CD1c-mLPA-Specific TCRs for Selective Leukemia Targeting
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for hematological disorders such as leukemia lack effective immunotherapies that specifically target leukemia cells without harming normal cells, and there is a need for improved strategies to prevent relapse after hematopoietic stem cell transplantation.
Innovation Solution
Development of T-cell receptors (TCRs) with antigenic specificity for CD1c molecules associated with self-lipids like methyl-lysophosphatidic acid (mLPA) to selectively target and kill leukemia cells, using recombinant expression vectors and host cells to enhance T-cell responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional immunotherapies are used to target leukemia cells, then therapeutic efficacy is achieved, but normal cells are also damaged causing harmful side effects
Solution Approach 1:
The TCR is engineered with specific complementarity determining regions (CDRs) that confer local antigen-binding specificity to the CD1c-mLPA complex. This localized molecular recognition ensures that only leukemia cells expressing this specific antigen-CD1 complex are targeted, while normal cells without this specific combination remain unaffected, thus resolving the contradiction between therapeutic efficacy and harm to normal cells
Solution Approach 2:
The patent modifies the TCR structure by introducing specific amino acid substitutions in the CDR regions (e.g., CDR3β with specific sequences from SEQ ID NO: 30, 36, 42, 48, or 54) to optimize binding affinity and specificity for the CD1c-mLPA complex. These parameter changes at the molecular level enable precise targeting of leukemia cells while minimizing off-target effects on normal cells
2Reliability
If T-cell responses are enhanced to improve leukemia cell killing, then therapeutic efficacy increases, but risk of systemic GVHD increases
Solution Approach 1:
The TCR is designed with specific local binding properties that recognize only the CD1c-mLPA complex found on leukemia cells. This localized specificity prevents the T cells from attacking normal host tissues, thereby enhancing anti-leukemia efficacy while minimizing the risk of graft-versus-host disease
Solution Approach 2:
The CD1c molecule acts as an intermediary that presents the mLPA antigen to the TCR. This intermediary mechanism allows the T cells to specifically target leukemia cells through the CD1c-mLPA complex while ignoring normal cells that do not express this specific complex, thus resolving the contradiction between enhanced therapeutic efficacy and reduced GVHD risk
3Measurement precision
If TCR specificity is increased to selectively target leukemia cells, then precision of targeting improves, but complexity of TCR structure increases
Solution Approach 1:
The TCR is segmented into distinct functional domains: variable regions (Vα and Vβ) containing complementarity determining regions (CDRs 1-3) for antigen recognition, and constant regions (Cα and Cβ) for signal transduction. This segmentation allows the CDRs to be optimized for high precision binding to CD1c-mLPA while the constant regions provide stable structural framework, balancing targeting precision with structural manageability
Solution Approach 2:
The TCR design utilizes universal TCR structural elements and constant regions that are cons across different T cell receptors, while only the CDR regions need to be customized for specific antigen recognition. This multi-functionality approach allows the same basic TCR structure to achieve high precision targeting through variable CDR sequences, reducing overall structural complexity while maintaining high specificity
Data Source
AI summary
The present invention relates to a TCR or functional variant thereof having antigenic specificity for CD1c molecules associated with a self-lipid, preferably (mLPA) or derivative thereof, to relative polypeptide, protein, nucleic acid, recombinant expression vector, host cell, population of cells, antibody and pharmaceutical composition. The present invention also relates to the uses of said TCR and relative products, in particular for use in the treatment and/or prevention of an hematological disorder.