pH-Selective Cytokine Muteins for Tumor Targeting
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Solution Overview
Problem
Cytokines, such as IL-2, face reduced efficacy in acidic tumor microenvironments due to pH-sensitive binding to receptors, leading to impaired anti-tumor responses in cancer treatment.
Innovation Solution
Development of modified cytokines, or cytokine muteins, with specific amino acid modifications that exhibit enhanced activity at acidic pH and reduced activity at neutral pH, allowing for selective binding and activation in acidic tumor microenvironments.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type cytokines are used for cancer immunotherapy, then anti-tumor immune responses are activated, but the efficacy is reduced in acidic tumor microenvironments due to pH-sensitive binding
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence of IL-2 to create muteins with altered pH sensitivity. Specifically, mutations such as K37Q, K43Q, and K64Q change the charge properties of the cytokine, enabling it to maintain binding affinity at acidic pH (6.2-6.5) while reducing affinity at neutral pH (7.4), thus resolving the contradiction between efficacy in acidic tumor microenvironment and sensitivity to pH changes.
Solution Approach 2:
The invention applies local quality by creating cytokine variants that exhibit different binding properties at different pH levels. The modified IL-2 muteins are designed to have high binding affinity specifically in the acidic tumor microenvironment (pH 6.2-6.5) while having reduced binding at neutral pH (7.4) in healthy tissues, thereby achieving location-specific therapeutic action.
2Reliability
If IL-2 is used to promote effector T cell growth, then anti-tumor immunity is enhanced, but regulatory T cell activation also occurs causing toxicity
Solution Approach 1:
The patent applies local quality by engineering IL-2 muteins that selectively activate effector T cells in the acidic tumor microenvironment while sparing regulatory T cells in neutral pH healthy tissues. The pH-dependent binding properties ensure that therapeutic action is localized to the tumor site, reducing systemic toxicity and off-target effects.
Solution Approach 2:
The invention applies dynamics by creating cytokine variants whose binding affinity dynamically changes with pH. The modified IL-2 exhibits high affinity for T cell receptors at acidic pH (activating effector cells in tumors) and low affinity at neutral pH (minimizing activation in healthy tissues), thereby dynamically adapting its biological activity to the local environment.
3Productivity
If cytokine binding to receptors is enhanced at neutral pH, then immune activation occurs, but binding is disrupted in acidic tumor microenvironments
Solution Approach 1:
The patent applies parameter changes by systematically mutating lysine residues (K37, K43, K64) to glutamine or other amino acids with different charge properties. This alters the electrostatic interactions between IL-2 and its receptors, shifting the pH dependence of binding to favor acidic conditions, thereby resolving the contradiction between binding efficiency and pH stability.
Data Source
AI summary
Disclosed are modified cytokines which, relative to wild-type forms, comprise one or more amino acid modifications. Relative to the activity of wild type cytokines, these modified cytokines exhibit enhanced activity at an acidic pH and often reduced activity at neutral pH. The disclosed modified cytokines are for use in medicine and/or for the treatment and/or prevention of an immunological condition or cancer.