Heterodimeric Antibody Monovalent CD3 Binding
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current bispecific antibodies face challenges such as rapid clearance in vivo, manufacturing obstacles, and nonspecific activation due to lack of constant regions, leading to toxicity, especially when engaging co-target antigens multivalently without the primary target antigen.
Innovation Solution
Development of heterodimeric antibodies with specific monomeric structures and amino acid substitutions that allow for monovalent binding to CD3 and CD38, utilizing scFv and Fc domains to achieve targeted antigen engagement while minimizing off-target activation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If antibody fragments are used to make bispecifics, then high expression levels and favorable penetration benefits are achieved, but rapid clearance in vivo and manufacturing obstacles occur due to lack of constant region
Solution Approach 1:
The antibody is divided into separate heavy and light chains that can be independently expressed and then assemble into functional bispecific antibodies. This segmentation allows for optimized expression of individual chains while maintaining the stability benefits of complete antibody structures with constant regions.
Solution Approach 2:
The patent combines antibody fragments with constant regions to create hybrid structures that possess both the desirable properties of fragments (small size, high expression) and the stability benefits of complete antibodies (Fc region-mediated long half-life, Fc receptor binding).
2Ease of manufacture
If full length antibody-like formats are engineered with dual binding, then manufacturing obstacles are reduced, but nonspecific activation and toxicity occur due to bivalent binding to co-target antigens
Solution Approach 1:
The patent removes one antigen binding site from each heavy chain, extracting the bivalent binding capability and replacing it with a monovalent scFv fragment. This ensures that only one antigen binding site per antibody molecule is present for each target, preventing nonspecific cross-linking and activation.
Solution Approach 2:
The antibody structure is made asymmetric with different binding valencies at different locations. One arm binds CD3 monovalently while the other binds the tumor antigen monovalently, creating localized monovalent interactions that prevent unwanted cross-linking and nonspecific activation.
3Force
If bivalent binding to co-target antigen is achieved, then binding affinity is increased, but cytokine storm and toxicity result from nonspecific activation
Solution Approach 1:
The antibody design allows dynamic control of binding valency through the heterodimeric structure. The scFv-Fc fusion protein can engage antigens in a controlled manner, presenting monovalent binding that avoids the fixed bivalent configuration responsible for nonspecific activation and cytokine storm.
Data Source
Figure 1A
Figure 1B
Figure 1C
AI summary
The present invention is directed to novel heterodimeric antibodies.