PD-1-Targeted Mutant IL-7 Immunoconjugates for Selective T-Cell Activation
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Solution Overview
Problem
Existing cytokine immunotherapies using interleukin-7 (IL-7) face challenges such as toxicity, tumor tolerance, and immunosuppression due to activation of Treg cells, and tumors evade immune targeting through PD-1 interaction with its ligands, limiting their effectiveness in cancer treatment.
Innovation Solution
Conjugating a mutant IL-7 polypeptide with reduced IL-7Rα affinity and an antibody that binds to PD-1, enabling targeted delivery to immune effector cells like CD8+ PD1+ TCF+ T cells, enhancing tumor-specific CTL activation and reversing PD-1-induced suppression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If IL-7 is used to stimulate T-cell development and activation, then immune response is enhanced, but toxicity and immunosuppression occur due to activation of Treg cells
Solution Approach 1:
The patent applies local quality by creating mutant IL-7 polypeptides with modified binding characteristics that selectively activate effector T cells while avoiding Treg cell activation. The mutations in the IL-7 polypeptide structure alter its interaction specificity with different T cell populations, enabling localized immune enhancement without systemic immunosuppression.
Solution Approach 2:
The patent uses an antibody as an intermediary to deliver the mutant IL-7 polypeptide specifically to PD-1 expressing immune effector cells. This antibody-mediated targeting ensures that IL-7 activity is concentrated at the desired site (PD-1+ effector cells) while minimizing off-target effects on Treg cells and other immune populations.
2Productivity
If IL-7 binds to IL-7Rα to activate T cells, then T-cell proliferation increases, but tumor tolerance develops and effectiveness decreases
Solution Approach 1:
The mutant IL-7 polypeptides are engineered with altered binding affinity characteristics that preferentially interact with PD-1 expressing effector T cells rather than inducing broad T-cell proliferation. This selective activation maintains tumor treatment effectiveness by avoiding the development of tumor tolerance that occurs with non-selective IL-7 stimulation.
Solution Approach 2:
The patent employs parameter changes by modifying the IL-7 polypeptide structure through specific mutations that alter its binding affinity and specificity. These structural modifications change the interaction parameters between IL-7 and its receptor, enabling selective activation of anti-tumor effector cells while preventing tumor tolerance.
3Reliability
If tumors interact with PD-1 ligands to evade immune detection, then immune targeting fails, but blocking PD-1 may cause off-target immune activation
Solution Approach 1:
The patent uses an antibody as an intermediary to specifically target and deliver mutant IL-7 to PD-1 expressing immune effector cells. This antibody-mediated delivery system overcomes tumor-mediated immune evasion by ensuring IL-7 reaches its intended target despite PD-1 ligand interference, while the specificity of the antibody reduces off-target activation risks.
Solution Approach 2:
The patent segments the immune activation function by separating the targeting function (performed by the antibody binding to PD-1) from the activation function (performed by the mutant IL-7 polypeptide). This segmentation allows precise control over which cells receive activation signals, preventing off-target effects while overcoming tumor evasion mechanisms.
4Quantity of substance
If conventional IL-7 is administered systemically, then broad immune activation occurs, but selectivity for tumor-specific T cells is lost
Solution Approach 1:
The patent introduces an antibody intermediary that confers selectivity to the IL-7 delivery system. The antibody binds specifically to PD-1 on immune effector cells, thereby directing the mutant IL-7 polypeptide to this specific population. This intermediary approach maintains broad immune activation capacity while achieving selectivity for tumor-relevant effector T cells.
Solution Approach 2:
The mutant IL-7 polypeptide retains the universal function of activating T cells through IL-7Rα signaling, while the antibody component adds the specific targeting function. This multi-functional immunoconjugate system combines the broad immunostimulatory capability of IL-7 with the selective targeting capability of the anti-PD-1 antibody.
Data Source
AI summary
The present invention generally relates to mutant interleukin-7 polypeptides, immunoconjugates, particularly immunoconjugates comprising a mutant interleukin-7 polypeptide and an antibody that binds to PD-1. In addition, the invention relates to polynucleotide molecules encoding the mutant interleukin-7 polypeptides or the immunoconjugates, vectors and host cells comprising such polynucleotide molecules. The invention further relates to methods for producing the mutant interleukin-7 polypeptides, immunoconjugates, pharmaceutical compositions comprising the same, and uses thereof.