Cysteine-Engineered Antigen-Binding Domains for Antigen Escape
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Solution Overview
Problem
Current immunotherapies face challenges such as adverse effects, antigen loss, and cancer cell resistance due to antigen downregulation or mutation, necessitating the development of multi-specific antibody constructs that target multiple antigens, particularly the altered cellular microenvironment in cancers like BCL and breast cancer.
Innovation Solution
Development of cysteine-engineered antigen-binding domains that bind specifically to target cells in an antigen-dependent and thiol-dependent manner, enabling effective treatment of cancers undergoing antigen escape by targeting the cellular microenvironment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional single-antigen antibody therapy is used, then specific targeting of tumor-associated antigen is achieved, but cancer cells develop resistance through antigen loss, downregulation, or mutation
Solution Approach 1:
The patent applies multi-functionality by engineering antigen-binding domains with dual binding modes: antigen-dependent binding for specific targeting and thiol-dependent binding for universal targeting of cancer cell microenvironment. This allows a single therapeutic construct to target multiple antigens simultaneously, preventing cancer cells from developing resistance through single antigen loss or mutation.
Solution Approach 2:
The patent changes the binding parameter from purely antigen-specific to dual-mode binding by introducing cysteine residues that form thiol-dependent interactions. This parameter change enables the antibody to bind both through traditional antigen recognition and through thiol-group interactions with the altered cellular microenvironment of cancer cells, thereby overcoming antigen escape mechanisms.
2Measurement precision
If antibody therapy targets a single tumor-associated antigen, then specific targeting is achieved, but adverse effects such as neurotoxicity or cytokine release syndrome occur
Solution Approach 1:
The patent applies local quality by creating heterogeneity in binding specificity within a single therapeutic construct. Different antigen-binding domains within the same molecule exhibit different binding characteristics: some bind with high antigen specificity while others bind through thiol-dependent mechanisms to the altered microenvironment. This local differentiation allows preferential targeting of cancer cells while sparing healthy tissues, thereby reducing adverse effects.
3Adaptability or versatility
If cysteine engineering is applied to antigen-binding domains, then thiol-dependent binding to altered cellular microenvironment is achieved, but structural stability may be affected
Solution Approach 1:
The patent applies preliminary action by carefully selecting and positioning cysteine residues during the design phase to ensure they participate in thiol-dependent binding without disrupting the overall structural stability of the antigen-binding domain. The cysteine residues are strategically placed to form bonds with the altered cellular microenvironment while maintaining the integrity of the antigen-binding site, thus preventing structural destabilization.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The cysteine-engineered antigen-binding domains enhance the efficacy of cancer treatment by effectively targeting multiple cancer cell types, including those resistant to conventional therapies, through T cell activation and cytotoxicity, as demonstrated in B-cell lymphoma and breast cancer models.
Implementation Method 1
The antigen-binding domain binds specifically to target cells in an antigen-dependent manner and/or additionally in a thiol-dependent manner
Implementation Method 2
cancer cells often have an altered redox potential due to altered expression of enzymes regulating cell membrane redox system
Data Source
Figure 1A~1C
Figure 1D~2B
Figure 2C~3A
AI summary
The invention pertains to an antigen-binding domain, which comprise a heavy chain variable region and optionally a light chain variable region. The antigen-binding domain is capable of binding to an antigen. At least one of the complementarity-determining regions contains an amino acid residue, other than cysteine, with a solvent-accessible surface area ranging from 0.00 to 0.75 and is located at a distance of 3 to 14 A from the antigen and is substituted to a thiol containing amino acid. This unique configuration enhances the antigen-binding domain antigen-binding and cytotoxicity capabilities.