Engineered CDR3 Anti-CTLA-4 Binding Proteins for Selective Immune Modulation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
There is a need for developing CTLA-4 antigen-binding proteins (ABPs) that can be used for treatment, diagnosis, and research of various diseases, including cancer and autoimmune diseases, as existing therapies have varying success and there is a lack of effective tools for modulating CTLA-4 activity.
Innovation Solution
The development of novel ABPs with specific binding affinity for CTLA-4, including monoclonal, chimeric, humanized, and human antibodies, as well as alternative scaffold proteins, which can inhibit or activate CTLA-4, induce killing of Tregs, and modulate immune responses through mechanisms such as ADCC and ADCP, and are used in pharmaceutical compositions and diagnostic kits.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CTLA-4 inhibitors are used to antagonize binding of CTLA-4 to its ligands, then immune system activation against tumors is enhanced, but the therapeutic success varies and off-target effects may occur
Solution Approach 1:
The patent applies local quality by designing antibodies with engineered CDR3 regions that specifically recognize and bind to CTLA-4 with high affinity and selectivity. The modified CDR3 sequences are tailored to interact with specific epitopes on CTLA-4, ensuring targeted inhibition of the CTLA-4/CD80 and CTLA-4/CD86 interactions while minimizing off-target effects. This localized modification of the antibody binding region enhances both therapeutic efficacy and selectivity.
Solution Approach 2:
The patent employs parameter changes by systematically modifying the amino acid sequences in the CDR3 regions of the antibodies. Specific substitutions, deletions, or additions in the CDR3-L and CDR3-H sequences alter the binding parameters (affinity, specificity, kinetics) of the antibodies toward CTLA-4. These parameter optimizations enable the antibodies to achieve enhanced therapeutic efficacy while maintaining or improving selectivity for CTLA-4 over other immune checkpoint molecules.
2Reliability
If soluble fusion proteins of CTLA-4 (CTLA-4-Ig) are used to suppress T cell inflammatory activity, then autoimmune diseases are prevented, but the binding affinity and avidity are limited compared to natural CTLA-4
Solution Approach 1:
The patent applies copying by creating antibody versions that replicate and enhance the natural binding capabilities of CTLA-4. Instead of using soluble CTLA-4 fusion proteins with limited affinity, the patent generates antibodies whose CDR3 regions are designed to copy and improve upon the natural CTLA-4 binding interface. These antibody copies achieve superior binding affinity and avidity for CD80 and CD86, thereby enhancing immune suppression efficacy while maintaining specificity.
Solution Approach 2:
The patent employs composite materials by combining engineered CDR3 regions with stable antibody frameworks. The CDR3 sequences are optimized to provide high-affinity binding to CTLA-4, while the surrounding framework regions ensure proper folding, stability, and solubility. This composite structure integrates the binding power of natural CTLA-4 with the engineering advantages of monoclonal antibodies, resulting in molecules with enhanced binding affinity and therapeutic reliability.
3Productivity
If existing CTLA-4 antibodies are used for cancer treatment, then some types of cancer are treated with varying success, but there is a lack of effective tools for modulating CTLA-4 activity with high precision
Solution Approach 1:
The patent applies segmentation by dividing the antibody structure into distinct functional modules: the CDR3 regions are engineered for high-specificity binding to CTLA-4, while the framework regions and Fc portions are optimized for stability, effector functions, and pharmacokinetics. This modular design allows independent optimization of binding specificity and therapeutic effectiveness, enabling precise modulation of CTLA-4 activity with enhanced treatment effectiveness across different cancer types.
Solution Approach 2:
The patent employs universality by designing antibodies that can universally bind to CTLA-4 with high precision across different tumor microenvironments and patient populations. The engineered CDR3 sequences are optimized to recognize conserved epitopes on CTLA-4, ensuring consistent and precise binding regardless of the cancer type or stage. This universal binding capability enhances treatment effectiveness while maintaining high binding specificity across diverse clinical scenarios.
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 ABPs effectively modulate CTLA-4 activity, enhancing immune response against tumors and autoimmune diseases, providing therapeutic and diagnostic tools for cancer and autoimmune conditions.
Implementation Method 1
novel ABPs with binding specificity for CTLA-4
Implementation Method 2
induce killing of Tregs, and modulate immune responses through mechanisms such as ADCC and ADCP
Data Source
AI summary
Provided herein are antigen-binding proteins (ABPs) that selectively bind to CTLA-4 and its isoforms and homologs, and compositions comprising the ABPs. Also provided are methods of using the ABPs, such as therapeutic and diagnostic methods.