CD8-Targeted IL-2 and IL-21 Fusion Proteins for Selective T-Cell Modulation
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Solution Overview
Problem
Existing cytokine therapies for modulating CD8+ T cells face challenges as they can activate counter-regulatory pathways, leading to regulatory T cell responses and inhibitory pathways, necessitating improved therapeutics that target CD8+ T cells without activating these pathways.
Innovation Solution
Administering a combination of IL-21 and IL-2 fusion proteins, each comprising an antibody that specifically binds to human CD8, to treat diseases by targeting CD8+ T cells, with the proteins optionally administered concurrently, sequentially, or simultaneously, and provided in kits with pharmaceutically acceptable carriers.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If cytokine immunotherapy is used to activate immune cells and potentiate immune responses, then immune response potency is improved, but counter-regulatory pathways are activated leading to regulatory T cell responses and inhibitory pathways
Solution Approach 1:
The patent segments the immune response modulation by using two distinct fusion proteins: one targeting CD8+ T cells with IL-21 and another with IL-2. This segmentation allows selective activation of different T cell subsets, potentiating anti-tumor immunity while avoiding broad activation of counter-regulatory pathways that would occur with non-specific cytokine therapy.
Solution Approach 2:
The patent uses fusion proteins as intermediaries that combine cytokine signaling (IL-21 or IL-2) with CD8-specific targeting. These fusion proteins act as mediators that deliver cytokine signals specifically to CD8+ T cells, thereby potentiating immune responses without activating regulatory T cells through non-specific cytokine exposure.
2Productivity
If cytokines are used to stimulate multiple downstream cellular events, then cellular activation and proliferation are improved, but specificity to CD8+ T cells deteriorates due to pleiotropic effects on other immune cells
Solution Approach 1:
The patent applies local quality by confining the cytokine effect to a specific cell population through the CD8-targeting moiety. The fusion proteins deliver IL-21 or IL-2 signals locally to CD8+ T cells, inducing activation and proliferation specifically in this population while leaving other immune cell subsets unaffected, thus maintaining cellular specificity despite the pleiotropic nature of cytokines.
Solution Approach 2:
The CD8-targeting antibody portion of the fusion protein serves as an intermediary that directs the cytokine signal specifically to CD8+ T cells. This intermediary mechanism ensures that the productive effects of cytokine stimulation (activation, proliferation) are confined to the intended cell type, preventing off-target effects on other immune cells.
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
The combination of IL-21 and IL-2 fusion proteins induces a more effective immune response, delaying cancer progression, reducing tumor volume, and inhibiting tumor growth compared to either protein alone, while avoiding activation of counter-regulatory pathways.
Implementation Method 1
an antibody that specifically binds to human CD8, or antigen-binding fragment
Implementation Method 2
Biological activity of cytokines is mediated by binding to their respective cytokine receptors on the cell surface, typically with very high affinity, resulting in their ability to potently stimulate signal transduction downstream
Data Source
AI summary
Provided herein are anti-CD8 antigen binding molecules and fusion polypeptides with IL-2 or IL-21 comprising the CD8 antigen binding molecules for selectively modulating the function of CD8+ T cells over other immune cells. The present disclosure provides methods for using IL-2 and IL-21 fusion proteins in combination to treat a disease.