pH-Dependent Mutant IL-2 Polypeptides for Targeted Cancer Immunotherapy
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Solution Overview
Problem
Current IL-2 immunotherapy is limited by toxicity due to vascular leak syndrome, tumor tolerance through activation-induced cell death, and immunosuppression by regulatory T cells, with existing mutants failing to overcome these issues effectively.
Innovation Solution
Development of pH-dependent mutant interleukin-2 polypeptides with specific amino acid substitutions that reduce binding to the IL-2 receptor at neutral pH but facilitate binding at acidic tumor microenvironment pH, thereby enhancing therapeutic index and reducing systemic toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type IL-2 is used for immunotherapy, then lymphocyte expansion and antitumor effects are achieved, but vascular leak syndrome and systemic toxicity occur
Solution Approach 1:
The patent creates an IL-2 variant with pH-dependent binding properties that allows it to selectively act in the acidic tumor microenvironment while remaining inactive at neutral systemic pH. This local activation strategy concentrates therapeutic effects at the tumor site and minimizes systemic exposure, thereby improving the therapeutic index by decoupling efficacy from toxicity
Solution Approach 2:
The patent introduces amino acid substitutions (e.g., K37Q, R81Q) that fundamentally change the pH-sensitivity parameter of IL-2 receptor binding. These mutations cause the IL-2 to exhibit high affinity for IL-2R at acidic pH (tumor environment) but low affinity at neutral pH (systemic circulation), enabling conditional activation only in the tumor microenvironment and reducing vascular leak syndrome
2Reliability
If IL-2 is used to stimulate effector T cells, then antitumor immunity is enhanced, but regulatory T cell expansion and activation-induced cell death occur
Solution Approach 1:
The pH-dependent IL-2 variant selectively activates immune cells within the acidic tumor microenvironment while leaving systemic immune regulation unchanged. This spatially restricted activation prevents systemic expansion of regulatory T cells and activation-induced cell death of effector T cells, thereby enhancing antitumor immunity without triggering immunosuppressive feedback mechanisms
Solution Approach 2:
The acidic pH of the tumor microenvironment acts as an intermediary that triggers selective activation of the mutant IL-2. This pH-mediated switching mechanism ensures that only tumor-associated immune cells are activated, preventing systemic immunosuppression while maintaining local antitumor immunity
Data Source
AI summary
The present invention generally relates to pH-dependent mutant interleukin-2 polypeptides that exhibit reduced IL-2 receptor binding at neutral pH and retained IL-2 receptor binding at reduced pH. In addition, the invention relates to immunoconjugates comprising said pH-dependent mutant IL-2 polypeptides, polynucleotide molecules encoding the pH-dependent mutant IL-2 polypeptides or immunoconjugates, and vectors and host cells comprising such polynucleotide molecules. The invention further relates to methods for producing the pH-dependent mutant IL-2 polypeptides or immunoconjugates, pharmaceutical compositions comprising the same, and uses thereof.