The New Era of Bispecific Antibodies
After years of research and development, the field of bispecific antibodies (BsAbs) is gaining momentum. More than a dozen bispecific antibodies have secured FDA approval. These new therapies have added much-needed therapeutic value to challenging disease states such as relapsed/refractory multiple myeloma. In 12 months, three distinct CD3-engaging bispecific antibodies were approved for this indication alone. In 2024, the first bispecific indicated to treat solid tumors - extensive stage small cell lung cancer (ES-SCLC) - joined the ranks. Many hundreds more BsAbs are in the clinical pipeline with indications beyond blood cancers and even solid tumors. Their potential applications for autoimmune diseases and rare conditions are generating new approaches for challenging ailments.
As a class, bispecific antibodies unlock new potential for targeted therapeutics. The unique ability of BsAbs to simultaneously target two distinct antigens not available to traditional monoclonal antibodies can improve therapeutic efficacy and reduce the potential for systemic side effects. At the same time, they introduce new development and manufacturing challenges. A nuanced understanding of the therapeutic goals and technical challenges associated with bispecific antibodies is essential for successful development. From early-stage optimization to large-scale manufacturing, it is vital to ensure bispecific antibody stability, scalability, and clinical effectiveness. This process requires close collaboration between drug developers and contract development and manufacturing organizations (CDMOs) with complex antibody development expertise.
Behind the Scenes: Developing Bispecific Antibodies
Developing and manufacturing bispecific antibodies is a multi-step process requiring careful optimization. The journey begins with the design of the complementarity-determining regions (CDRs), the key components of an antibody that determine its specificity and binding affinity to antigens. Identifying CDRs with the desired properties to effectively target both antigens of interest is crucial to the therapy’s success. Once the CDRs are identified, the most promising regions are incorporated into bispecific antibody platforms, which are uniquely engineered for dual antigen recognition.
Next, lead candidates are evaluated for both efficacy and developability. While assessing binding affinity and therapeutic efficacy is crucial in the early stages of bispecific antibody development, evaluating developability is also essential. Effectiveness evaluation involves testing the investigational drug’s binding affinity, stability, and pharmacokinetics. Examining aggregation, viscosity, and overall stability helps inform developability assessments.
Once suitable lead candidates are identified, the focus shifts to developing a cell line to produce the bispecific antibody. This process requires selecting an appropriate cell system and optimizing it for efficient expression of the bispecific antibody. Key considerations for cell line development include the bispecific antibody’s yield, purity, and reproducibility. During this step, biopharma companies and CDMO partners should also be evaluating manufacturability to ensure that the therapy can efficiently scale from clinical trials to longer-term commercial manufacturing.
All is going well, the final step for a successful bispecific program is full-scale production. Production is scaled up, allowing the investments made in the early phases of development to pay off through a seamless transition to larger-scale manufacturing. Stringent quality control measures ensure that the final product is effective, safe, and consistent, making it suitable for clinical trials and market release testing. Each phase of antibody design and manufacturing requires a careful balance between efficacy and developability to facilitate a smooth move to large-scale production, ensuring that the final product is effective and reliable for patients.
The Dual Focus of Bispecific Antibody Development
A dual focus on efficacy and developability is paramount when developing bispecific antibodies. In terms of efficacy, the selection of a bispecific antibody platform after CDR discovery is a very important part. This is because the property of the CDR may vary depending on the platform, and the type of platform required may vary depending on the mechanism of action (MoA) to be applied. Factors such as the stability of the bispecific therapeutic, its potential for aggregation, and its manufacturability all play crucial roles in whether a bispecific antibody can transition from the lab into clinical use. Neglecting developability or selecting the wrong candidate can lead to the failure of a program after years of investment.
To ensure successful drug development, developers must collaborate with CDMOs that prioritize both efficacy and the developability of bispecific antibodies. Teams must select the appropriate bispecific antibody format, assess its stability, and be vigilant about potential challenges such as aggregation and unwanted immunogenicity from the earliest stages of development. Effective screening and early-stage optimization are crucial for identifying and mitigating potential manufacturing pitfalls. This proactive approach is essential to ensure that the bispecific antibody is viable for large-scale production.
Bispecific antibodies present unique challenges throughout the development journey. One of the most notable is the correct pairing of light and heavy chains. Bispecific antibodies consist of two different arms; optimizing their pairing can be difficult. If the heavy and light chains fail to align properly, it can result in reduced binding affinity or improper folding, impairing its therapeutic potential. Poor chain pairing may also lead to production inefficiencies and a high rate of misfolding, which complicates the purification process.
Aggregation continues to be one of the most common and persistent issues in the development of bispecific antibodies. Large and complex molecules, like bispecific antibodies, are prone to aggregation. Aggregation can reduce their therapeutic efficacy and compromise safety through accelerated clearance or immunogenicity. To address potential aggregation issues, it is crucial to screen antibody sequences for their propensity to aggregate. Also, bispecific platforms and engineering technologies play an important role before moving on to the next stage. Not only can formulation conditions be optimized to maintain antibody stability, but cell line development and up and downstream processes are also critical for successful process development. Process development and formulation experts from CDMO partners play a vital role in this area, ensuring bispecific antibodies remain stable, monomeric, and effective from production through clinical trials and manufacturing.
When it comes to performance and safety, the need to minimize unwanted adverse effects should be front-of-mind with BsAb development. Bispecifics can occasionally trigger undesirable immune responses, which is concerning for therapies targeting autoimmune diseases or cancer, as aberrant inflammation can worsen symptoms or lead to additional complications. Developers and their CDMO partners must thoroughly evaluate and optimize the immunogenicity of bispecific antibodies early in the developmental process to reduce risks and prioritize patient safety.
Bispecific Applications: From Cancer to Autoimmune to Rare Diseases
As our understanding of tumor immunology continues to improve, bispecific antibodies are set to play a crucial role in the next generation of cancer immunotherapies. One of the most exciting developments is the use of bispecific antibodies that engage immune cells. One arm of the bispecific antibody targets a cancer cell, while the other arm engages immune cells to trigger cell destruction. This strategy harnesses the body’s natural immune system as a powerful tool to capture and attack cancer cells specifically. By directing immune effector cells - such as T cells, natural killer (NK) cells, or macrophages - bispecific antibodies can guide these cells to the tumor. Furthermore, traditional MoA, such as targeting two antigens in cancer cells helps to overcome resistance mechanisms that make cancer challenging to treat. This “two-pronged” attack mechanism enhances the efficacy of the treatment and minimizes the opportunity for off-target effects commonly associated with traditional therapies.
Beyond oncology, bispecific antibodies are also being investigated as a treatment for certain autoimmune diseases. In these conditions, the immune system mistakenly attacks the body’s tissues or cells, and bispecific antibodies can suppress harmful immune responses and restore normal cellular function. By targeting specific antigens while simultaneously recruiting the immune system to regulate abnormal responses, bispecific antibodies offer a novel approach to treating diseases that have previously been difficult to address with traditional therapies. For instance, bispecific antibodies could target both antigens involved in autoimmune diseases and the immune cells that attack healthy tissues.
Moreover, there could be another application for oncology. For this disease state, the BsAbs could serve as a delivery tool of small molecule drugs to intracellular targets. Dual binding properties of BsAbs enable increased delivery efficiency of small molecule drugs compared to monoclonal antibodies, providing a level of specificity that traditional small molecules or monoclonal antibodies cannot achieve.
Looking Ahead: A Multitude of Options
Bispecifics are the beginning of a new era. As this modality continues to thrive, new opportunities are identified, such as their integration with antibody-drug conjugates (ADCs). ADCs combine the specificity of antibodies with the cell-killing power of cytotoxic drugs. However, the specificity of monoclonal antibodies can limit the effectiveness of these therapies. By engineering bispecific antibodies that recognize different tumor-associated antigens, ADCs can be engineered with enhanced precision, allowing them to target tumor cells more accurately while minimizing damage to healthy tissue. For example, a bispecific ADC could target two distinct tumor antigens, ensuring the cytotoxic payload is delivered exclusively to the cancerous tissue. This hybrid approach has the potential to increase the therapeutic success of ADCs, making them more effective as a cancer treatment while reducing side effects.
Multispecific antibodies add yet another element to bispecific antibodies, increasing the number of antigen recognition sites. Multispecific antibodies are gaining popularity as they expand the capabilities of bispecifics, allowing for greater precision in therapeutic applications. These next-generation therapies can simultaneously target multiple aspects of disease pathology, including various tumor antigens, combinations of immune checkpoints, and pathways involved in cancer and autoimmune diseases. By integrating multiple specificities into a single molecule, multispecifics can potentially treat complex, multifaceted diseases, offering new hope for conditions that have been challenging to address with alternative approaches.
Ultimately, as bispecific antibodies evolve and advance, the importance of developing effective and manufacturable therapies cannot be overstated. With the right balance of innovation, scientific rigor, and collaborative partnerships, bispecific antibodies have the potential to redefine medicine, providing more precise, effective, and safer therapeutic options for patients worldwide.
Author Details
Jina Kim, Director Of Antibody Technology Discovery, Samsung Biologics
Haejin Kweon, Senior Scientist of Antibody Technology Discovery, Samsung Biologics
Publication Details
This article appeared in American Pharmaceutical Review:
Vol. 28, No. 1
Jan/Feb 2025
Pages: 44-46
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