mRNA Checkpoint Peptide Delivery for Targeted T-Cell Activation
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Solution Overview
Problem
Existing cancer treatments targeting immune system checkpoints, such as Ipilimumab, do not effectively augment T cell anti-tumor responses in a significant proportion of patients, leaving room for improvement and risking undesirable autoimmune effects.
Innovation Solution
Administering mRNA encoding immunogenic peptide fragments of immune system checkpoint components, such as IDO1, PD1, and Arginase1, to enhance T cell activation by expressing multiple copies of these fragments simultaneously, utilizing a structured mRNA format with 5' and 3' untranslated regions and a 3' tailing sequence, optionally formulated in lipid nanoparticles.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional checkpoint inhibitors like Ipilimumab are administered, then some patients achieve tumor response, but the majority of patients do not benefit and autoimmune effects occur
Solution Approach 1:
The patent uses mRNA to provide a temporary, controllable copy of the checkpoint protein sequence, which is expressed only where and when needed. This allows the immune system to recognize and attack the checkpoint protein without permanently altering the patient's genome, reducing the risk of autoimmune effects while maintaining treatment effectiveness.
Solution Approach 2:
The patent changes the delivery parameter from direct protein administration or genetic modification to mRNA transient expression. This parameter change allows precise control over when and where the checkpoint protein is expressed, improving treatment effectiveness while minimizing harmful autoimmune effects by limiting expression to the tumor microenvironment.
2Adaptability or versatility
If multiple different peptides are administered directly, then multiple checkpoints can be targeted, but co-formulation is difficult
Solution Approach 1:
The patent merges multiple different peptide sequences into a single mRNA molecule, allowing simultaneous encoding of multiple checkpoint proteins (e.g., CTLA-4, PD-1, PD-L1, CTLA-6). This eliminates the need for complex co-formulation of multiple separate peptide preparations while maintaining the ability to target multiple checkpoints simultaneously.
Solution Approach 2:
The mRNA platform serves as a universal delivery system that can encode multiple different proteins and peptides in a single molecule. This multi-functional approach allows one therapeutic agent to simultaneously target multiple immune checkpoints, improving versatility while simplifying manufacturing compared to administering multiple separate peptide formulations.
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
This approach augments T cell anti-tumor responses, potentially benefiting a greater proportion of patients without inducing autoimmune diseases, by effectively expressing immunogenic peptide fragments within cells to stimulate a targeted immune response.
Implementation Method 1
mRNA encoding at least one immunogenic peptide fragment of a polypeptide component of an immune system checkpoint
Implementation Method 2
Expression of the immunogenic peptide fragment(s) leads to an immune response against the said checkpoint component
Data Source
AI summary
The present invention relates to mRNAs useful in cancer therapies as well as mRNAs for use in a method for the prevention or treatment of cancer in a subject.