Humanized Antibody Framework Residue Selection for IL-20 Binding
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Solution Overview
Problem
Existing anti-IL-20 antibodies, such as mAb 7E, are mouse antibodies that elicit immune responses in humans, limiting their clinical use due to lower affinities and higher immunogenicity compared to humanized analogs.
Innovation Solution
Development of humanized antibodies like FLB5M5, which incorporate mutated CDR sequences and framework region modifications from mouse antibodies, resulting in higher affinities and lower immunogenicity, using molecular biology techniques and affinity maturation processes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If mouse antibodies (mAb 7E) are used as therapeutic agents, then high binding affinity for IL-20 is achieved, but immune responses are elicited in humans
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence parameters of the antibody framework regions. Specifically, mouse framework residues are replaced with human framework residues while preserving CDR sequences, thereby changing the immunogenicity parameter while maintaining binding affinity through careful selection of homologous human sequences
Solution Approach 2:
The patent uses human framework sequences as an intermediary between mouse CDR sequences and human physiology. The human framework acts as a mediator that accommodates the mouse CDR binding interface while reducing immune recognition, creating a bridge that maintains function while reducing harm
2Object-affected harmful factors
If humanized antibodies are created by grafting CDR sequences into human framework, then immunogenicity is reduced, but binding affinity decreases
Solution Approach 1:
The patent applies local quality by making the antibody heterogenous in a targeted manner: the CDR regions retain mouse sequence characteristics optimized for IL-20 binding, while only the framework regions are humanized. This localized approach preserves binding function in critical areas while reducing immunogenicity in non-critical framework areas
Solution Approach 2:
The patent carefully selects which framework residues to change from mouse to human based on homology analysis. By changing only specific framework parameters that are tolerant to humanization while preserving those that are critical for CDR positioning, the patent maintains binding affinity while reducing immunogenicity
Data Source
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AI summary
A humanized antibody, or a scFv, Fab, or F(ab')2 thereof, includes: a heavy chain variable region, or a homologous variant thereof, wherein the heavy chain variable region includes: heavy chain framework regions, CDRH1 that has the sequence of SEQ ID NO:19, CDRH2 that has the sequence of SEQ ID NO:20, and CDRH3 that has the sequence of SEQ ID NO:21, wherein the heavy chain variable region and the homologous variant share at least 90% sequence identity in the heavy chain framework regions; and a light chain variable region, or a homologous variant thereof, that includes: light chain framework regions, CDRL1 that has the sequence of SEQ ID NO:22, CDRL2 that has the sequences of SEQ ID NO:23, and CDRL3 that has the sequences of SEQ ID NO:24, wherein the light chain variable region and the homologous variant share at least 90% sequence identity in the light chain framework regions.