Fc-Free CTLA4-Binding Proteins for Reduced Toxicity
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Solution Overview
Problem
Current immunotherapies targeting CTLA4, such as ipilimumab, have limited efficacy and are associated with significant toxicity, necessitating the development of safer and more effective strategies for cancer treatment.
Innovation Solution
Engineered CTLA4-binding proteins that target multiple epitopes on CTLA4, such as Epitope 1 (134MYPPPY139) and Epitope 2 (65SICT68), and are devoid of the Fc region, demonstrating synergistic T cell activation and enhanced blocking activity compared to existing antibodies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If ipilimumab is used to block CTLA4, then T cell activation is enhanced, but toxicity and side effects increase
Solution Approach 1:
The invention segments the antibody structure by removing the Fc region to create F(ab')2 fragments. This segmentation allows the protein to retain CTLA4-blocking activity while eliminating Fc-mediated toxic effects such as complement activation and Fc receptor engagement, thereby resolving the contradiction between efficacy and toxicity
Solution Approach 2:
The harmful Fc region is extracted and removed from the antibody structure, leaving only the antigen-binding Fab regions. This extraction eliminates the source of toxicity while preserving the therapeutic mechanism of CTLA4 blockade, achieving better safety profile without sacrificing antitumor activity
2Reliability
If ipilimumab is used to treat cancer, then some tumors respond, but long-term success rate remains limited at 22%
Solution Approach 1:
The invention modifies the local quality of the antibody by altering its structural composition (removing Fc region) and creating biparatopic binding capability. This local modification enables simultaneous engagement of multiple CTLA4 epitopes, enhancing T cell activation potency and overcoming the limited efficacy of conventional monoclonal antibodies
Solution Approach 2:
The engineered F(ab')2 proteins possess multiple functions: they block CTLA4 ligand binding, activate T cells, and do so with enhanced potency compared to full-length antibodies. This multi-functionality with improved activity addresses the limited success rate of current therapies
3Reliability
If full-length CTLA4 antibodies with Fc region are used, then Fc receptor interaction is achieved, but this is not required for optimal CTLA4-blocking activity
Solution Approach 1:
The Fc region is extracted from the antibody structure, demonstrating that it is not essential for CTLA4-blocking activity. This simplification removes unnecessary structural complexity while maintaining the core therapeutic function of blocking CTLA4 ligand binding
Solution Approach 2:
The F(ab')2 fragments represent a simplified, shorter-lived alternative to full-length antibodies. They achieve the same CTLA4-blocking function without the complexity and potential adverse effects of the Fc region, providing a more efficient therapeutic approach
Data Source
AI summary
The present disclosure provides engineered antigen-binding proteins that bind to cytotoxic T-lymphocyte-associated antigen-4 (CTLA4). Nucleic acids, vectors, host cells, and conjugates are also provided herein. Further provided are kits and pharmaceutical compositions comprising said entities as well as methods of making the engineered antigen-binding proteins and methods of treating a subject in need thereof.