The Benefit of Technological Advancements to BsAb Development

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Research and development on bispecific antibodies (BsAbs) are currently at the forefront of cancer immunology therapies. Researchers as well as drug developers are quicker to innovate promising immuno-oncology solutions based on bispecific—and multispecific—antibodies. There remain a host of obstacles yet to overcome in the bispecifics field, such as complex design, immunogenicity, a limited half-life, and off-target effects, among other hurdles (1).

However, in recent years, the presence of approved BsAbs on the market has grown, representing the developmental and regulatory success of these therapies. This year has also seen considerable advancement in the BsAbs field.

Current advancements

Several BsAbs achieved their first regulatory approvals in 2024, such as ivonescimab, which was approved for second-line treatment of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) in China (2) and which has demonstrated promising clinical results, says Desmond Schofield, chief business officer, evitria. Similarly, cadonilimab, a programmed cell death (PD)-1/cytotoxic T lymphocyte antigen 4 (CTLA-4) BsAb, received approval for advanced gastric and cervical cancers in China (3). Schofield also points out other noteworthy regulatory and developmental milestones that have been reached, including Johnson & Johnson's definitive agreement with Swiss biotech Numab Therapeutics to acquire global rights to NM26, a Phase II-ready bispecific antibody for atopic dermatitis (4). “The biopharmaceutical industry also boasts a pipeline filled with bispecific antibody candidates for a wide array of therapeutic applications,” Schofield says.

Atul Mohindra, head of Biologics R&D, Lonza, notes that biological pipelines are evolving from standard antibody formats to next-generation biologics such as BsAbs due to these molecules’ increased potential for precision targeting and higher potency. He points to several factors that are driving the surge in development and approval of BsAbs, which include increased therapeutic potential, enhanced specificity, novel mechanisms of action, advances in engineering, industry investment, and regulatory support.

“However, these newer molecular formats bring unique challenges related to their development, manufacturing, and analytical methods, which can lead to delayed timelines and added costs,” Mohindra cautions.

In addition to these developmental advancements, Mohindra says that several bispecific products were approved in the United States by FDA in 2024 alone, including tarlatamab for the treatment of extensive-stage small cell lung cancer (SCLC) (5). Other bispecifics have been approved by FDA in more recent years, such as mosunetuzumab for the treatment of adults with advanced follicular lymphoma (6).

Breaking through the wall

In noting the difficult challenges facing developers, Mohindra emphasizes the characteristically highly engineered nature of BsAbs as well as their complex structures. “They can be prone to aggregation and problematic post-translational modifications, leading to low-titer immunogenicity and immunotoxicity problems,” he explains. However, the use of artificial intelligence (AI) has been a “breakthrough” technology when it comes to the development of BsAbs, he adds.

Having a toolbox approach, as Lonza does, for example, and using AI technology to develop in-silico tools, vector design/screening, and analytical method development can help de-risk the production of bispecific molecules. This approach allows for the screening of titer and product assembly at an early stage of development, “leading to more informed decisions and a faster speed to market for companies pursuing the growing area of bispecific molecules,” Mohindra says.

Schofield discusses the development of bispecific antibody drug conjugates (BsADCs), which has been one of the most exciting breakthroughs this year in the bispecifics field. “These [products] combine the specificity of bispecific antibodies with the potent cytotoxicity of drug conjugates, enhancing therapeutic efficacy while minimizing off-target effects,” he explains. “Another notable advancement is in the development of switchable bispecific antibodies that can be toggled on or off to improve safety and efficacy in cancer treatments. Furthermore, several new technologies are now available that minimize the product related impurities, thus streamlining process development,” Schofield adds.

Meanwhile, Schofield says that the industry is addressing the complexity of BsAb design with innovative engineering and high-throughput production techniques. “For instance,” he explains, “early in the discovery process, combinatorial methods are employed to create extensive panels of bispecific antibodies, aiding in the identification of the most promising candidates. To mitigate issues such as immunogenicity and off-target effects, researchers are enhancing the precision of target engagement and optimizing antibody formats.” In addition, the challenges associated with BsAb assembly are being addressed through various strategies intended to guide and ensure correct assembly of different chains. An example that Schofield gives is evitria’s agreement with Lonza (7), which the companies entered into in May 2024, to access Lonza’s bispecific pairing technology (bYlok). This technology helps evitria address the problem of heavy and light chain mispairing.

“With the biopharmaceutical sector shifting towards more complex protein formats, ensuring the manufacturability and scalability of these novel therapies is crucial. Bispecific antibodies require precise pairing of heavy and light chains (HC–LC) to function effectively. Incorrect pairing can lead to reduced efficacy and increased immunogenicity. Traditional methods for producing bispecific antibodies often result in low yields and a mixture of correctly and incorrectly paired molecules,” says Mohindra.

Mohindra explains that Lonza’s technology (bYlok) takes a design engineering approach to developing BsAbs, the key being that this technology has the ability to improve the precision of HC–LC pairing within the BsAb. “This [precision] is achieved by strategically modifying the disulfide bonds in the antibody structure. By altering the position of these bonds, [the] technology promotes the formation of the correct heterodimer species, resulting in a more accurate and efficient production process,” he states.

Mohindra emphasizes that, by driving correct HC–LC pairing, BsAb yields can be improved during the purification process, and the risks of unwanted immunogenicity can be reduced.

Selecting the therapeutic target

Immuno-oncology is a major therapeutic target for BsAb development. And BsAbs are proving to be a promising therapeutic approach in the field of immuno-oncology because of their ability to simultaneously engage multiple targets, which leads to more potent and selective tumor cell destruction. BsAbs are primarily used to redirect immune cells, such as T cells or natural killer cells, towards tumor cells, says Mohindra.

“BsAbs can also activate immune cells more efficiently, leading to a stronger anti-tumor response. Lastly, BsAbs can reduce off-target toxicity because they can be designed to target specific tumor antigens, minimizing damage to healthy tissues. For these reasons, BsAbs offer great potential in the immune-oncology field,” Mohindra further states. “Today, BsAbs are being investigated for a variety of cancer types, including hematological malignancies and solid tumors. Currently, 11 FDA-approved BsAbs are on the market, nine of which are indicated for cancer treatment.”

Applied to immuno-oncology, BsAbs primarily engage T cells and direct them to cancer cells. Schofield notes that this approach has been highly effective in treating hematological malignancies and is now being explored for solid tumors. “Bispecific T-cell engagers (BiTEs) [such as] blinatumomab have paved the way, and newer bispecifics targeting multiple pathways are showing promise in clinical trials,” Schofield says.

Schofield adds that “cis-engaging bispecific antibodies are designed to target two antigens on the same cell, thereby enhancing the precision and efficacy of cancer immunotherapy. This dual-targeting approach not only improves the specificity of the treatment but also reduces the likelihood of off-target effects, making it a promising strategy for treating various types of cancer, including both hematological malignancies and solid tumors. Checkpoint inhibitors that used to be applied in combination therapy, now become an essential part of bispecific antibodies, too.”

Engineering the future of BsAbs

Both Schofield and Mohindra anticipate a bright future for BsAb development. For Schofield, the future looks promising based on advancements in protein engineering and biomanufacturing. “The focus is on creating more precise and effective bispecifics that can target multiple antigens simultaneously. This includes developing multispecific antibodies and next-generation bispecifics that can overcome resistance mechanisms and improve patient outcomes,” Schofield states.

Schofield also expects the integration of AI and machine learning in the design and optimization processes to accelerate the development of these innovative therapies.

“BsAbs are poised to revolutionize therapeutic landscapes,” says Mohindra. “We’re witnessing a surge in BsAb development, particularly in oncology. However, their potential extends far beyond cancer, such as autoimmune diseases, neurological disorders, and infectious diseases,” he adds, explaining that technological innovations are fueling this growth. “Novel formats, engineered Fc regions, and computational design are optimizing BsAbs for better performance and reduced immunogenicity,” Mohindra states.

Mohindra also anticipates that advancements in bioprocessing and analytical testing technologies will be crucial in meeting the increasing demand for BsAbs. These advancements will offer benefits such as reducing cost and time-to-market, he notes. “To overcome these hurdles, researchers and manufacturers are exploring alternative approaches. For instance, combining the use of next-generation cell lines with enhanced productivity with AI technologies leads to improved yields and reduced costs. In addition, advanced analytical methods and in-line testing technologies offer a greater ability to ensure the development of BsAbs. Additionally, techniques [such as] continuous processing and intensified downstream purification can streamline manufacturing and reduce overall costs” Mohindra says.

Mohindra concludes with the thought that, by investing in these innovative approaches, the biopharma industry is working towards making BsAb production more efficient, cost-effective, and accessible. “As research and development continue to advance, we can expect to see even more promising BsAbs-based therapies to prevent, treat, or diagnose diseases in the future, addressing unmet medical needs,” he adds.

References

1. Cambridge Healthtech Institute. Bispecific and Multi-Specific Antibody Therapeutics: Advancing Biotherapeutic Formulation, Analysis, and Delivery. immuno-oncologyeurope.com/bispecific-antibody (accessed Sept. 11, 2024).
2. Akeso. Ivonescimab in Combination with Chemotherapy Approved in China by NMPA for 2L+ EGFRm NSCLC based on HARMONi-A Clinical Trial: Positive Trend Observed in Overall Survival towards Ivonescimab Plus Chemotherapy. Press Release. May 31, 2024.
3. Akeso. Akeso's Cadonilimab Receives Second Indication Approval from NMPA for First-Line Treatment of Gastric/GEJ Cancer in All-Comers Population. Press Release. Sept. 30, 2024.
4. Johnson & Johnson. Johnson & Johnson Strengthens Pipeline to Lead in Atopic Dermatitis with Acquisition of Yellow Jersey Therapeutics. Press Release. July 11, 2024.
5. FDA. FDA Grants Accelerated Approval to Tarlatamab-dlle for Extensive Stage Small Cell Lung Cancer. Press Release. May 16, 2024.
6. FDA. FDA Grants Accelerated Approval to Mosunetuzumab-axgb for Relapsed or Refractory Follicular Lymphoma. Press Release. Dec. 22, 2022.
7. evitria. evitria and Lonza Sign License Agreement to Provide Fast Access to bYlok Bispecific Antibodies for Discovery-Stage Transient Expression Research. Press Release. May 10, 2024.

About the author

Feliza Mirasol is the science editor for BioPharm International.