S1P and JAK Modulators for Iatrogenic Autoimmune Colitis
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Solution Overview
Problem
Current treatments for iatrogenic autoimmune colitis induced by chemotherapeutic agents, such as immune checkpoint inhibitors, are inadequate in managing severe immune-related adverse effects, which can lead to life-threatening conditions like bowel perforation.
Innovation Solution
Administration of specific chemical entities including sphingosine 1-phosphate receptor modulators, Janus kinase inhibitors, lanthionine synthetase C-like 2 modulators, integrin modulators, and immunosuppressants to the gastrointestinal tract to reduce immune responses and inflammation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If checkpoint inhibitor therapy is administered to treat cancer, then immune response against tumor is enhanced, but immune-related adverse effects including severe colitis occur
Solution Approach 1:
The patent segments the immune system response by selectively modulating specific immune pathways. Checkpoint inhibitors block CTLA-4 or PD-1 pathways to enhance anti-tumor immunity, while the disclosed compounds target specific inflammatory pathways (e.g., JAK-STAT, NF-κB) to suppress colitis without compromising cancer treatment efficacy. This selective segmentation allows differential control of immune responses in different tissue contexts.
Solution Approach 2:
The patent introduces intermediary compounds that mediate between the checkpoint inhibitor therapy and the immune system. These compounds (e.g., JAK inhibitors, S1P modulators, integrin inhibitors) act as intermediaries to dampen excessive immune activation in the gut while allowing the checkpoint inhibitors to maintain their anti-tumor activity. The intermediaries translate the harmful immune response into a controlled state.
2Object-affected harmful factors
If high doses of immunosuppressants are administered to treat severe colitis, then inflammation is reduced, but systemic toxicity increases
Solution Approach 1:
The patent applies local quality by designing compounds and delivery systems that concentrate immunosuppressive activity specifically in the gastrointestinal tract. Rectal administration, mesalamine formulations, and compounds with gut-specific uptake mechanisms ensure high local drug concentrations at the site of colitis while maintaining low systemic exposure. This spatial differentiation of drug concentration reduces systemic toxicity while effectively treating inflammation.
Solution Approach 2:
The patent utilizes parameter changes by modifying drug properties to achieve selective gut targeting. This includes adjusting molecular weight, lipophilicity, and chemical stability to enhance intestinal absorption and retention. Formulation parameters such as pH-dependent release, controlled-release matrices, and targeted delivery vehicles are employed to change the pharmacokinetic parameters, ensuring high local bioavailability with reduced systemic circulation.
Data Source
AI summary
This disclosure features compounds and compositions for use in methods of treating iatrogenic autoimmune colitis in a subject in need thereof, e.g., iatrogenic autoimmune colitis induced by one or more chemotherapeutic agents (e.g., a chemotherapeutic immunomodulatory; e.g., an immune checkpoint inhibitor; e.g., an immune checkpoint inhibitor that targets CTLA-4). The methods Include administering to the subject one or more chemical entities including, but not limited to, sphingosine 1-phosphate (S1P) receptor modulators; Janus kinase (JAK) inhibitors; lanthionine synthetase C-like 2 (LANCL2) modulators; integrin modulators; and immunosuppressants (e.g., cyclosporine).