Antibodies Targeting Aberrant EGFR Modifications
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Solution Overview
Problem
Current EGFR antibodies have limitations in their range of applicability and efficacy due to their ability to bind to normal tissues with high endogenous EGFR levels, such as the liver and skin, and their effectiveness is restricted to a proportion of tumors expressing the de2-7 EGFR variant, which is not universally present in all EGFR-positive tumors.
Innovation Solution
Development of specific binding members, particularly antibodies and fragments thereof, that recognize an EGFR epitope enhanced by aberrant post-translational modification, specifically binding to amplified or mutated EGFR, including de2-7 EGFR, without significant binding to normal EGFR, thereby targeting tumors with amplified EGFR regardless of their de2-7 status.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If EGFR antibodies are used to target tumors, then anti-tumor activity is achieved, but normal tissue uptake occurs in organs with high endogenous EGFR levels such as liver and skin
Solution Approach 1:
The antibody is designed to recognize a specific local feature (aberrant post-translational modification) that is present only in tumor cells, not in normal cells. This local quality distinction allows the antibody to differentiate between tumor and normal tissues, achieving selective binding to tumors while avoiding normal tissue uptake.
Solution Approach 2:
The invention targets a parameter change in the EGFR protein - specifically aberrant post-translational modifications that occur in tumor cells but not in normal cells. By detecting this parameter change rather than the protein itself, the antibody achieves tumor selectivity while maintaining anti-tumor activity.
2Reliability
If EGFR antibodies target de2-7 EGFR variant, then specificity to tumor cells is improved, but applicability is limited to only a proportion of tumors expressing this variant
Solution Approach 1:
The antibody is designed to recognize a universal feature (aberrant post-translational modification) that is present across multiple tumor types and EGFR variants, including both de2-7 EGFR and amplified wild-type EGFR. This universal recognition mechanism expands the antibody's applicability to a broader range of tumors while maintaining tumor cell specificity.
Solution Approach 2:
Instead of targeting a specific protein variant structure, the antibody targets a parameter change (aberrant post-translational modification) that occurs in multiple tumor contexts. This approach allows the antibody to bind to various EGFR forms (de2-7, amplified wild-type, and other variants) that share the same aberrant modification pattern, thereby expanding versatility.
Data Source
AI summary
The present invention relates to specific binding members, particularly antibodies and fragments thereof, which bind to amplified epidermal growth factor receptor (EGFR) and to the de2-7 EGFR truncation of the EGFR. In particular, the epitope recognized by the specific binding members, particularly antibodies and fragments thereof, is enhanced or evident upon aberrant post-translational modification. These specific binding members are useful in the diagnosis and treatment of cancer. The binding members of the present invention may also be used in therapy in combination with chemotherapeutics or anti-cancer agents and/or with other antibodies or fragments thereof,