Humanized Antibodies Against CEACAM1 via Framework Back-Mutations
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Solution Overview
Problem
There is a need for humanized antibodies that are safer and more potent for therapeutic and diagnostic use in diseases involving CEACAM protein expression or activation, with a focus on providing long-lasting and durable responses in cancer treatment, as existing antibodies may induce adverse immune responses and have limited efficacy.
Innovation Solution
Development of humanized monoclonal antibodies specific to CEACAM1 with specific 'back-mutations' in their variable region sequences to minimize immunogenicity and maintain binding affinity, incorporating key mutations in the human framework to restore correct CDR presentation and minimize T cell epitopes, resulting in high-affinity, non-immunogenic antibodies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If murine-derived antibodies are used for therapeutic application, then binding affinity to CEACAM1 is achieved, but adverse immune responses occur due to immunogenicity
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence parameters of the antibody framework regions. Specifically, humanized antibodies are created by replacing murine framework residues with human equivalents while maintaining CDR sequences, thereby changing the immunogenicity parameter while preserving binding affinity to CEACAM1
Solution Approach 2:
The patent uses human framework sequences as an intermediary between the murine CDRs and the human immune system. This intermediary humanized structure allows the antibody to bind CEACAM1 effectively while being recognized as self by the human immune system, thus reducing adverse immune responses
2Object-affected harmful factors
If fully humanized antibodies are created, then immunogenicity is reduced, but binding affinity and CDR presentation may be compromised
Solution Approach 1:
The patent applies local quality by making selective substitutions only in specific framework regions rather than throughout the entire antibody sequence. The CDR regions maintain their original murine sequences for optimal binding, while only specific framework residues are humanized to reduce immunogenicity, creating a locally optimized solution
Solution Approach 2:
The patent carefully controls the degree of humanization by selecting specific framework residues for substitution. By changing parameters such as the number and position of humanized residues, the patent optimizes the balance between reducing immunogenicity and maintaining binding affinity through proper CDR presentation
Data Source
AI summary
Humanized antibodies, capable of specific binding to human CEACAM1 molecules containing human-to-murine back-mutations in non-CDR variable regions, and their encoding polynucleotide sequences are provided. Pharmaceutical compositions comprising these antibodies as well as methods of their use in treating and diagnosing cancer and other conditions are also provided.