Humanized ROR2 Antibodies Thermal Stability Aggregation
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Solution Overview
Problem
There is a need for high-quality, fully human anti-ROR2 antibodies that can specifically bind to human ROR2 (hROR2) and also cross-react with ROR2 from standard toxicology species like mice and cynomolgus monkeys, with excellent developability parameters such as low aggregation propensity and high thermal stability. These antibodies are required for the development of targeted cancer therapies and diagnostic tools.
Innovation Solution
The development of novel, high-affinity fully human monoclonal antibodies that specifically bind to the extracellular domain of ROR2, using human antibody transgenic mice (H2L2 mice) immunized with recombinant hROR2, followed by enrichment of splenic B cells and generation of cellular IgG1 display libraries. These antibodies are characterized by their ability to bind hROR2 and cross-react with ROR2 from other species, and are further developed into antibody drug conjugates (ADCs), antibody effector conjugates (AECs), and chimeric antigen receptors (CARs).
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antibody development methods are used, then antibodies can be obtained, but they lack high thermal stability and have high aggregation propensity
Solution Approach 1:
The patent applies parameter changes by modifying the antibody structure through humanization - replacing non-human amino acid sequences with human sequences while maintaining the antigen-binding CDR regions. This structural parameter change results in antibodies with improved thermal stability (melting temperature >75°C) and reduced aggregation propensity, directly resolving the contradiction between obtainability and stability.
2Reliability
If conventional antibody development methods are used, then antibodies can be obtained, but they show high immunogenicity in human subjects
Solution Approach 1:
The patent applies parameter changes by humanizing the antibody sequences - changing the amino acid composition from non-human (mouse, rabbit) to human sequences. This parameter change in sequence composition reduces immunogenicity while maintaining binding function, resolving the contradiction between low immunogenicity and development complexity.
Solution Approach 2:
The patent applies segmentation by dividing the antibody into functional regions: the CDR (complementarity-determining region) segments that provide antigen-binding specificity are retained from non-human sources, while the framework regions are replaced with human sequences. This segmentation allows the antibody to maintain binding function while reducing immunogenicity.
3Adaptability or versatility
If conventional antibody development methods are used, then antibodies can be obtained, but they do not cross-react with ROR2 from standard toxicology species
Solution Approach 1:
The patent applies universality by designing antibodies that can bind to ROR2 across multiple species (human, mouse, cynomolgus monkey, rabbit). The humanized antibody framework provides a universal binding platform that recognizes conserved epitopes in ROR2 across species, enabling both cross-species reactivity and maintained binding specificity.
Data Source
AI summary
The present invention relates to fully human antibodies and conjugates thereof, which specifically bind to the extracellular domain of receptor tyrosine kinase-like orphan receptor 2 (ROR2).