Humanized Antibodies Against CEACAM1 with Framework Back-Mutations
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Solution Overview
Problem
Current cancer treatments, particularly immunotherapies targeting CEACAM1, face challenges in achieving long-lasting and potent responses due to immunogenicity and limited safety profiles of non-human antibodies, necessitating the development of humanized antibodies that are both specific and non-immunogenic.
Innovation Solution
The creation of humanized monoclonal antibodies against CEACAM1 with specific back-mutations in their variable region sequences, designed to minimize T cell epitopes and maintain binding affinity, utilizing CDR grafting to restore correct CDR presentation while reducing immunogenicity, resulting in high-affinity, non-immunogenic, and highly-specific antibodies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If non-human monoclonal antibodies are used for CEACAM1 blockade, then binding affinity and specificity are achieved, but immunogenicity increases and safety profile deteriorates
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. Back-mutations are strategically introduced to restore critical structural features without significantly increasing immunogenicity.
Solution Approach 2:
The patent uses human framework regions as an intermediary between the murine CDR sequences and the human immune system. The humanized antibody structure acts as a mediator that maintains the antigen-binding capability of murine antibodies while reducing immunogenicity through human-like framework sequences. This intermediary approach allows the antibody to function effectively in human patients with improved safety profiles.
2Object-affected harmful factors
If humanization process is applied to reduce immunogenicity, then safety profile is improved, but binding affinity and CDR presentation may deteriorate
Solution Approach 1:
The patent applies local quality by making targeted modifications at specific positions within the framework regions rather than uniform changes throughout the entire antibody structure. Back-mutations are introduced at localized positions where they are most critical for maintaining CDR presentation and binding affinity. This localized approach ensures that humanization benefits are achieved without compromising the essential binding characteristics of the antibody.
Solution Approach 2:
The patent employs preliminary action by strategically pre-positioning back-mutations in the humanized framework sequences before final antibody production. These back-mutations are identified and incorporated in advance to ensure proper CDR conformation and binding affinity are maintained. This preliminary structuring prevents potential loss of binding capability that might occur during subsequent antibody expression and purification processes.
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.