecedented demand for specialized manufacturing infrastructure and a niche, highly-skilled workforce to run it.

The world’s leading CDMOs are responding with multi-billion-dollar investments, racing to build the advanced platforms and secure the large-scale capacity required. But building facilities is only half the battle. The concurrent war for talent—for the analytical chemists, the MSAT engineers, the bioconjugation experts, and the QA specialists who possess the rare experience needed for these complex programs—is just as intense, and perhaps more difficult to win.

The winners in the next decade of biopharma will be the innovators and manufacturing partners who recognized this pivot early. They are the ones who understood that for bispecific antibodies, the path to the patient runs not just through brilliant science, but through a highly specialized, technologically advanced, and expertly staffed manufacturing network. The race for capacity and talent is on, and it will define the future of this therapeutic revolution.

Hiring in Bispecific Antibodies, and/or CDMO? Need some guidance/advice? Click here to talk to us directly: www.progensearch.com/talk-to-uk