Camelidae Antigen Binding Polypeptides for Reduced Immunogenicity
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Solution Overview
Problem
Current monoclonal antibody platforms face limitations due to immunogenicity issues, complexity in humanization, and reduced affinity and potency during the process, particularly with rodent-derived antibodies, and limitations in diversity and stability of synthetic libraries and transgenic mouse systems.
Innovation Solution
Development of antigen binding polypeptides using VH and VL domains from Camelidae species, which exhibit high sequence and structural homology with human antibodies, allowing for the production of recombinant chimeric monoclonal antibodies with enhanced specificity and affinity, minimizing immunogenicity and requiring minimal engineering.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If rodent-derived monoclonal antibodies are used, then production is simplified, but immunogenicity increases and therapeutic utility is limited
Solution Approach 1:
The patent changes the species origin parameter of the antibody variable domains from rodent to Camelidae, while maintaining the overall antibody structure and production methodology. This parameter change reduces immunogenicity in human hosts while preserving ease of manufacture through similar recombinant production techniques
Solution Approach 2:
The patent creates chimeric antibodies by combining Camelidae-derived variable domains (VH and VL) with human constant domains. This composite structure maintains the antigen-binding capabilities of non-human antibodies while incorporating human sequences to reduce immunogenicity and improve therapeutic utility
2Adaptability or versatility
If mouse CDRs are grafted onto human framework regions to achieve humanization, then human content increases, but structural homology may be compromised and the process becomes complex and time-consuming
Solution Approach 1:
Instead of grafting mouse CDRs onto human frameworks (conventional humanization), the patent inverts the approach by using Camelidae variable domains that naturally exhibit high sequence and structural homology with human antibodies. This eliminates the need for complex CDR grafting and back-mutation processes while achieving similar or superior human-like structural properties
Solution Approach 2:
The patent changes the source of variable domains from mouse to Camelidae species, which naturally possess higher sequence homology with human antibodies. This parameter change simplifies the humanization process by eliminating multiple mutation steps while maintaining or improving structural homology and binding affinity
3Adaptability or versatility
If synthetic human combinatorial antibody libraries are used, then fully human antibodies are produced, but diversity is limited and affinity maturation requires additional time
Solution Approach 1:
The patent changes the source of antibody variability from synthetic combinatorial libraries to naturally diverse Camelidae antibody repertoires. Camelidae species possess naturally high sequence diversity in their variable domains, eliminating the need for time-consuming affinity maturation processes while maintaining full human compatibility
4Reliability
If transgenic mice expressing human IgG repertoire are used, then in vivo selection of CDRs is achieved, but B cell maturation may be impaired and diversity is reduced
Solution Approach 1:
The patent copies the beneficial feature of in vivo selection from transgenic mouse systems by immunizing live Camelidae animals with target antigens. This natural immunization process selects for high-affinity antibodies in vivo, eliminating the need for transgenic mouse models while preserving diversity and avoiding B cell maturation issues
Data Source
AI summary
The invention relates to a platform technology for production of antigen binding polypeptides having specificity for a desired target antigen which is based on the conventional antibody repertoire of species in the family Camelidae, and to antigen binding polypeptides obtained using this technology platform. In particular, the invention provides an antigen binding polypeptide comprising a VH domain and a VL domain, wherein at least one hypervariable loop or complementarity determining region (CDR) in the VH domain or the VL domain is obtained from a VH or VL domain of a species in the family Camelidae.