IL-2 Mutant Design for Selective IL-2Rβγ Activation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Traditional IL-2 therapies for tumor immunotherapy activate both effector T cells (Teff) and regulatory T cells (Tregs), leading to severe side effects like vascular leakage syndrome (VLS), as high doses are needed to preferentially stimulate Teff cells.
Innovation Solution
Development of interleukin-2 mutants with specific amino acid modifications that selectively agonize IL-2Rβγ, reducing affinity for IL-2Rα, thereby minimizing Treg activation and enhancing Teff activation, using computer-aided molecular design and phage display library screening.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If high dose IL-2 is used to activate Teff cells, then anti-tumor response is improved, but Treg activation increases leading to VLS
Solution Approach 1:
The patent applies local quality by introducing specific amino acid substitutions at key binding interfaces of IL-2 (positions 35, 38, 42, 43, 45, 62, and 72) to differentially modulate receptor binding properties. These localized modifications create IL-2 mutants with enhanced selectivity for IL-2Rβγ over IL-2Rα, enabling preferential Teff activation while reducing Treg activation and associated VLS toxicity
Solution Approach 2:
The patent employs parameter changes by systematically varying amino acid residues at seven critical binding positions to alter the physicochemical properties of IL-2. Through computer-aided molecular design and phage display screening, specific parameter combinations (amino acid substitutions) were identified that optimize the balance between Teff activation potency and Treg activation selectivity, thereby improving therapeutic index
2Reliability
If IL-2 is used to stimulate Teff proliferation, then therapeutic efficacy is improved, but affinity for IL-2Rα increases causing Treg activation
Solution Approach 1:
The patent applies local quality by introducing specific amino acid substitutions at key binding interfaces of IL-2 (positions 35, 38, 42, 43, 45, 62, and 72) to differentially modulate receptor binding properties. These localized modifications create IL-2 mutants with enhanced selectivity for IL-2Rβγ over IL-2Rα, enabling preferential Teff activation while reducing Treg activation and associated VLS toxicity
Solution Approach 2:
The patent converts the harmful high affinity binding to IL-2Rα into a beneficial selective advantage by engineering mutants with reduced IL-2Rα affinity. The amino acid substitutions that initially might seem to reduce overall binding capability actually create differential binding profiles that favor IL-2Rβγ, thereby converting potential harm (loss of binding) into benefit (enhanced selectivity and reduced Treg activation)
Data Source
AI summary
The present invention relates to an interleukin-2 (IL-2) mutant and an application thereof. Key sites were selected by means of computer-aided molecular design, and an IL-2 mutant phage display library was constructed based on synthetic biology techniques and combined with forward and reverse screening strategies to screen for a biased IL-2 mutant. Compared with wild-type IL-2, the IL-2 mutant of the present invention has reduced IL-2Rα receptor affinity and increased or equivalent IL-2Rβ receptor affinity, and can activate effector T cells, activate NK cells, and stimulate the release of interferon γ in a biased manner. Also provided in the present invention are a nucleic acid encoding the novel IL-2 mutant and a vector and a host cell comprising the nucleic acid, and further provided are a method for preparing the novel IL-2 mutant, a pharmaceutical combination comprising the novel IL-2 mutant, and a therapeutic use of the novel IL-2 mutant.