Humanized Anti-TGF-beta Antibody Engineering
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Developing human antibodies specific to TGF-beta is challenging due to self-tolerance and sequence conservation between human and mouse TGF-beta molecules, making it difficult to raise antibodies that effectively neutralize TGF-beta activity in therapeutic applications.
Innovation Solution
A humanized antibody is created by incorporating non-human hypervariable region residues into a human variable heavy domain with specific framework region substitutions and complementarity-determining region residues, allowing it to bind TGF-beta with high affinity and neutralize its activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If non-human antibodies are used to bind TGF-beta, then binding affinity can be achieved, but immunogenicity increases and therapeutic efficacy decreases
Solution Approach 1:
The patent applies parameter changes by modifying the antibody's amino acid sequence parameters - specifically humanizing the constant regions and selecting specific framework region sequences while retaining non-human CDR sequences. This changes the antibody from fully non-human to humanized, reducing immunogenicity while preserving binding affinity through the retained CDR regions.
Solution Approach 2:
The patent uses human framework regions and constant regions as intermediaries to bridge between the non-human CDR binding specificity and the human immune system. The humanized framework acts as a mediator that supports the non-human CDR while reducing immunogenic recognition, enabling therapeutic use.
2Object-affected harmful factors
If human antibodies are raised against human TGF-beta, then immunogenicity is reduced, but self-tolerance prevents effective antibody production
Solution Approach 1:
The patent applies preliminary action by pre-selecting and engineering specific CDR sequences from non-human antibodies that have proven binding capability before introducing them into the human antibody framework. This preliminary selection of functional CDRs overcomes the self-tolerance barrier by providing pre-validated binding regions that can be expressed in the human system.
Solution Approach 2:
The patent creates a composite antibody structure combining human framework/constant regions with non-human CDR regions. This composite approach allows the antibody to function as human (reducing immunogenicity) while retaining non-human binding specificity (overcoming self-tolerance), effectively merging advantages of both sources.
3Ease of manufacture
If mouse TGF-beta sequences are used for antibody development, then antibody production is easier, but sequence conservation reduces binding specificity to human TGF-beta
Solution Approach 1:
The patent applies local quality by concentrating the species-specific binding determinants in the CDR regions while using human framework regions for structural support. The local CDR sequences retain mouse or other non-human specificity for human TGF-beta epitopes, while the human framework provides the appropriate structural context for high-affinity binding without cross-reactivity issues.
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 humanized antibody effectively binds to TGF-beta, neutralizing its activity and providing a therapeutic option for treating TGF-beta-related disorders, including cancer and fibrotic diseases, with improved specificity and affinity compared to non-human antibodies.
Implementation Method 1
A humanized antibody is created by incorporating non-human hypervariable region residues into a human variable heavy domain with specific framework region substitutions and complementarity-determining region residues, allowing it to bind TGF-beta with high affinity and neutralize its activity.
Data Source
AI summary
Humanized anti-TGF-beta antibodies are provided, as well as methods for their preparation and use, including methods for treating TGF-beta disorders, for example, cancer. Also provided are articles of manufacture designed for various uses that contain the humanized antibodies.