pH-Responsive Multi-Specific Antibodies for Tumor-Selective Binding
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Solution Overview
Problem
Existing multi-specific antibodies do not effectively exhibit conditional activity, maintaining low activity at normal physiological conditions while significantly increasing activity at aberrant conditions, such as tumor microenvironments, and require destabilizing mutations that counteract standard activity improvement rules.
Innovation Solution
Development of multi-specific antibodies with reversible binding properties, specifically designed to have greater affinity and avidity for cell and tumor-reactive lymphocyte antigens at aberrant conditions compared to normal conditions, utilizing IgG antibodies conjugated with scFv antibodies and various formats like bispecific antibody conjugates and hybrid IgG2 molecules.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If destabilizing mutations are introduced to reduce antibody activity at normal physiological conditions, then conditional activity at aberrant conditions is improved, but the antibody's overall stability and activity are reduced
Solution Approach 1:
The patent applies parameter changes by introducing mutations that alter the antibody's conformational equilibrium in response to pH changes. The mutations shift the equilibrium toward an inactive conformation at physiological pH but allow activation at aberrant pH conditions, thereby changing the activity parameter based on environmental conditions rather than permanently reducing stability
Solution Approach 2:
The patent implements dynamics by creating an antibody that dynamically transitions between active and inactive conformations based on pH conditions. The antibody structure includes pH-sensitive elements that allow reversible conformational changes, enabling the antibody to adapt its activity state according to the local microenvironment rather than maintaining a fixed activity level
2Power
If mutations are introduced to improve activity at higher temperatures according to Q10 rule, then kinetic activity is doubled, but activity at normal operating temperature is reduced
Solution Approach 1:
The patent applies parameter changes by introducing temperature-sensitive conformational transitions that allow the antibody to maintain optimal activity across varying temperatures. The structural modifications enable the antibody to adopt different conformational states that are optimized for different temperature ranges, rather than permanently sacrificing normal-temperature activity for high-temperature performance
3Adaptability or versatility
If multi-specific antibody formats are used to bind multiple antigens, then therapeutic potential is increased, but structural complexity and manufacturing difficulty increase
Solution Approach 1:
The patent applies segmentation by dividing the multi-specific antibody into modular domains with distinct functions. The antibody structure includes separable antigen-binding regions and pH-sensitive regulatory regions that can be independently optimized and assembled, reducing the complexity of designing and manufacturing multi-specific antibodies while maintaining their therapeutic potential
Data Source
AI summary
A multi-specific antibody contains at least one binding site for a cell specific antigen and at least one binding site for a tumor-reactive lymphocyte antigen and a multi-specific antibody including an IgG antibody or fragment thereof that binds to a first antigen; and at least one scFv antibody that binds to a second antigen that is different from the first antigen and is linked to a C terminus of at least one light chain or heavy chain of said IgG antibody or fragment. The multi-specific antibody reversibly binds to at least one of the cell specific antigen and tumor-reactive lymphocyte antigen or the first antigen and the second antigen with a greater affinity at an aberrant condition than at a normal physiological condition. Conjugates of the multi-specific antibodies and methods for generating the multi-specific antibody are also provided.