Humanized Antibodies Against Interferon-Alpha
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current humanized anti-IFN-α antibodies suffer from functional deficiencies such as lower affinity and stability, and undesirable immunogenicity, limiting their effectiveness in treating autoimmune diseases like systemic lupus erythematosus.
Innovation Solution
Development of humanized antibodies with fewer donor amino acid residues than the murine CDRs, specifically designed to bind IFN-α subtypes A, 2, B2, C, F, G, H2, I, J1, K, 4a, 4b, and WA, while minimizing immunogenicity, using a combination of CDR truncation and strategic back mutations to enhance stability and affinity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If murine antibodies are used to neutralize IFN-α activity, then binding affinity and neutralization potency are achieved, but immunogenicity increases making them unsuitable for human use
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence parameters of the antibody - specifically humanizing the murine antibody sequence while preserving the CDR regions. This changes the immunogenicity parameter (reducing it) while maintaining binding affinity through strategic retention of murine CDR sequences in a human framework
Solution Approach 2:
The patent creates a composite antibody structure combining human framework regions with murine CDR regions. This hybrid structure allows the antibody to have human-like properties (low immunogenicity) while retaining the functional binding characteristics of the murine parent antibody
2Object-affected harmful factors
If humanized antibodies are created by grafting murine CDRs onto human scaffold, then immunogenicity is reduced, but functional deficiencies such as lower affinity and stability occur
Solution Approach 1:
The patent applies local quality by making the antibody partially human and partially murine - specifically keeping the CDR regions (which provide binding function) while humanizing the framework regions. This local differentiation allows the antibody to have low immunogenicity in the framework while maintaining high functional stability through the murine CDRs
Solution Approach 2:
The patent modifies the degree of humanization parameter - not fully humanizing the antibody but rather partially humanizing it while retaining critical murine sequences. This parameter adjustment maintains functional stability while reducing immunogenicity
3Reliability
If back point mutations are introduced to compensate for functional deficiencies, then affinity and stability are improved, but immunogenicity and stability may deteriorate with too many mutations
Solution Approach 1:
The patent applies partial action by introducing only the necessary back mutations to achieve functional compensation - not over-mutating. This selective approach improves affinity and stability while minimizing the risk of increasing immunogenicity or reducing stability through excessive mutations
Data Source
AI summary
The present invention provides humanized anti-human IFN-α monoclonal antibodies useful for therapeutic applications in humans. Preferred antibodies are humanized versions of murine antibodies ACO-1 and ACO-2, as well as variants thereof.