Chimeric Molecules for TCR Clustering and Costimulation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current adoptive cell therapies, such as those using tumor-infiltrating lymphocytes (TILs), face limitations in effectively targeting tumor cells due to the lack of costimulatory ligands expressed by tumor cells, which hampers the activation and expansion of T-cells, limiting their antitumor efficacy.
Innovation Solution
Development of chimeric molecules that provide costimulation when the endogenous T-cell receptor (TCR) is engaged with its cognate antigen, incorporating TCR clustering domains and signaling domains like CD40, to enhance T-cell activation and proliferation by promoting clustering and signaling, thereby increasing cytokine secretion and activation markers.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If tumor cells are used as targets for adoptive cell therapy, then antitumor response is improved, but costimulatory ligand availability on tumor cells is insufficient, limiting T-cell activation and expansion
Solution Approach 1:
The patent introduces chimeric molecules as intermediaries that bridge the gap between TCR engagement and costimulatory signaling. These molecules contain TCR clustering domains that recruit endogenous CD3 complexes and signaling domains that provide costimulatory signals, effectively mediating the interaction between T-cells and tumor antigens without requiring tumor cells to express costimulatory ligands.
Solution Approach 2:
The invention merges two distinct functions into a single chimeric molecule: TCR clustering (antigen recognition) and costimulatory signaling. By combining the extracellular domain of a TCR with intracellular signaling domains of costimulatory molecules like CD28 or CD137, the construct simultaneously captures antigen-specificity and provides the necessary costimulatory signals that would otherwise be absent from tumor cells.
2Measurement precision
If endogenous TCR is engaged with cognate antigen, then antigen-specificity is improved, but costimulatory signals are insufficient, leading to activation induced cell death
Solution Approach 1:
The chimeric molecules merge the antigen-specific recognition function of the endogenous TCR with the survival-promoting costimulatory signals. The TCR clustering domain maintains antigen-specificity while the signaling domain (containing CD28 or CD137 intracellular domains) provides the costimulatory signals needed for T-cell survival and proliferation, preventing activation-induced cell death.
Solution Approach 2:
The invention creates a composite signaling construct that combines elements from different molecular families: the extracellular domain of a TCR (for antigen recognition) fused with intracellular signaling domains from costimulatory receptors like CD28 or CD137. This composite structure integrates multiple functional properties into a single molecule that can simultaneously provide antigen-specificity and costimulatory signaling.
3Reliability
If chimeric molecules with TCR clustering domains are used, then T-cell activation is improved, but molecular complexity increases
Solution Approach 1:
The chimeric molecule is segmented into distinct functional domains: an extracellular TCR domain for antigen recognition and clustering, a transmembrane domain for membrane anchoring, and an intracellular signaling domain for costimulatory signal transduction. This segmentation allows each domain to perform its specific function while maintaining overall molecular functionality.
Solution Approach 2:
The chimeric molecules exhibit multi-functionality by simultaneously performing antigen recognition, TCR clustering, and costimulatory signaling. A single molecular construct accomplishes multiple tasks that would traditionally require separate molecules, including capturing antigen-specific TCRs, clustering them for signal amplification, and providing costimulatory signals for T-cell activation and survival.
Data Source
AI summary
The present invention relates to a chimeric molecule useful in adoptive cell therapy (ACT), and cells comprising the same. The chimeric molecule can act as a modulator of cellular activity enhancing responses when an endogenous T-cell receptor (TCR) is engaged with its cognate antigen. The present invention also provides proteins, nucleic acids encoding the chimeric molecule and therapeutic uses thereof.