Bispecific antibodies (bsAbs) unlock novel therapeutic mechanisms by simultaneously targeting two antigens, while antibody-drug conjugates (ADCs) deliver potent cytotoxic payloads directly to diseased cells. The GeniusBsAb™ platform, with its unique common light chain technology, has pioneered a new approach to bsAbs and bsADCs development. This platform enables the efficient generation of fully human, native-format bsAbs with minimal chain mispairing and optimal developability profiles.

Overview of Bispecific Antibodies

Bispecific antibodies represent a advanced class of therapeutic molecules engineered to recognize two distinct epitopes or antigens simultaneously. This unique capability unlocks powerful therapeutic mechanisms impossible for conventional monoclonal antibodies, such as redirecting immune cells like T cells directly to tumor cells, blocking two signaling pathways synergistically, or delivering payloads more precisely to diseased tissues. The primary advantages of bispecific antibodies include enhanced efficacy through dual-target engagement, the potential for reduced off-target effects, and the ability to create novel therapeutic functions that can address complex diseases like cancer and autoimmune disorders more effectively.

Fig.1 Examples of bispecific antibodies (bsAb) formats and structural diversity: (a-f) IgG-like bsAbs and (g-l) fragment-based bsAbs. (Register A C, et al., 2021)

Challenges in Bispecific Antibody Development

A major challenge in the development of bispecific antibodies (bsAbs) is chain mispairing, where the heavy and light chains of two distinct specificities are mismatched, resulting in a heterogeneous mixture of active and inactive material that is difficult to purify. This complexity often requires complex protein engineering and cumbersome downstream processing, increasing development costs and time. Furthermore, ensuring the final molecule possesses favorable drug-like properties is a major hurdle. Finally, even if a drug candidate is selected, scaling up production to achieve high-purity, consistent yields of the bsAbs remains a significant barrier to clinical and commercial success.

GeniusBsAb™: Fully Human Bispecific Antibody Platform

The GeniusBsAb™ platform is a groundbreaking transgenic mouse model engineered for the efficient discovery of fully human bispecific antibodies and bispecific ADCs. Its key innovation lies in the in-situ replacement with a complete human heavy chain variable region repertoire paired with a common light chain variable region. This innate design naturally circumvents the pervasive challenge of light chain mispairing, enabling the generation of pure, stable, and developable bispecific antibodies directly from a native in vivo environment. By leveraging a fully human immune system, the platform delivers high-quality leads with low immunogenicity risk, significantly streamlining the development path for next-generation bispecific therapeutics.

Fig.2 GeniusBsAb™ mice feature fully human heavy chain variable regions and an in-situ replaced common light chain, effectively eliminating light chain mispairing issues in bispecific antibody assembly.

Platform Core: GeniusBsAb™ Mice

The GeniusBsAb™ mouse model serves as the foundational engine of our bispecific antibody platform, uniquely designed to overcome critical manufacturing challenges. By leveraging its innate common light chain architecture, the platform achieves a remarkable correct assembly rate of >95% for bispecific antibodies. This high fidelity in chain pairing eliminates the heterogeneity typical of traditional methods, drastically simplifying downstream purification and process development. As a result, the GeniusBsAb™ mouse significantly reduces the complexity and cost of CMC (chemistry, manufacturing, and controls) activities, accelerating the transition from candidate selection to clinical-scale production.

Fig.3 The GeniusBsAb™ mouse enables over 95% correct assembly efficiency, substantially streamlining downstream CMC process development for bispecific antibodies.

Advantages of GeniusBsAb™ Platform

The GeniusBsAb™ platform is a cutting-edge solution engineered to overcome the complexities of bispecific antibody development. Its integrated design provides a suite of critical advantages from discovery to candidate selection.

Versatile Molecular Design

The platform supports the assembly of diverse modalities, including scFvs, peptides, VHHs, and cytokines, using robust technologies like Knobs-into-Holes. This flexibility enables the creation of tailored bispecific formats optimized for specific therapeutic mechanisms.

Innate Common Light Chain Advantage

A core innovation of the platform is its ability to generate fully human antibodies with a common light chain. This intrinsic feature ensures efficient and precise heavy chain pairing for bispecific assembly, dramatically minimizing mispairing issues and simplifying downstream purification.

High-Quality Antibody Generation

By combining the fully human immune repertoire of the GeniusBsAb™ mouse with the high-throughput screening capabilities of Beacon technology, the platform rapidly identifies leads with exceptional diversity and affinity.

Scalable In Vivo Validation

The platform incorporates powerful in vivo screening systems to functionally validate bispecific candidates. This critical step identifies the most effective and safe target combinations, de-risking selection and accelerating the path to clinical development.

Bifunctional Molecule Capability

The platform excels in developing advanced bifunctional molecules, such as antibody-cytokine fusions (immunocytokines). These constructs leverage superior synergy between target engagement and immune modulation, significantly enhancing the drugability of cytokine-based therapies.

Applications of the GeniusBsAb™ Platform

The GeniusBsAb™ platform is engineered to support the development of a wide spectrum of next-generation bispecific and multifunctional therapeutics. Its versatility enables the creation of highly specific molecules tailored to advanced mechanistic approaches.

GeniusBsAb™ Platform: Empowering Bispecific ADC Development

A bispecific antibody-drug conjugate (bsADC) is an advanced therapeutic agent that combines the dual-targeting precision of a bispecific antibody with the potent cell-killing ability of a cytotoxic drug, enabling enhanced tumor selectivity and efficacy. The GeniusBsAb™ platform uniquely advances bsADC development by generating native-format, fully human bispecific antibodies with inherent common light chain architecture. The key advantages are as follows:

• Effortless Assembly with High Fidelity: The common light chain design enables straightforward bispecific antibody formation with minimal mispairing, while yielding molecules with ideal physicochemical properties for ADC development.
• Diverse Epitope Targeting Capability: The GeniusBsAb™ mouse generates antibodies with superior diversity, enabling access to novel epitopes and cross-species reactivity for broader therapeutic applications.
• Rapid Generation of Optimized Candidates: The platform accelerates the production of high-quality bispecific ADCs suitable for high-throughput in vitro and in vivo screening, streamlining the path to candidate selection.

Fig.4 Develop bispecific antibody drug conjugates (ADCs) using GeniusBsAb™ mice.

Case Study

Fig.5 (A) GeniusBsAb™ mice exhibit normal B cell development, with only a slight delay compared to wild-type (WT) mice. (B) The median length of the heavy chain CDR3 in naive GeniusBsAb™ mice (14aa) is comparable to the average length of human CDR3.

Pipeline

GeniusBsAb™ platform redefines bispecific antibody and antibody-drug conjugate (ADC) development by delivering native-format, fully human molecules with unmatched efficiency. From initial discovery to functional screening, Protheragen offers integrated, end-to-end solutions designed to navigate and overcome your most complex drug development hurdles. Contact us today to explore how our platform can empower your pipeline and bring innovative therapies to patients faster.