Multispecific Antigen-Binding Molecules with Fc Multimerization
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Solution Overview
Problem
Current bispecific and multispecific antigen-binding molecules lack innovative formats that improve functionalities, particularly in targeting T-cell antigens and target antigens simultaneously with enhanced binding capabilities.
Innovation Solution
Development of multispecific antigen-binding molecules comprising a single polypeptide chain with both N-terminal and C-terminal antigen-binding domains for T-cell antigens and a second polypeptide chain with antigen-binding domains for target antigens, utilizing multimerizing domains for association, including immunoglobulin Fc domains and scFv or Fab domains for enhanced binding and specificity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional FcFc* or IgG-HC-scFv formats are used for bispecific antibodies, then the molecules can bind T-cell antigens and target antigens, but the binding affinity and cytotoxic activity are insufficient
Solution Approach 1:
The antibody molecule is divided into separate functional domains: Fc regions for multimerization and antigen binding, and scFv regions for target antigen binding. This segmentation allows optimization of each domain's function independently, improving overall binding affinity while maintaining manageable complexity through modular design.
Solution Approach 2:
The invention creates composite antibody structures combining Fc domains (for multimerization and T-cell antigen binding) with scFv domains (for target antigen binding). This composite approach integrates the advantages of different molecular formats to achieve enhanced binding affinity and cytotoxic activity.
2Reliability
If conventional bispecific antibody formats are used, then the molecules can target both T-cell antigens and target antigens, but the cytotoxic activity is not enhanced sufficiently
Solution Approach 1:
The invention merges multiple functional capabilities into a single antibody molecule: T-cell antigen binding through Fc regions, target antigen binding through scFv regions, and multimerization through Fc-Fc interactions. This consolidation enhances cytotoxic activity by bringing together all necessary functions in one molecule while preserving functional versatility.
Solution Approach 2:
The invention transitions from conventional monovalent or bivalent binding to multivalent binding through Fc multimerization. This dimensional change in binding valency significantly enhances cytotoxic activity by increasing the avidity and stability of T-cell-target cell interactions.
3Reliability
If new multispecific formats are developed with both N-terminal and C-terminal T-cell antigen binding domains, then binding affinity and cytotoxic activity improve, but the molecular structure becomes more complex
Solution Approach 1:
The Fc region serves multiple universal functions: it provides T-cell antigen binding capability, enables multimerization through Fc-Fc interactions, and contributes to overall molecular stability. This multi-functionality reduces the need for additional specialized domains, managing structural complexity while enhancing binding affinity.
Solution Approach 2:
The invention changes key molecular parameters including the arrangement of antigen-binding domains (N-terminal and C-terminal scFv regions), the multimerization state of Fc regions, and the linkage methods between domains. These parameter changes optimize binding affinity while keeping the polypeptide chain structure manageable through systematic variation.
Data Source
AI summary
The present invention provides multispecific antigen-binding molecules that bind both a T-cell antigen (e.g., CD3) and a target antigen (e.g., a tumor associated antigen, a viral or bacterial antigen), and which include a single polypeptide chain that is multivalent (e.g., bivalent) with respect to T-cell antigen binding, and uses thereof.