Humanized Antibody Back-Mutations for CEACAM1 Binding
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Solution Overview
Problem
Current cancer treatments, particularly in immunotherapy, face challenges with the need for more effective and longer-lasting therapies that target novel pathways, and there is a lack of safer and more potent humanized antibodies recognizing specific CEACAM proteins for diagnostic and therapeutic use.
Innovation Solution
Development of humanized antibodies with specific 'back-mutations' in their variable region sequences to maintain conformation and binding affinity, minimizing immunogenicity, and using these antibodies to target CEACAM1 for optimizing cancer patient selection and treatment by determining CEACAM1 expression levels on tumor-infiltrating immune cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If humanized antibodies are developed to target CEACAM1 for cancer therapy, then safety and specificity are improved, but binding affinity and conformational stability may be compromised
Solution Approach 1:
The patent applies local quality by making specific back-mutations only in the framework regions (FR1, FR2, FR3, FR4) of the antibody variable domains, rather than throughout the entire sequence. These localized mutations restore conformational stability and binding affinity while preserving the humanized characteristics of the antibody, thus resolving the contradiction between reduced immunogenicity and maintained binding affinity
Solution Approach 2:
The patent changes the amino acid sequence parameters in the framework regions by introducing specific back-mutations (e.g., changing certain residues back to their original murine sequences). This parameter modification restores the conformational properties necessary for high-affinity binding to CEACAM1 while maintaining the overall humanized structure that reduces immunogenicity
2Reliability
If novel immune checkpoint pathways are targeted for cancer treatment, then treatment effectiveness is improved, but lack of established biomarkers makes patient selection difficult
Solution Approach 1:
The patent performs preliminary action by developing and validating biomarker assays (such as flow cytometry and immunohistochemistry methods) that can detect CEACAM1 expression levels on tumor-infiltrating lymphocytes before treatment. This allows clinicians to identify suitable patients in advance, resolving the information gap that would otherwise hinder effective patient selection for novel immunotherapies
3Power
If CEACAM1 blockade is used to enhance immune response, then anti-tumor activity is improved, but understanding of optimal patient selection remains insufficient
Solution Approach 1:
The patent implements feedback by establishing a diagnostic system that measures CEACAM1 expression levels on tumor-infiltrating lymphocytes and uses this information to guide treatment decisions. This feedback loop provides the missing information about which patients are most likely to benefit from CEACAM1 blockade therapy, enabling optimized patient selection based on quantitative biomarker data
Data Source
AI summary
Provided are methods and compositions comprising antibodies capable of specific binding to human CEACAM1 molecules, for treating and diagnosing cancer as well as assessing CEACAM1 expression in tumor infiltrating immune cells (TILs) in a biological sample obtained from a [cancer] subject.