Caninized CTLA-4 Antibodies for Species-Specific Immune Checkpoint Blocking
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
There are no caninized monoclonal antibodies available that effectively block the binding and activity of canine CTLA-4, limiting therapeutic options for treating cancer and infections in canines.
Innovation Solution
Development of caninized anti-human CTLA-4 antibodies with specific binding affinity for canine CTLA-4, capable of blocking its interaction with CD80 and/or CD86, utilizing specific CDR sequences from mammalian CTLA-4 antibodies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If human CTLA-4 antibodies are used, then high binding affinity for human CTLA-4 is achieved, but they cannot effectively bind to canine CTLA-4 due to species specificity
Solution Approach 1:
The patent applies asymmetry by selectively replacing only the CDR regions (which provide antigen-binding specificity) from the human antibody with corresponding canine CDR sequences, while retaining the human antibody's framework regions that provide stable structure and high affinity binding characteristics. This asymmetric hybridization enables the antibody to bind canine CTLA-4 effectively.
Solution Approach 2:
The caninized antibody serves as an intermediary molecule that bridges the gap between human antibody technology and canine therapeutic needs. By incorporating canine CDR sequences, the antibody acts as a mediator that can recognize and bind to canine CTLA-4 while maintaining the structural stability and pharmacokinetic properties of human IgG antibodies.
2Adaptability or versatility
If caninized antibodies are developed, then species-specific binding to canine CTLA-4 is achieved, but development complexity and time increase
Solution Approach 1:
The patent extracts only the essential CDR regions (amino acids 31-35, 50-56, and 96-102 of the heavy chain and corresponding light chain regions) from the canine antibody sequence, while retaining the majority of the human antibody framework. This selective extraction minimizes the engineering complexity by modifying only the necessary portions rather than redesigning the entire antibody molecule.
Solution Approach 2:
The patent applies local quality by making targeted modifications only in the CDR regions where antigen-binding specificity is determined, while leaving the framework regions unchanged. This localized approach to antibody engineering reduces overall complexity by concentrating modifications only where they are most needed for achieving species-specific binding.
3Object-affected harmful factors
If conventional antibody humanization is used, then reduced immunogenicity in humans is achieved, but reverse humanization (caninization) for canine therapy is not addressed
Solution Approach 1:
The patent inverts the conventional humanization approach by applying reverse humanization (caninization) - taking a human antibody and modifying it to bind canine antigen. Instead of making a canine antibody more human-like to reduce immunogenicity, the patent makes a human antibody more canine-like to achieve species-specific binding, thereby enabling therapeutic use in canine patients.
Data Source
AI summary
The present invention provides caninized anti-human CTLA-4 antibodies that have specific sequences and a high binding affinity for canine CTLA-4. The invention also relates to use of these antibodies in the treatment of cancer in canines and other companion animals.