Engineered IL-1beta Antibodies with Optimized CDRs
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Solution Overview
Problem
There is a need for therapeutic antibodies that effectively bind and neutralize human IL-1β to treat and prevent inflammatory diseases such as atherosclerotic cardiovascular disease, heart failure, cancer, and rare inherited disorders.
Innovation Solution
Engineered human antibodies with specific heavy and light chain variable regions, including particular complementarity determining regions (CDRs), are developed to exhibit potent IL-1β neutralizing activity and high specificity for IL-1β.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing IL-1β antibodies like Canakinumab are used, then IL-1β neutralizing activity is achieved, but binding affinity and neutralizing potency are insufficient compared to the need for highly effective therapeutics
Solution Approach 1:
The patent applies parameter changes by systematically modifying amino acid sequences at specific positions in the complementarity determining regions (CDRs) of the antibody. Multiple amino acid substitutions are introduced at defined positions (e.g., HCDR1: AASGFTFSSYSX1S where X1 is Phe or Leu; HCDR2: AISVSGGSTYYAX2SVKG where X2 is Pro or Asp; HCDR3: ARDDLIX3TRGTFYNWFDP where X3 is Thr or Pro) to optimize binding affinity and neutralizing potency against IL-1β, transforming the antibody from a functional but less effective molecule to a high-affinity therapeutic.
Solution Approach 2:
The patent segments the antibody into distinct functional regions with specific sequences: heavy chain variable region (VH) with defined HCDRs, light chain variable region (VL) with defined LCDRs, and constant regions. This segmentation allows independent optimization of each region's sequence to achieve the desired binding characteristics while maintaining overall antibody structure and function.
2Reliability
If therapeutic antibodies are developed with high specificity for IL-1β, then treatment efficacy is improved, but development complexity and manufacturing difficulty increase
Solution Approach 1:
The patent applies local quality by introducing specific amino acid mutations only at defined positions within the complementarity determining regions (CDRs) while maintaining the overall antibody structure and sequence elsewhere. For example, only specific positions in HCDR1, HCDR2, and HCDR3 are modified to achieve high specificity, while the framework regions and constant regions remain standard, thus localizing the complexity to only where needed for functionality.
Solution Approach 2:
The patent uses copying by employing standardized antibody frameworks and constant regions that can be replicated across different antibody molecules. The defined CDR sequences are copied into the appropriate framework structures, allowing for consistent production of antibodies with high specificity through repeated use of proven structural templates.
3Productivity
If existing antibodies are used for treating inflammatory diseases, then treatment is provided, but the antibodies do not achieve comparable or greater neutralizing activity required for optimal clinical outcomes
Solution Approach 1:
The patent applies partial or excessive action by introducing multiple amino acid substitutions at specific positions to achieve excessive binding affinity compared to what was previously thought necessary. The defined mutations (e.g., at positions X1, X2, X3 with specific amino acid choices) create an over-optimized binding interface that exceeds the minimum required for therapeutic effectiveness, ensuring superior neutralizing activity and clinical outcomes.
Data Source
AI summary
The present invention provides engineered human interleukin-1 beta antibodies, cells and vectors comprising DNA encoding the same, and methods for producing the antibodies. In addition, the present invention provides the use of the human engineered interleukin-1-beta antibodies for the treatment of inflammatory disease, such as cardiovascular disease and cancer.