IL-10 Muteins with Local Quality Mutations for Inflammatory Disease
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Solution Overview
Problem
Current treatments for inflammatory conditions such as inflammatory bowel disease (IBD) using IL-10 have limitations due to stability issues and adverse effects on CD8+ T cells and B cells, and existing therapies face challenges in effectively targeting inflammatory pathways.
Innovation Solution
Development of IL-10 muteins that are stable as monomers and retain immunosuppressive activity on monocytes and macrophages while reducing stimulation of CD8+ T cells and B cells, combined with antigen binding proteins like anti-TREM-1 or anti-PD-1 antibodies to treat inflammatory diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type IL-10 is used to suppress inflammatory cytokines in monocytes and macrophages, then anti-inflammatory activity is achieved, but stimulation of CD8+ T cells and B cells occurs causing adverse effects
Solution Approach 1:
The patent applies local quality by introducing site-specific mutations in the B-cell epitope region of IL-10 (particularly in helices A, B, and F) to eliminate B cell stimulation while preserving the anti-inflammatory activity in monocytes and macrophages. This targeted modification of specific regions maintains the desired function while removing the harmful effect.
Solution Approach 2:
The patent employs parameter changes by mutating specific amino acid residues in the IL-10 sequence to alter its immunogenic properties. These parameter changes in the protein structure modify the epitope characteristics, reducing recognition by anti-IL-10 antibodies and decreasing stimulation of CD8+ T cells and B cells while maintaining suppressive activity on inflammatory cells.
2Reliability
If PEGylated IL-10 is administered to treat Crohn's disease, then modest efficacy is achieved, but dose-limiting toxicity occurs
Solution Approach 1:
The patent applies local quality by modifying specific regions of IL-10 (particularly B-cell epitopes in helices A, B, and F) to reduce immunogenicity and toxicity. These localized mutations eliminate the harmful immune responses that caused dose-limiting toxicity in PEGylated IL-10, allowing higher doses to be administered safely while maintaining therapeutic efficacy in inflammatory bowel disease.
3Object-affected harmful factors
If IL-10 mutations are introduced to reduce B cell stimulation, then adverse effects are reduced, but stability as monomer may be compromised
Solution Approach 1:
The patent applies local quality by introducing mutations specifically in the B-cell epitope regions (helices A, B, and F) while carefully selecting amino acid substitutions that preserve the overall structural integrity and monomer stability of IL-10. This targeted approach reduces B cell stimulation without compromising the protein's compositional stability.
Data Source
AI summary
Abstract: The present disclosure relates, in general, to muteins of IL-10 that are stable as monomers, antigen binding proteins that bind to TREM-1, and antigen binding proteins comprising IL-10 muteins and antigen binding moieties, e.g., anti-TREM-1 antibodies, and compositions thereof. The disclosure also provides methods of treating inflammatory disease, such as inflammatory bowel disease or ulcerative colitis, using the compositions.