Humanized Antibody Variable Domain Engineering for Alpha v Beta 6 Binding
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Solution Overview
Problem
Current antibodies targeting αvβ6 integrin are immunogenic in humans, leading to adverse effects and reduced efficacy due to their murine origin, necessitating the development of humanized antibodies with reduced antigenicity and preserved antigen binding affinity.
Innovation Solution
Humanized antibodies are created by replacing murine variable domains with human sequences, specifically designed to retain binding specificity to αvβ6 integrin while minimizing immunogenicity, using recombinant DNA technology to engineer antibody genes and produce modified antibody molecules with humanized variable domains.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If murine antibodies are used to target αvβ6 integrin, then antigen binding affinity is achieved, but immunogenicity increases leading to adverse effects
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence parameters of the antibody variable domains. Specifically, murine variable domains are replaced with human sequences while maintaining critical binding residues, thereby changing the immunogenicity parameter while preserving antigen binding affinity for αvβ6 integrin
Solution Approach 2:
The patent creates composite antibody structures by combining human antibody framework regions with selected murine or non-human variable domain sequences. This composite approach allows the antibody to exhibit reduced immunogenicity from the human framework while retaining high binding affinity through the preserved variable domain regions
2Reliability
If murine antibodies are used to target αvβ6 integrin, then therapeutic efficacy is achieved, but adverse effects increase due to antigenicity
Solution Approach 1:
The patent modifies the immunogenicity parameter by replacing murine variable domain sequences with human sequences, thereby reducing adverse effects while maintaining therapeutic efficacy through preserved antigen binding capability to αvβ6 integrin
Solution Approach 2:
The patent introduces human antibody framework regions as intermediaries between the therapeutic function (provided by variable domains) and the human immune system. This intermediary human sequence reduces recognition as foreign while maintaining the therapeutic binding function
3Object-affected harmful factors
If humanized antibodies are created by replacing murine variable domains with human sequences, then immunogenicity is reduced, but binding specificity must be preserved
Solution Approach 1:
The patent applies local quality by making the variable domains (which determine binding specificity) distinct from the framework regions. The variable domains retain their original sequence characteristics necessary for αvβ6 binding, while the human framework regions provide reduced immunogenicity, creating local functional differentiation
Solution Approach 2:
The patent segments the antibody into distinct functional regions: variable domains responsible for binding specificity and framework regions responsible for immunogenicity. This segmentation allows independent optimization of each region's properties
Data Source
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AI summary
The present invention is in the fields of cell biology, immunology and oncology. Specifically, the invention relates to humanized antibodies that recognizes v 6 integrins which comprises a variable region of nonhuman origin and at least -a portion of an immunoglobulin of human origin. The invention also relates to processes for their preparation, to pharmaceutical compositions comprising them and to methods of treating various diseases by administering humanized anti- v 6 antibodies. The invention also relates to the identification of differential expression of the integrin avß6 on the surfaces of tumor cells and tissues, the use of this differential expression in determining the metastatic potential of tumor cells, and methods of diagnosis and treatment/prevention of tumor metastasis and for elimination of residual metastatic tumor cells using ligands, particularly antibodies, that bind to integrin avß6.