Asymmetric CD3ε Antibody Affinity Reduces Toxicity
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Solution Overview
Problem
Existing bispecific antibodies for recruiting cytolytic T cells to kill tumor cells face challenges such as unfavorable toxicity, potential immunogenicity, and manufacturing issues, limiting their clinical use.
Innovation Solution
Development of novel CD3ε specific binding proteins with high affinity for tumor antigens and weak affinity for T cells, featuring high thermostability, reduced deamidation risk, and humanized to decrease immunogenicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional bispecific antibodies are used to recruit cytolytic T cells to kill tumor cells, then T cell recruitment and tumor cell killing activity are achieved, but toxicity increases and manufacturing becomes difficult
Solution Approach 1:
The patent applies parameter changes by modifying the affinity characteristics of the bispecific antibody. Specifically, the CD3ε binding domain is engineered to have reduced affinity compared to conventional bispecific antibodies, while the tumor antigen binding domain maintains high affinity. This differential affinity modification allows the antibody to bind tumor cells with high specificity while reducing off-target binding to normal T cells, thereby reducing toxicity while preserving tumor cell killing efficacy
Solution Approach 2:
The patent implements local quality by creating asymmetric binding properties in different regions of the bispecific antibody. The CD3ε binding region is designed with reduced affinity to minimize systemic T cell activation and toxicity, while the tumor antigen binding region is designed with high affinity to ensure strong tumor cell recruitment. This localized differentiation of binding strength allows the antibody to perform its therapeutic function while reducing harmful side effects
2Reliability
If conventional bispecific antibodies are used to recruit cytolytic T cells, then tumor cell killing activity is achieved, but immunogenicity increases
Solution Approach 1:
The patent reduces immunogenicity by changing the structural parameters of the antibody. The CD3ε binding domain is engineered with modified amino acid sequences that reduce recognition by the human immune system, while maintaining the ability to bind CD3ε with sufficient affinity for T cell recruitment. This parameter modification decreases the likelihood of the antibody itself being targeted by the immune system, thereby reducing immunogenicity while preserving therapeutic efficacy
3Reliability
If high potency bispecific antibodies are developed to improve tumor cell killing, then efficacy increases, but manufacturing complexity increases
Solution Approach 1:
The patent simplifies manufacturing by changing the stability parameters of the antibody structure. The reduced affinity design of the CD3ε binding domain results in a more stable protein structure that is less prone to aggregation and degradation during manufacturing and storage. This structural stabilization eases manufacturing processes, improves batch consistency, and simplifies quality control while maintaining sufficient therapeutic efficacy through the high-affinity tumor antigen binding domain
Data Source
AI summary
The disclosure provides antigen binding domains that bind cluster of differentiation 3 (CD3) protein, comprising the antigen binding domains that bind CD3ε, polynucleotides encoding them, vectors, host cells, methods of making and using them.