Antibody-drug conjugates (ADCs), with their advantages of both accurate antibody targeting and efficient small molecule killing, have become one of the hot spots in antibody drug research and development. Through decades of development, ADC technologies including coupling and linker/payload have made great breakthroughs. However, the currently approved targets of ADCs are very limited, and safe and effective innovative targets remain the key to ADC research and development.
Bispecific antibodies will show a new drug mechanism that is not present in monospecific antibodies or antibody combinations. Similarly, bispecific ADCs targeting dual tumor-associated antigens (TAAs) have multiple potential anti-tumor advantages: 1. Targeting dual tumor-driven signaling pathways at the same time to overcome drug resistance; 2. Efficiently binding to and killing tumor cells co-expressing dual TAAs to increase the tumor targeting specificity and reduce off-target toxicity; and 3. Showing a new dynamic mechanism of dual-target binding and endocytosis, resulting in a more efficient tumor killing synergy.
Advantages of Bispecific ADC platform based on RenLite Mouse
1.The fully human antibodies produced by RenLite® mice have a common light chain, which can effectively solve the mismatch problem between heavy chain and light chain in the development of BsAbs, and improve the accuracy of assembly.
2.RenLite® mice can produce antibodies with diverse epitopes and high affinities. In addition, KIH (knobs-into-holes) technology is used to connect the heavy chains of two parent monoclonal antibodies, ensuring the successful assembly of a BsAb molecule with a stable monoclonal antibody structure
3.Supported by “Project Integrum” of Biocytogen and an integrated antibody discovery, coupling technology, pharmacology and efficacy platform, we will conduct high-throughput antibody discovery and screening on hundreds of TAA targets, screen all potential bispecific ADC combinations for efficacy in vivo and in vitro, and validate them on our own large-animal translational medicine platform to obtain more valuable translation data and improve the clinical success rate.
Bispecific ADCs Development
1) The HER2×TROP2 BsAb backbone showed increased endocytosis activity and selectivity.
2) The HER2×TROP2 BsAb backbone exhibits a high level of purity, desirable stability and other physicochemical properties.
3) YH012 showed enhanced the potency of in vitro tumor cell killing and improved selectivity of payload delivery compared to the monovalent HER2/TROP2-ADC. In vivo treatment with YH012 showed sustained and dose-dependent tumor growth inhibition, which was more pronounced than the effects of parental mAb-ADCs and monovalent ADCs.
4) The efficacy, dose-dependence, and safety of YH012 were verified in the large animal translational medicine studies.