hIL-2 Immunoconjugate Targeting PD-1 T Cells
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Solution Overview
Problem
Current immune checkpoint inhibitors, such as PD-1 antagonists, have limited efficacy in cancer treatment due to low tumor T-cell infiltration and poor proliferative T-cell responses in non-responders, and many patients develop acquired resistance over time.
Innovation Solution
Administration of an anti-human PD-1 (hPD-1) antibody-modified human interleukin-2 (hIL-2) immunoconjugate, comprising a modified hIL-2 protein with specific amino acid substitutions and an anti-hPD-1 antibody or its antigen-binding fragment, alone or in combination with an antagonistic anti-PD-1 antibody.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If PD-1 antagonists are administered to stimulate T-cell responses, then T-cell activation is enhanced, but efficacy is limited in patients with low tumor T-cell infiltration and poor proliferative T-cell responses
Solution Approach 1:
The patent introduces an immunoconjugate that acts as an intermediary by coupling PD-1 antibody to IL-2 cytokine. This hybrid molecule selectively delivers IL-2 signaling directly to PD-1-expressing T cells at the tumor site, overcoming the limitation of systemic IL-2 administration and enhancing T-cell proliferation in patients with poor responses to PD-1 antagonists alone
Solution Approach 2:
The invention merges two therapeutic mechanisms into a single immunoconjugate molecule: PD-1 blockade (via anti-PD-1 antibody component) and T-cell proliferation stimulation (via IL-2 component). This combination allows simultaneous achievement of T-cell activation and selective IL-2 delivery to tumor-infiltrating T cells, improving efficacy in non-responders
2Reliability
If high-dose IL-2 is administered to stimulate T-cell proliferation, then T-cell effector and memory responses are enhanced, but off-target effects and toxicity increase
Solution Approach 1:
The immunoconjugate implements local quality by concentrating IL-2 signaling activity specifically at the tumor site where PD-1-expressing T cells are located. The anti-PD-1 antibody component provides tumor-specific targeting, ensuring that the proliferative stimulus is delivered locally to relevant T cells while minimizing systemic exposure and off-target effects
Solution Approach 2:
The PD-1 antibody component serves as a targeting intermediary that directs the IL-2 cytokine to PD-1-expressing T cells at the tumor microenvironment. This targeted delivery mechanism replaces non-specific systemic IL-2 administration, achieving T-cell proliferation while reducing toxicity through selective localization
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 approach enhances T-cell activation and proliferation, potentially overcoming resistance to PD-1 inhibitors and improving cancer treatment outcomes by selectively delivering IL-2 signaling to PD-1-expressing T cells.
Implementation Method 1
Human IL-2 (hIL-2) is a Type 1 four α-helical bundle, glycosylated cytokine produced by CD4+ T cells and CD8+ T cells. Autocrine and paracrine IL-2 signaling occurs through engagement of either a high-affinity trimeric receptor complex comprising IL-2Rα (CD25), IL-2Rβ (CD122), and IL-2Rγ (CD132)
Implementation Method 2
an anti-hPD-1 antibody, or antigen-binding fragment thereof, that immunospecifically binds to hPD-1
Data Source
AI summary
Disclosed herein are methods of treating a cancer in a subject using an anti-hPD-1 antibody-modified human interleukin-2 (hIL-2) immunoconjugate alone or in combination with an antagonistic anti-PD-1 antibody.