Heterodimer Design for Immune Cell Targeting
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Solution Overview
Problem
Current dual signaling proteins (DSPs) face limitations in effectively targeting and modulating immune responses, particularly in cancer treatment, due to challenges in specific binding and activation of immune cells.
Innovation Solution
Development of heterodimers comprising a dimerizing moiety attached to amino acid sequences of type I and type II membrane proteins, enabling targeted binding and activation of immune cells, such as PD1 and 4-1BBL, to enhance immune modulation and cancer treatment efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If dual signaling proteins (DSPs) are used to target and modulate immune responses, then immune modulation capability is improved, but specific binding and activation of immune cells remains insufficient
Solution Approach 1:
The invention segments the immune modulation function into two separate monomers (type I membrane protein and type II membrane protein) that independently bind to their respective ligands. This segmentation allows each monomer to be optimized for specific binding to its target ligand, while the dimerization domain ensures proper assembly. The result is improved specificity in immune cell targeting while maintaining versatile immune modulation capabilities through different ligand-receptor combinations.
Solution Approach 2:
The invention creates a composite protein structure by combining two different membrane protein monomers with distinct ligand-binding specificities into a single heterodimeric molecule. This composite structure enables simultaneous engagement of two different immune cell surface receptors, enhancing both the specificity of binding and the versatility of immune modulation. The dimerization domain acts as a linker that properly orients the two functional domains.
2Measurement precision
If heterodimers with dimerizing moiety are constructed, then targeted binding precision is improved, but device complexity increases
Solution Approach 1:
The dimerization domain serves as an intermediary element that mediates the association between the two monomers. This intermediary component has the specific function of facilitating heterodimer formation through well-defined interaction interfaces (such as IgG Fc domains or fibronectin type III domains). By using a dedicated dimerization domain as mediator, the invention achieves precise control over heterodimer assembly and orientation, improving binding precision while managing structural complexity through modular design.
Solution Approach 2:
The dimerization domain is designed to be universal and can be applied across different heterodimer configurations. The same dimerization domain architecture can accommodate various combinations of type I and type II membrane proteins, allowing the basic structural framework to remain consistent while changing the ligand-binding specificities. This universality reduces the need to redesign the entire structure for different applications, managing complexity through standardized components.
Data Source
AI summary
Heterodimers are provided. Accordingly, there is provided a heterodimer comprising a dimerizing moiety attached to at least one amino acid sequence of at least one type I membrane protein capable of at least binding a natural ligand or receptor of said at least one type I membrane protein and to at least one amino acid sequence of at least one type II membrane protein capable of at least binding a natural ligand or receptor of said at least one type II membrane protein. Also provided are nucleic acid constructs and systems encoding the heterodimer, host-cells expressing same and methods of use thereof.