Immunomodulatory Fusion Proteins for T Cell Activation
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Solution Overview
Problem
Current immunotherapies, such as adoptive T cell transfer and recombinant TCR or CAR T cell therapies, face challenges in effectively activating T cells due to downregulated co-stimulatory molecules in the tumor microenvironment, requiring exogenous stimuli like IL-2, and lack alternative compositions that provide immunomodulatory signals for enhanced T cell activation.
Innovation Solution
Development of fusion proteins with specific binding domains that span a distance similar to the immunological synapse, combining extracellular components that bind targets like CD200 or CD47 with intracellular signaling domains of CD28 or CD137, allowing for co-stimulatory signals without the need for exogenous co-stimulation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If exogenous co-stimulatory signals (e.g., IL-2) are administered to activate T cells, then T cell activation is improved, but treatment complexity and requirement for external support increase
Solution Approach 1:
The patent combines the antigen recognition function (TCR or CAR) with the co-stimulatory signaling function into a single integrated receptor complex on the T cell surface. This merging eliminates the need for separate exogenous co-stimulatory signals by providing both activation signals endogenously through the engineered receptor structure itself.
Solution Approach 2:
The engineered T cells are designed to be self-sufficient for activation by integrating co-stimulatory domains directly into the receptor structure. The T cells can autonomously generate both the primary activation signal (through antigen binding) and the co-stimulatory signal (through integrated intracellular domains) without requiring external IL-2 or other co-stimulatory support.
2Reliability
If T cells are genetically modified with recombinant TCR or CAR to enhance tumor targeting, then antigen specificity is improved, but dependence on exogenous co-stimulation increases due to downregulated co-stimulatory molecules in tumor microenvironment
Solution Approach 1:
The patent merges the antigen recognition capability (via TCR or CAR extracellular domains) with co-stimulatory signaling capability (via integrated intracellular domains such as CD28, 4-1BB, or OX40 signaling domains) into a unified receptor structure. This allows the T cell to receive both activation signals from a single receptor engagement event, eliminating dependence on exogenous co-stimulation even in the tumor microenvironment where co-stimulatory molecules are downregulated.
Solution Approach 2:
The engineered receptor is a composite structure combining different functional domains: an antigen-binding domain (from TCR or CAR) fused with co-stimulatory signaling domains. This composite receptor provides multiple signaling functions within a single molecular entity, enabling the T cell to operate independently of the tumor microenvironment's co-stimulatory status.
3Reliability
If fusion protein length is increased to span immunological synapse distance, then ability to deliver co-stimulatory signal is improved, but molecular complexity increases
Solution Approach 1:
The fusion protein is segmented into distinct functional modules: an extracellular antigen-binding domain, a transmembrane domain for membrane anchoring, and one or more intracellular co-stimulatory signaling domains. This segmentation allows each domain to perform its specific function while maintaining overall structural organization and facilitating independent optimization of each module.
Solution Approach 2:
The fusion protein structure is designed to be universally applicable by using conserved transmembrane domain architectures and well-characterized co-stimulatory signaling domains (such as CD28, 4-1BB, OX40) that can be combined with various antigen-binding specificities. This multi-functional design allows the same structural framework to deliver co-stimulatory signals across different target antigens and T cell subsets.
Data Source
AI summary
Described herein are immunomodulatory fusion proteins containing an extracellular binding domain and an intracellular signaling domain, wherein binding of a target can generate a modulatory signal in a host cell, such as a T cell. Some immunomodulatory fusion proteins as described comprise a SIRPĪ± extracellular component and hydrophobic and intracellular components comprising transmembrane and/or signaling domains of a CD28, respectively. Such fusion proteins are capable of delivering a positive or costimulatory signal in response to a binding event that in a natural setting would result in an inhibitory signal. Uses of immune cells expressing such immunomodulatory fusion proteins to treat certain diseases, such as cancer or infectious disease, are also described.