Asymmetric Antigen Binding Molecules for Tumor Targeting
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Conventional multispecific antibodies for cancer immunotherapy face challenges in reducing off-target toxicity and optimizing T-cell mediated tumor cell killing due to fixed distances between tumor targeting domains and CD3 binding domains, which do not account for varying epitope distances on tumor cells.
Innovation Solution
The development of on-cell formed trispecific heterodimeric antibodies composed of antigen binding molecules with unpaired VL or VH domains that reconstitute the anti-CD3 Fv domain upon binding to tumor cell surface antigens, allowing for asymmetric combinations that optimize targeting of different epitopes and enhanced T-cell activation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional multisspecific antibodies are used with fixed distances between tumor targeting domains and CD3 binding domains, then the structural stability is maintained, but the efficacy of T-cell mediated tumor cell killing is reduced due to inability to account for varying epitope distances
Solution Approach 1:
The antibody is divided into separate modules: tumor antigen binding domains (scFv or Fab fragments) and CD3 binding domain (anti-CD3 Fv), connected by flexible linkers. This segmentation allows independent optimization of each domain while maintaining overall functionality, enabling the antibody to adapt to varying epitope distances on tumor cells.
Solution Approach 2:
The antibody structure incorporates flexible peptide linkers between functional domains, transforming the rigid fixed-distance structure into a dynamic configuration that can adapt to different epitope positions on tumor cell surfaces, thereby optimizing T-cell engagement and killing efficacy.
2Power
If CD3 is engaged with high binding affinity to enhance T-cell activation, then the potency increases, but off-target toxicity is increased due to T-cell activation independent of target cell presence
Solution Approach 1:
The CD3 binding capability is extracted as a separate functional domain (anti-CD3 Fv) that requires co-engagement with tumor antigen binding for full activation. This separation allows the CD3 domain to maintain high affinity for potent T-cell activation while the overall system requires dual binding, reducing off-target effects.
Solution Approach 2:
The antibody design incorporates tumor antigen binding as a prerequisite condition before CD3 engagement can lead to full T-cell activation. This preliminary binding requirement acts as a safety mechanism that prevents off-target T-cell activation by ensuring target cell presence before potent activation occurs.
3Reliability
If dual targeting of two different TAAs is implemented to reduce off-target effects, then the selectivity over normal tissues is improved, but the complexity of antibody development increases
Solution Approach 1:
The antibody platform is designed with universal modular components that can be combined in various configurations to target different TAA pairs. The standardized anti-CD3 Fv domain and interchangeable tumor antigen binding domains allow rapid development of dual-targeting antibodies for different cancer types without redesigning the entire molecule, reducing development complexity.
Data Source
AI summary
The present disclosure provides combinations or sets of two antigen binding molecule, in particular asymmetric combinations of such antigen binding molecules. Each of the two antigen binding molecules is composed of a targeting moiety with specificity for a tumor associated antigen fused to either the VL or VH domain of an antibody Fv domain specific for CD3. Once the two antigen binding molecules bind to their target antigen on the surface of a cell, the complementary VL and VH domain are capable to associate with each other thereby reconstituting the functional CD3 specific Fv domain and non-covalently dimerizing the two antigen binding molecules. The thus on-cell formed trispecific heterodimeric antibody molecule is capable of engaging and stimulating cytotoxic T-cells for tumor cell destruction.