Humanized Anti-BTLA Antibody with Low Immunogenicity
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Solution Overview
Problem
Current anti-BTLA antibodies face challenges such as immunogenicity in humans, leading to adverse immune responses and reduced efficacy due to rodent origin, and difficulties in predicting binding properties and biological functions in humanized constructs.
Innovation Solution
Development of isolated anti-human BTLA antibodies or antigen-binding fragments with specific properties like blocking BTLA-HVEM binding, cross-reactivity with cynomolgus monkey BTLA, and low KD≤0.28 nM binding affinity, utilizing specific CDR sequences to ensure low ADCC effect and improved human compatibility.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If rodent origin antibodies are used to target BTLA, then binding affinity and initial therapeutic effect are achieved, but immunogenicity increases leading to adverse immune responses and reduced efficacy
Solution Approach 1:
The patent applies parameter changes by humanizing the antibody sequence - changing the species origin from rodent to human through sequence modification. The anti-BTLA antibody is engineered with human framework regions while retaining the functional CDRs, fundamentally altering the immunogenicity parameter to reduce adverse immune responses while maintaining therapeutic efficacy
Solution Approach 2:
The patent uses human framework regions as an intermediary between the rodent CDR sequences and the human immune system. The human framework regions serve as a bridge that allows the non-human CDRs to function while being less recognized as foreign by the human immune system, thereby reducing immunogenicity
2Object-affected harmful factors
If humanized antibody constructs are created to reduce immunogenicity, then adverse immune responses are reduced, but binding properties and biological functions become difficult to predict
Solution Approach 1:
The patent segments the antibody into distinct functional regions with specific roles: human framework regions for reduced immunogenicity and predetermined CDR sequences for defined binding properties. This segmentation allows independent optimization and prediction of each region's contribution to overall antibody function
Solution Approach 2:
The patent applies local quality by assigning different characteristics to different parts of the antibody molecule. The framework regions are humanized for low immunogenicity, while the CDR regions are specifically designed or selected to ensure high affinity binding to BTLA. Each region has optimized local properties that contribute to the overall function
3Object-affected harmful factors
If CDR sequences are modified to improve human compatibility, then immunogenicity is reduced, but binding affinity and specificity may be compromised
Solution Approach 1:
The patent extracts the functional binding capability from the rodent antibody CDRs and preserves them in the humanized construct. By separating the binding function (in CDRs) from the immunogenic framework regions, the patent maintains high binding affinity while reducing immunogenicity through humanization of the framework
Data Source
AI summary
The present invention relates to an anti-BTLA antibody or an antigen-binding fragment thereof comprising: at least one light chain CDR domain selected from SEQ ID NOs: 7, 8, 9, 10, 11, 12, 16, 17, 18, 22, 23, 24, 31, 32 and 33, and/or at least one heavy chain CDR domain selected from SEQ ID NOs: 1, 2, 3, 4, 5, 6, 13, 14, 15, 19, 20, 21, 25, 26, 27, 28, 29 and 30. The present invention also relates to a nucleic acid molecule encoding the antibody or the antigen-binding fragment thereof, a corresponding expression vector and a host cell, as well as therapeutic use of the antibody or the antigen-binding fragment thereof, the nucleic acid molecule, the expression vector and the host cell.