Trimeric Antigen Binding Molecules via CMP Domain
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Solution Overview
Problem
Designing ideal bispecific antibodies remains a challenge due to difficulties in achieving optimal physico-chemical properties and therapeutic efficacy, particularly in targeting specific antigens on tumor cells while minimizing immunogenicity and improving biodistribution.
Innovation Solution
Development of trimeric antigen binding molecules comprising three fusion polypeptides with antigen binding moieties fused to a trimerization domain derived from human cartilage matrix protein, which forms a stable coiled-coil structure through disulfide bonds, enhancing avidity and serum half-life.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Strength
If conventional dimeric or tetrameric antibody assemblies are used, then binding strength is enhanced, but the complexity of assembly and control of oligomerization becomes difficult
Solution Approach 1:
The patent extracts the oligomerization function from the antibody structure itself and implements it separately through the CMP trimerization domain. This separation allows the antibody binding function and oligomerization function to be independently optimized and controlled, resolving the contradiction between enhanced binding strength and assembly complexity.
Solution Approach 2:
The CMP trimerization domain acts as an intermediary element that mediates the formation of stable trimeric structures. This intermediary provides a controlled and predictable assembly mechanism, avoiding the complexity of direct antibody-antibody oligomerization while achieving the desired multivalent binding enhancement.
2Strength
If multimerization is used to increase binding affinity, then functional affinity is improved, but molecular weight optimization for pharmacokinetics becomes challenging
Solution Approach 1:
The patent changes the oligomerization state parameter from dimeric or tetrameric to trimeric, which optimizes the molecular weight for pharmacokinetic properties. The trimeric structure provides an optimal balance between enhanced binding affinity (through multivalency) and appropriate molecular weight for serum half-life and tissue distribution.
3Stability of the object's composition
If artificial oligomerization domains are used, then trimerization is achieved, but immunogenicity increases due to non-human origin
Solution Approach 1:
The patent uses a trimerization domain derived from human cartilage matrix protein, which is homogeneous with human protein sequences. This homogeneity reduces immunogenicity compared to non-human oligomerization domains while maintaining the desired stable trimeric structure formation.
4Adaptability or versatility
If bispecific antibody formats are designed, then targeting versatility is improved, but achieving optimal physico-chemical properties becomes more difficult
Solution Approach 1:
The patent segments the bispecific antibody into separate functional modules: the CMP trimerization domain for structural organization and the antigen-binding moieties for target recognition. This segmentation allows independent optimization of each module, making physico-chemical property optimization more manageable while maintaining targeting versatility.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The trimeric antigen binding molecules exhibit increased affinity and stability, allowing effective targeting of tumor cells at lower concentrations and improved biodistribution, potentially leading to enhanced therapeutic outcomes in cancer treatment.
Implementation Method 1
each comprising at least one antigen binding moiety fused to a trimerization domain derived from human cartilage matrix protein... which forms a stable coiled-coil structure through disulfide bonds
Data Source
Figure 1a~1b
Figure 2a~2b
Figure 3
AI summary
The present invention pertains to a trimeric antigen binding molecule comprising three fusion polypeptides, each comprising at least one antigen binding moiety fused to a trimerization domain derived from human cartilage matrix protein.In addition, the present invention relates to polynucleotides encoding such trimeric antigen binding molecules, and vectors and host cells comprising such polynucleotides. The invention further relates to methods for producing the trimeric antigen binding molecules of the invention, and to methods of using these trimeric antigen binding molecules in the treatment of disease.