Mutant IL-2 Immunoconjugate Targeting PD-1 for Cytotoxic T Cell Activation
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Solution Overview
Problem
Current IL-2 immunotherapy faces challenges such as toxicity from vascular leak syndrome, tumor tolerance due to activation-induced cell death, and immunosuppression by regulatory T cells, along with limitations in targeting tumor cells effectively, leading to suboptimal therapeutic outcomes and severe side effects.
Innovation Solution
A mutant IL-2 polypeptide conjugated with an antibody that binds to PD-1, specifically targeting cytotoxic T lymphocytes, thereby reducing affinity to regulatory T cells and enhancing immune response by reversing PD-1 mediated suppression, while maintaining efficacy through IL-2Rβγ signaling.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional IL-2 immunotherapy is used, then anti-tumor activity is achieved, but toxicity from vascular leak syndrome and immunosuppression by regulatory T cells occurs
Solution Approach 1:
The invention segments the IL-2 receptor interaction by designing mutant IL-2 polypeptides that selectively bind to specific IL-2R subunit compositions (preferring βγ dimers over αβγ trimers), thereby segmenting the patient population into those who benefit from anti-tumor activity versus those who experience immunosuppression from Treg activation
Solution Approach 2:
The mutant IL-2 polypeptides possess local quality differences in their binding properties, with enhanced affinity for IL-2Rβγ signaling complexes while reduced affinity for high-affinity IL-2Rαβγ receptors on Treg cells, creating localized selective action at the molecular binding level
2Reliability
If IL-2 targets both T cells and regulatory T cells, then immune response is activated, but immunosuppression occurs due to regulatory T cell activation
Solution Approach 1:
The invention inverts the conventional approach by designing IL-2 mutants that preferentially activate effector T cells while sparing regulatory T cells, essentially reversing the typical pattern where IL-2 activates both cell types equally or where Treg activation dominates the immunosuppressive outcome
Solution Approach 2:
The mutant IL-2 polypeptides utilize parameter changes in receptor binding affinity, with modified amino acid sequences that alter the binding characteristics to favor intermediate-affinity IL-2Rβγ receptors over high-affinity IL-2Rαβγ receptors, thereby changing the selectivity parameter of IL-2 action
3Reliability
If high-dose IL-2 is administered, then anti-tumor effects are enhanced, but severe side effects and vascular leak syndrome occur
Solution Approach 1:
The invention applies partial action by using mutant IL-2 polypeptides that provide sufficient anti-tumor activity through selective T cell activation without the excessive dosing required for conventional IL-2, thereby achieving the desired immune response with reduced total IL-2 exposure and fewer severe side effects
Data Source
AI summary
The present invention generally relates to immunoconjugates, particularly immunoconjugates comprising a mutant interleukin-2 polypeptide and an antibody that binds to PD-1. In addition, the invention relates to polynucleotide molecules encoding the immunoconjugates, and vectors and host cells comprising such polynucleotide molecules. The invention further relates to methods for producing the mutant immunoconjugates, pharmaceutical compositions comprising the same, and uses thereof.