Multivalent Immunoglobulin Loop Modification for Specific Epitope Binding
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Solution Overview
Problem
Current multivalent immunoglobulin formats face challenges such as immunogenicity, in vivo half-life issues, and production difficulties, limiting their effectiveness in targeting cell surface proteins for therapeutic applications, particularly in cancer treatment and pathogen-infected cells.
Innovation Solution
A modular system is developed that allows for the design of multivalent immunoglobulins by modifying structural loop regions to bind specifically to cell surface molecules, enabling cross-linking of receptors, and combining these modified immunoglobulins with unmodified ones to create combination immunoglobulins, which can be engineered to bind to specific epitopes not recognized by unmodified immunoglobulins.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If multivalent immunoglobulin formats are used to enhance binding potency, then therapeutic efficacy is improved, but immunogenicity increases and in vivo half-life decreases
Solution Approach 1:
The patent segments the immunoglobulin structure into modular domains (Fc regions, variable regions, linker regions) that can be independently designed and assembled. This allows optimization of each segment's properties - the Fc regions maintain native human sequences to reduce immunogenicity, while the variable regions are engineered for high-affinity binding, resolving the contradiction between therapeutic efficacy and immunogenicity
Solution Approach 2:
The patent creates universal building blocks (standardized Fc regions, variable regions, and linkers) that can be combined in various configurations to generate multivalent immunoglobulins with different valencies and specificities. This modular universal system allows the same Fc domain to be reused across multiple constructs, maintaining consistent low immunogenicity while achieving diverse high-potency applications
2Reliability
If multivalent immunoglobulin formats are used to enhance binding potency, then therapeutic efficacy is improved, but production difficulties increase
Solution Approach 1:
The patent divides the complex multivalent immunoglobulin into separate expressible modules (individual Fc regions, variable regions, and linkers) that can be produced independently in standard mammalian expression systems. This segmentation simplifies production by allowing each module to be optimized and manufactured separately using established bioprocessing techniques, then assembled through controlled association
Solution Approach 2:
The patent merges multiple functional modules into a single polypeptide chain or coordinated assembly where Fc regions, variable regions, and linkers are co-expressed and self-assemble into the final multivalent structure. This merging approach streamlines production by utilizing the cell's natural protein folding and assembly mechanisms, reducing the need for complex post-production purification and assembly steps
3Adaptability or versatility
If structural loop regions are modified to bind specific epitopes, then binding specificity is improved, but structural stability may be compromised
Solution Approach 1:
The patent applies local quality changes by modifying only the structural loop regions (framework regions) of the variable domains while leaving the core CDR regions and Fc domains unchanged. This localized modification approach allows introduction of specific epitope-binding properties through loop mutations without disrupting the overall structural integrity and stability of the immunoglobulin molecule
Solution Approach 2:
The patent utilizes parameter changes by systematically varying amino acid sequences in the structural loop regions to optimize both binding specificity and structural stability. Through directed evolution and rational design, loop region parameters (sequence, length, composition) are tuned to achieve high-affinity epitope binding while maintaining proper folding and thermal stability of the overall protein structure
Data Source
AI summary
The present invention provides a multivalent immunoglobulin or part thereof binding specifically to at least two cell surface molecules of a single cell with at least one modification in at least one structural loop region of the immunoglobulin determining binding to an epitope of the cell surface molecules wherein the unmodified immunoglobulin does not significantly bind to the epitope, its use and methods for producing it.