improving-manufacturability-of-bispecific-antibodies
Bispecific antibodies hold immense promise, but their complexity often derails development due to manufacturability issues like instability and aggregation. Discover how a formulation-first strategy can overcome these challenges and accelerate your path to the clinic.
Menu
Making Bispecific Antibodies Manufacturable: A Formulation-First Approach
FAQ
Current Situation
Typical Market Trends
Current Challenges and How They Are Solved
How Leukocare Can Support These Challenges
Value Provided to Customers
Making Bispecific Antibodies Manufacturable: A Formulation-First Approach
Bispecific antibodies (bsAbs) are no longer a niche concept; they are a fast-growing class of therapeutics at the forefront of treating complex diseases.[1] By binding to two different targets, they unlock mechanisms that traditional monoclonal antibodies cannot.[2] This potential is driving significant growth, with the market projected to reach over $15 billion by 2030.[3]
But for all their clinical promise, their structural complexity creates serious headaches during development. Many promising candidates fail before they ever reach the clinic, not because the science is wrong, but because of manufacturability. Issues like instability, aggregation, and purification challenges can derail timelines and exhaust budgets. For CMC and Drug Product teams, the pressure is on to turn these complex molecules into stable, safe, and effective drugs.
This article looks at the real-world challenges of making bispecific antibodies and how a formulation-focused strategy from the beginning can clear the path to the clinic.
Current Situation
Developing a bispecific antibody is a high-stakes endeavor. Their engineered structures, often combining fragments in non-natural ways, make them inherently less stable than their monoclonal predecessors.[4, 6] Problems like aggregation, where proteins clump together, are common and can compromise the product's effectiveness and safety.[7, 8] This instability complicates the entire manufacturing process, from purification to final formulation, often requiring more complex and costly steps to get a pure, stable product.[10, 9]
Typical Market Trends
The momentum behind bispecifics is undeniable. The number of bispecifics in clinical trials has grown exponentially, from under 100 in 2015 to over 650 in 2025.[11] This surge is fueled by their success in oncology, where they can redirect the body's own immune cells to attack tumors.[12] With this growth comes increased scrutiny from regulatory bodies, who expect a deep understanding of the molecule's behavior and a robust manufacturing process.[13, 14] Companies are also pushing for subcutaneous delivery to improve patient convenience, which requires developing high-concentration formulations that can make stability problems even worse.[15]
Current Challenges and How They Are Solved
For teams on the ground, the day-to-day challenges of bispecific development are very practical.
Instability and Aggregation: This is the most common and critical hurdle.[17] Because bispecifics are engineered, they often have exposed hydrophobic regions or awkward structural conformations that make them prone to clumping together or breaking apart.[4, 6] The solution lies in early and intelligent formulation work. Instead of waiting until late-stage development, leading teams screen a wide range of pH conditions, buffers, and excipients during candidate selection.[18] This "developability assessment" helps identify which candidates are most likely to be stable and manufacturable before committing significant resources.[19]
Difficult Purification: The manufacturing process often produces a mix of desired bispecific antibodies, half-antibodies, and other mispaired forms.[21] Separating the target molecule is a significant challenge in downstream processing. A well-designed formulation can help by ensuring the target molecule remains stable during harsh purification steps, such as low-pH viral inactivation, which can otherwise cause the product to aggregate.
High-Concentration Demands: Formulating a bispecific at concentrations over 100 mg/mL for subcutaneous injection is a major goal, but it amplifies every stability issue.[15] At high concentrations, molecules are crowded together, increasing the chances of aggregation and unmanageable viscosity. This requires a deep understanding of the molecule's specific behavior and the careful selection of excipients that can keep the protein stable and the solution injectable.
How Leukocare Can Support These Challenges
We understand these challenges because we work with biotech companies every day to solve them. Our approach is built on partnership and science, designed to anticipate problems, not just react to them.
For the fast-track biotech under pressure to get to BLA quickly, we act as a strategic co-pilot. We use predictive modeling and AI-based tools to accelerate formulation development, helping you find a stable, regulatory-sound formulation faster. We provide the data-driven story needed to give your board and investors confidence.
For the mid-size biotech that hits a wall with existing partners on a new or difficult modality, we offer a way to break in. We can take on a specific challenge, like achieving lyostability for a complex molecule, as a pilot project. We deliver results first, proving our value without disrupting your established workflows, and then help you scale.
For the large pharma team tackling a new modality, we provide the deep, specific insights that generic vendors cannot. We don't use templates. We become a true sparring partner for your internal team, using our technology platform to generate data-backed arguments and tailored materials to help you build internal know-how and make sound regulatory decisions.
Value Provided to Customers
Working with us translates into clear, tangible value for your program.
De-risking Your Path to IND/BLA: We help you build a formulation designed by science and guided by data. This means a more robust CMC package, fewer surprises during development, and a smoother regulatory journey.
Saving Time and Critical Material: We know your drug substance is precious. Our intelligent screening methods get to an optimized formulation with less material, preserving your resources for other critical studies.
Creating a Strong CMC Story: A well-characterized, stable formulation is a cornerstone of a convincing CMC narrative for both investors and regulatory authorities. We provide the robust data that proves your product is well-understood and manufacturable.
Acting as a Seamless Extension of Your Team: We integrate with your existing structure, whether you have a full drug product team or are completely virtual. We handle the formulation complexities independently, reducing the coordination burden on your team and allowing you to focus on the bigger picture.
FAQ
1. At what stage should we start thinking about formulation for a bispecific antibody?
As early as possible. Ideally, formulation screening and developability assessment should happen during candidate selection.[19] Early data on stability and behavior can help you choose a molecule that is not only effective but also manufacturable, saving significant time and money down the road.
2. How does predictive modeling speed up development?
Predictive modeling uses algorithms and a database of formulation outcomes to analyze your molecule's structure and predict its stability in different conditions. This allows us to run thousands of "digital experiments" to identify the most promising formulation space before we start work in the lab. It narrows down the options, so wet-lab experiments are more focused, use less material, and get to a final formulation faster.
3. We already have a preferred CDMO for fill-finish. How do you work with them?
We work as a neutral, external formulation partner. Our role is to develop the optimal formulation "recipe" and provide a comprehensive data package to your CDMO. This makes the tech transfer process smoother and more efficient. We provide the science and the data; they provide the fill-finish execution. This collaborative model ensures everyone focuses on what they do best.[22]
4. What does a typical data package for a regulatory filing look like from you?
You receive a complete data package that is ready for the CMC section of your IND or BLA filing. This includes a full description of the chosen formulation, the rationale for its selection, and extensive stability data under various stress conditions (e.g., temperature, agitation, freeze-thaw cycles). The goal is to provide regulators with a clear and convincing story that your formulation is stable, robust, and well-characterized.[23]
