TLR9-Binding CAR Polypeptides for MDS Targeting
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Solution Overview
Problem
Current treatments for Myelodysplastic Syndromes (MDS) are limited, with no effective targeted therapies available for the majority of patients, and existing immunotherapies have not explored MDS as a target for chimeric antigen receptor (CAR)-T cell therapies.
Innovation Solution
Development of chimeric antigen receptor (CAR) polypeptides that target TLR9-expressing cancer cells, specifically designed for adoptive cell transfer, using immune effector cells genetically modified to express these CARs, which include an anti-TLR9 binding agent and signaling domains for activation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional targeted therapies are used for MDS treatment, then partial or complete cytogenetic remissions are achieved in del5q subtype patients, but the vast majority of non-del5q MDS patients do not benefit
Solution Approach 1:
The patent develops CAR-T cell therapy that targets TLR9, a molecule universally expressed on the plasma membrane of MDS cells across different subtypes including non-del5q MDS. This universal target allows the same therapeutic approach to be applied to all MDS patients regardless of cytogenetic subtype, resolving the limitation of lenalidomide which only works for del5q (8-12% of patients).
Solution Approach 2:
The invention changes the therapeutic parameter from chemotherapy-based targeted therapy (lenalidomide) to immunotherapy-based CAR-T cell therapy. This parameter change enables targeting of TLR9-expressing cells through immune recognition and destruction, providing a new mechanism of action that is effective across MDS subtypes where conventional therapies fail.
2Reliability
If CAR-T cell therapy is developed to target TLR9-expressing MDS cells, then a curative option is provided for majority of MDS patients, but the complexity of genetic modification and cell therapy increases
Solution Approach 1:
The patent uses TLR9 as an intermediary target molecule that is naturally present on MDS cells. By directing CAR-T cells to recognize this endogenous target, the therapy leverages the patient's own cellular machinery and natural immune recognition pathways, simplifying the overall approach compared to creating entirely new therapeutic molecules or modifying multiple cellular components.
3Reliability
If lenalidomide is used as targeted therapy, then sustained red blood cell transfusion independence is achieved in del5q patients, but this therapy is only effective for 8-12% of MDS population
Solution Approach 1:
The CAR-T cell therapy targets TLR9, which is expressed on plasma membranes of MDS cells across all cytogenetic subtypes. This universal targeting mechanism expands the treatable population from 8-12% (del5q only with lenalidomide) to the vast majority of MDS patients, including those with non-del5q subtypes who currently have no effective targeted therapy options.
Data Source
AI summary
Disclosed herein are chimeric antigen receptor (CAR) polypeptides that can be used with adoptive cell transfer to target and kill cancer cells that express TLR9 on their surface. Also disclosed are immune effector cells, such as T cells or Natural Killer (NK) cells that are engineered to express these CARs. Therefore, also disclosed are methods of providing an anti-tumor immunity in a subject with a TLR9-expressing cancer that involves adoptive transfer of the disclosed immune effector cells engineered to express the disclosed CARs.