Non-Immunogenic RNA Antigen Vaccination With PD-1 Blockade
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Solution Overview
Problem
Existing mRNA-based cancer vaccines induce high immunogenicity, leading to excessive activation of innate immune responses and reduced efficacy due to high PD-1 expression on induced immune effector cells, limiting their therapeutic potential.
Innovation Solution
Administer non-immunogenic RNA encoding a peptide or polypeptide with modified nucleosides to reduce immunogenicity, combined with a PD-1 axis binding antagonist to enhance antigen-specific immune responses, using immune effector cells with modified antigen receptors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If standard mRNA is used for vaccination, then immune effector cells are induced, but high PD-1 expression on induced cells reduces therapeutic efficacy
Solution Approach 1:
The patent applies parameter changes by modifying the immunogenicity parameter of the mRNA vaccine. By using non-immunogenic RNA formulations, the patent changes the immune activation parameters to induce immune effector cells with lower baseline PD-1 expression, thereby improving therapeutic efficacy while reducing the harmful effect of excessive PD-1 expression that limits treatment response
2Productivity
If high immunogenicity mRNA is used, then strong innate immune activation occurs, but this reduces vaccine efficacy due to excessive PD-1 upregulation
Solution Approach 1:
The patent optimizes the immunogenicity parameter of the mRNA formulation to achieve an optimal balance. By adjusting this parameter to be non-immunogenic, the patent maintains sufficient immune effector cell induction while preventing excessive PD-1 upregulation, thereby ensuring both productivity (immune response) and reliability (vaccine efficacy)
Solution Approach 2:
The patent introduces PD-1 axis binding antagonists as intermediary agents that mediate between the vaccine-induced immune response and the PD-1 checkpoint pathway. These antagonists block the harmful PD-1/PD-L1 interaction, allowing the immune response to be maintained while preventing the suppressive effect of PD-1 expression
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
Enhances antigen-specific immune responses and therapeutic efficacy by reducing innate immune activation and increasing PD-1/PD-L1 blockade susceptibility, leading to improved tumor targeting and eradication.
Implementation Method 1
non-immunogenic RNA encoding a peptide or polypeptide comprising an epitope... non-immunogenic RNA is rendered non-immunogenic by the incorporation of modified nucleosides
Implementation Method 2
PD-1 axis binding antagonist such as an anti-PD-1 antibody and/or an anti-PD-L1 antibody... leading to enhanced immune effector cell expansion and immune response
Implementation Method 3
immune effector cells carry an antigen receptor such as T cell receptor (TCR) or chimeric antigen receptor (CAR) having a binding specificity for the antigen
Implementation Method 4
Administering to the subject non-immunogenic RNA encoding vaccine antigen may provide (following expression of the RNA by appropriate target cells) vaccine antigen
Data Source
AI summary
The present disclosure relates to methods and agents for antigen vaccination and inducing effective antigen-specific immune effector cell responses such as T cell responses. These methods and agents are, in particular, useful for the treatment of diseases characterized by diseased cells expressing an antigen the immune effector cells are directed to. In some embodiments, the present disclosure relates to methods comprising administering to a subject (i) non-immunogenic RNA encoding a peptide or polypeptide comprising an epitope for inducing an immune response against an antigen in the subject, i.e., non-immunogenic RNA encoding vaccine antigen; and (ii) a PD-1 axis binding antagonist such as an anti-PD-1 antibody and/or an anti-PD-L1 antibody.