Intestinal Alkaline Phosphatase for CPI-Induced GI Toxicity
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Solution Overview
Problem
Immune checkpoint inhibitor (CPI) therapies for cancer treatment are limited by gastrointestinal (GI) distress such as diarrhea and colitis, necessitating the need for improved methods to prevent and reduce these side effects while maintaining therapeutic efficacy.
Innovation Solution
Administration of intestinal alkaline phosphatases (IAPs), including mammalian variants, to mitigate GI side effects by targeting LPS, flagellin, and CpG DNA, thereby enhancing gut homeostasis and reducing inflammation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If immune checkpoint inhibitors are administered for cancer treatment, then cancer therapy efficacy is improved, but gastrointestinal side effects such as diarrhea and colitis occur
Solution Approach 1:
The patent introduces intestinal alkaline phosphatase (IAP) as an intermediary substance that mediates between the CPI therapy and the gastrointestinal tract. IAP is administered to patients undergoing CPI treatment to prevent and reduce GI side effects by dephosphorylating harmful substrates (LPS, flagellin, CpG DNA) in the intestinal lumen, thereby protecting the gut from CPI-induced inflammation while allowing the cancer therapy to proceed effectively
Solution Approach 2:
The patent converts the harmful effect of CPI-induced gut inflammation into a beneficial outcome by using IAP to target and degrade the specific molecular patterns (LPS, flagellin, CpG DNA) that trigger the inflammation. This transforms the harmful inflammatory response into a controlled enzymatic degradation process, reducing GI toxicity while maintaining cancer treatment efficacy
2Object-affected harmful factors
If conventional methods are used to treat CPI-mediated GI side effects, then GI symptoms are reduced, but the need for additional immunosuppressive agents increases
Solution Approach 1:
The patent extracts the problematic substrates (LPS, flagellin, CpG DNA) from the intestinal environment through enzymatic degradation by IAP. By removing these harmful molecules at their source in the gut lumen, the patent eliminates the need for systemic immunosuppressive agents to treat GI side effects, simplifying the overall treatment regimen
Solution Approach 2:
The patent employs a self-service mechanism where IAP is administered orally and directly acts on the harmful substrates in the intestinal lumen. The enzyme performs its protective function locally in the gut without requiring systemic immunosuppression, allowing the patient's gastrointestinal tract to self-regulate and protect itself from CPI-induced damage
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
IAPs effectively prevent and reduce CPI-mediated GI side effects, such as diarrhea and colitis, while maintaining or improving the efficacy of cancer immunotherapy, potentially reducing the need for corticosteroids and other immunosuppressive agents.
Implementation Method 1
Alkaline phosphatase ('APs,' EC 3.1.3.1) is a hydrolase enzyme that can remove phosphate groups from various targets, including nucleotides and proteins
Implementation Method 2
APs also degrade intestine luminal NTPs (e.g., ATP, GTP, etc.), which promote the growth of good bacteria and reverses dysbiosis
Data Source
AI summary
The present disclosure relates, inter alia, to methods for the prevention and/or reduction of immune checkpoint inhibitor-mediated gastrointestinal side effects by administering therapeutic intestinal alkaline phosphatases. The present disclosure further relates to compositions comprising the combination of immune-checkpoint immunotherapies with therapeutic alkaline phosphatases and use of the compositions in the prevention and/or treatment of immune checkpoint inhibitor-mediated gastrointestinal side effects, such as colitis.