developing-low-viscosity-high-concentration-bsab-formulations
Developing bispecific antibodies for subcutaneous delivery often hits a wall: viscosity. This guide offers a data-forward approach to untangle the knot, clearing the path to stable, patient-friendly formulations. Discover how to overcome this pressing challenge.
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Untangling the Knot: A Practical Guide to Low-Viscosity, High-Concentration Bispecific Antibody Formulations
1. Current Situation
2. Typical Market Trends
3. Current Challenges and How They Are Solved
4. How Leukocare Can Support These Challenges
5. Value Provided to Customers
6. FAQ
Untangling the Knot: A Practical Guide to Low-Viscosity, High-Concentration Bispecific Antibody Formulations
For Directors of CMC and Drug Product Development, the path to a successful biologic is paved with complex challenges. Among the most pressing is the formulation of bispecific antibodies (bsAbs). These sophisticated molecules hold immense therapeutic promise, but their development, particularly for subcutaneous delivery, often hits a wall: viscosity.
This article offers a straightforward look at the current landscape, the hurdles teams like yours are facing, and how a data-forward, collaborative approach can clear the path to a stable, effective, and patient-friendly product.
1. Current Situation
The excitement around bispecific antibodies is justified. With their ability to engage two different targets, they are creating new treatment possibilities in oncology and autoimmune disease. The market reflects this, with projections showing a surge from approximately US$12 billion in 2024 to US$50 billion by 2030. [1] As of early 2025, 17 bispecific antibodies have gained approval in major markets, a number that is steadily climbing. [1]
A significant driver of this evolution is the move toward subcutaneous (SC) administration. Patients prefer the convenience of SC injections, which can be done at home, improving adherence to treatment regimens. This shift is fueling growth in the subcutaneous drug delivery market, expected to reach nearly USD 57 billion by 2030. [2]
SC delivery presents a core technical problem. The volume that can be comfortably injected is small, typically between 1-2 mL. [3] To deliver a therapeutic dose within this volume, formulations must be highly concentrated, often exceeding 100 mg/mL. At these concentrations, protein molecules are packed closely together, leading to strong intermolecular interactions that can cause a dramatic increase in viscosity. This creates a bottleneck that can stall development and compromise the final product's viability.
2. Typical Market Trends
We are seeing a few clear trends emerge as more companies tackle bsAb development:
A "Formulation First" Mentality: Teams are recognizing that formulation cannot be an afterthought. Early investment in formulation development is becoming standard practice to identify and mitigate risks like high viscosity and aggregation before they derail a program in late-stage development. This is especially true for virtual and fast-track biotechs where speed and a clean path to a Biologics License Application (BLA) are everything.
The Rise of Delivery Devices: The market for autoinjectors and wearable injectors is growing alongside the demand for SC biologics. [5, 6] These devices have their own performance limits, often struggling with viscosities above 20-25 cP. [7] This puts firm technical constraints on formulation teams from the very beginning.
Predictive Tools are Becoming Essential: The industry is moving away from purely empirical, trial-and-error screening. Machine learning and AI-driven platforms are gaining traction, helping teams predict formulation behavior, reduce the number of experiments, and save precious and expensive drug substance. [8, 9] This data-driven approach allows for a more intelligent and efficient development process.
3. Current Challenges and How They Are Solved
The central challenge is high viscosity. This isn't just a matter of being difficult to push through a syringe; it can also cause problems during manufacturing, such as with filtration and pumping, and may be linked to other instabilities like aggregation and opalescence. [10]
The molecular complexity of bsAbs, which often have asymmetric structures, makes them particularly prone to the strong protein-protein interactions that drive up viscosity. [11, 12]
Currently, development teams use several strategies to manage this:
Excipient Screening: This is the most common approach. Scientists screen a variety of small molecules, like amino acids (arginine, proline), salts, and sugars, to find ones that can disrupt the protein-protein interactions causing high viscosity. Finding the right excipient or combination is not always straightforward, and some can even destabilize the protein at the required concentrations. [13, 14, 15]
Optimizing Buffer Conditions: Adjusting the pH of the formulation can alter the surface charge of the protein, which can help reduce electrostatic interactions and lower viscosity. [14]
Rational Protein Engineering: In some cases, the antibody sequence itself can be modified to remove "hot spots" on the surface that are prone to interaction. This is a powerful but complex strategy that must be implemented very early in the discovery phase. [16]
Advanced Analytics: Techniques like dynamic light scattering (DLS) are used to measure protein-protein interactions and help predict which candidates are likely to have viscosity problems at high concentrations.
These methods are useful, but they can be slow and consume a large amount of material. [3] For small biotechs with limited resources or fast-moving programs under pressure, this can be a significant roadblock.
4. How Leukocare Can Support These Challenges
This is where a dedicated formulation partner can change the trajectory of a project. Our approach is designed to address the specific pain points we see across the industry, from virtual biotechs to large pharma.
We don’t believe in a one-size-fits-all solution. For a fast-track biotech leader under pressure to reach the BLA quickly, our focus is on speed and regulatory readiness. Our claim is direct: "We help you reach BLA faster, with a formulation designed by science, guided by data, and built for regulatory success."
For a mid-size biotech hitting a wall with a difficult molecule, we act as specialized reinforcements. We can tackle a single complex problem, like viscosity or stability, without disrupting your existing partnerships. Our promise is to "solve one complex problem, using our modeling platform and formulation intelligence to deliver results you can trust."
Our core is a data-centric methodology. We utilize a smart formulation platform that combines AI-driven predictive modeling with our extensive experience. This allows us to:
Forecast Stability and Viscosity: By modeling how a specific bsAb will behave in different formulations, we can intelligently narrow down the experimental space. This significantly reduces the amount of wet-lab work, saving time and, critically, preserving your valuable drug substance.
Provide a Clear Path Forward: We deliver more than just a formulation. We provide a structured development plan with comprehensive documentation formatted for investors and regulatory agencies, giving you a robust CMC story.
Act as a Strategic Partner: We work as an extension of your team. We understand the internal pressures and the need for clear, actionable data. Our goal is to provide proactive solutions and the scientific rationale to support your internal decision-making, helping you de-risk your development path. For companies tackling new modalities, we affirm: "We don't pitch templates, we guide your modality path with real data, real expertise, and tailored formulation design."
5. Value Provided to Customers
Working with a dedicated formulation partner provides tangible benefits that go beyond solving a technical problem.
De-risking Your Program: By identifying a stable, low-viscosity formulation candidate early, we help you avoid the immense cost and delay of a late-stage failure.
Accelerating Timelines: Our predictive approach shortens the development cycle. Less time spent on empirical screening means getting to the clinic and to the market faster.
Enabling a Patient-Centric Product: A successful high-concentration, low-viscosity formulation makes subcutaneous delivery possible. This improves the patient experience and can be a key differentiator in a competitive market.
Delivering Confidence and Clarity: You get a reliable partner who understands your goals and provides the data and strategic support to achieve them. We don't just execute; we think alongside you to ensure the project succeeds. For our CDMO partners, this means seamless integration: "We act as your formulation team, silent, seamless, and science-backed, always loyal to your client relationship."
6. FAQ
Q1: How early should we start thinking about high-concentration formulation for our bsAb?
It's never too early. Ideally, formulation considerations should begin during lead candidate selection. Early characterization can help identify molecules that are less prone to viscosity and stability issues, saving significant time and resources down the road.
Q2: My bsAb is already showing high viscosity in early experiments. Is it too late to fix?
Not at all. While an inherently well-behaved molecule is always preferred, advanced formulation strategies can often mitigate high viscosity. Through careful selection of pH and excipient combinations, guided by predictive modeling, it's possible to develop a viable formulation for molecules that initially seem challenging.
Q3: How much material do you need for an initial formulation screen?
Significantly less than traditional methods. Because our AI-powered platform predicts behavior and narrows the experimental design, we can conduct initial screens with a minimal amount of material. This is a major advantage for early-stage programs where drug substance is limited.
Q4: How does your AI platform work and what makes it different?
Our platform uses machine learning algorithms trained on a deep, proprietary database of formulation data. It analyzes the specific sequence and structure of your molecule to predict its behavior in various buffer and excipient combinations. What makes it different is the integration of this predictive power with the hands-on experience of our formulation scientists. The AI provides the map, but our experts guide the journey, ensuring we arrive at a practical, robust, and manufacturable solution.
