Dual Variable Domain Binding Proteins for IL-1β and IL-17
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Solution Overview
Problem
Current methods for producing multivalent binding proteins that target IL-1β and IL-17 are hindered by issues such as mis-paired by-products, reduced production yields, and the need for sophisticated purification procedures, as well as the lack of homogeneous preparations and specific properties for therapeutic applications.
Innovation Solution
Development of Dual Variable Domain (DVD) binding proteins comprising specific polypeptide chains with variable domains and linkers that form functional binding sites for IL-1β and IL-17, allowing for high-affinity binding and improved therapeutic modalities, including the use of specific linker sequences and Fc regions to enhance binding properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If quadroma technology is used to produce bispecific antibodies, then binding specificity is improved, but production yield is significantly reduced and mis-paired by-products are generated
Solution Approach 1:
The invention divides the antibody molecule into separate binding domains (first and second binding sites) that can be independently designed and assembled. Each binding site is formed by separate polypeptide chains that are later joined through disulfide bonds, allowing independent optimization of each binding specificity while maintaining overall production efficiency.
Solution Approach 2:
The invention uses disulfide bonds as intermediary linkages to join the first and second binding sites. These chemical bonds serve as reliable mediators that connect the separate polypeptide chains, ensuring stable formation of the bispecific antibody without requiring complex purification procedures to remove mis-paired by-products.
2Adaptability or versatility
If chemical conjugation of two different mAbs is used, then binding versatility is improved, but homogeneity of preparation is reduced
Solution Approach 1:
The invention merges the binding specificities of two different monoclonal antibodies into a single integrated protein structure. The first and second binding sites are formed by polypeptide chains that are co-translated and chemically joined through disulfide bonds, creating a homogeneous preparation where both binding specificities are permanently integrated rather than randomly assembled.
Solution Approach 2:
The invention ensures homogeneity by using a standardized protein framework where the first and second binding sites are formed by identical polypeptide chain configurations joined through consistent disulfide bond patterns. This standardized architecture ensures that all molecules in the preparation have the same structure and binding properties, eliminating the heterogeneity that arises from chemical conjugation methods.
3Ease of manufacture
If conventional binding protein structures are used, then ease of manufacture is improved, but specific binding properties for therapeutic applications are insufficient
Solution Approach 1:
The invention applies local quality by designing specific polypeptide sequences for the first and second binding sites that are optimized for their respective target antigens. While the overall protein framework maintains ease of manufacture through standardized folding and disulfide bond formation, the local binding regions contain specific amino acid sequences (such as those derived from SEQ ID NOs: 32-41 for IL-1β and SEQ ID NOs: 42-47 for IL-17) that provide high-affinity, specific binding properties suitable for therapeutic applications.
Data Source
AI summary
Engineered multivalent and multispecific binding proteins that bind IL-1β and/or IL-17 are provided, along with methods of making and uses in the prevention, diagnosis, and/or treatment of disease.