Raltitrexed and 5-MTHF Conjugates for Selective Treg Modulation
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Solution Overview
Problem
Current cancer treatments primarily target tumor cells, neglecting the role of genetically stable stromal cells in the tumor microenvironment (TME), which can promote tumor growth and metastasis through regulatory T cells (Tregs).
Innovation Solution
Development of compounds comprising raltitrexed or 5-methyltetrahydrofolate (5-MTHF) conjugated to therapeutic agents via linkers, which selectively target and immunomodulate Tregs, altering their pro-tumor activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current cancer treatments focus on targeting and killing tumor cells, then tumor cell destruction is improved, but the role of stromal cells promoting tumor growth and metastasis is neglected
Solution Approach 1:
The patent uses folate-conjugated therapeutic agents as intermediaries to deliver immunomodulatory compounds specifically to Tregs within the TME. The folate moiety targets the folate receptor overexpressed on Tregs, enabling selective delivery of therapeutic agents that can reprogram Tregs from pro-tumor to anti-tumor phenotype, thereby addressing the harmful effect of stromal cells without directly targeting tumor cells
Solution Approach 2:
The invention applies local quality by designing compounds with specific targeting moieties (folate) that confer selective accumulation at the TME, particularly within Tregs. This localized targeting allows the therapeutic agent to exert its immunomodulatory effect specifically where needed (in the TME) while minimizing systemic effects and leaving other tissues unaffected
2Reliability
If Tregs are targeted to alter their pro-tumor activity, then anti-tumor immunity is enhanced, but selective delivery to Tregs must be achieved amidst heterogeneous cell populations
Solution Approach 1:
The folate moiety serves as a mediator that bridges the therapeutic agent and Tregs by specifically binding to the folate receptor delta (FRδ) overexpressed on Tregs. This mediator enables selective delivery of the therapeutic payload to Tregs within the heterogeneous TME, overcoming the challenge of cell population heterogeneity through receptor-ligand specificity
Solution Approach 2:
The invention exploits parameter changes by utilizing the differential expression levels of the folate receptor on different cell types. Tregs exhibit overexpression of FRδ compared to other cell types in the TME, and this parameter difference (receptor expression level) is leveraged to achieve selective targeting and delivery to Tregs through folate-conjugated compounds
Data Source
AI summary
Compounds comprising a radical of a therapeutic agent conjugated to a radical of raltitrexed, 5-methyltetrahydrofolate (5-MTHF), an analog of raltitrexed, or an analog of 5-MTHF via a linker; compositions comprising same; and a method of immunomodulating Tregs.