68Ga-IL2 Radiopharmaceutical Kit for PET Imaging
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Solution Overview
Problem
Current methods for detecting interleukin-2 receptor (IL2R) positive cells using radiolabelling techniques face challenges such as high costs, low efficiency, poor stability, and suboptimal biodistribution, particularly with gamma-emitting radionuclides and high-temperature labelling processes, which hinder their clinical translation and PET imaging capabilities.
Innovation Solution
A 68Ga-radiolabelled desalanyl-1, serine-125 human IL2 (dsIL2) compound is developed using tris-(hydroxypyridinone-malemide) (THP-mal) as a chelator, allowing radiolabelling at room temperature without compromising receptor binding affinity, and is formulated into a user-friendly kit for PET imaging, suitable for use in nuclear medicine.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If gamma-emitting radionuclides (e.g., 99mTc, 67Ga, 111In) are used for radiolabelling IL2, then the radiopharmaceutical can be prepared with established methods, but the imaging resolution is insufficient and quantification of uptake in target lesions is not permitted
Solution Approach 1:
The patent changes the radionuclide parameter from gamma-emitting isotopes (99mTc, 67Ga, 111In) to positron-emitting 68Ga, enabling PET imaging with superior resolution and quantification capabilities. This parameter change resolves the measurement precision limitation while maintaining ease of manufacture through the use of 68Ga/68Ge generators and room-temperature labelling protocols
2Reliability
If DTPA or N3S chelating agents are conjugated to the N-terminus of IL2, then the radionuclide can be stably bound, but the binding of IL2 to its receptor is significantly reduced
Solution Approach 1:
The patent applies local quality by modifying specific amino acid residues (Cys58, Cys105, Cys125) rather than the N-terminus. The chelating agent is introduced at specific local sites through site-directed mutagenesis, preserving the overall structure and receptor-binding interface of IL2 while enabling stable radionuclide attachment at designated cysteine positions
Solution Approach 2:
The patent creates mutant versions of IL2 (e.g., C58S, C105S, C125S mutants) that replicate the function of wild-type IL2 but with modified cysteine residues. These copied variants allow selective chelator attachment at specific positions without compromising receptor binding, effectively decoupling the radionuclide attachment function from the receptor-binding function
3Productivity
If high-temperature labelling processes are used for radiolabelling, then the labelling efficiency can be improved, but the protein stability is compromised and receptor binding affinity is reduced
Solution Approach 1:
The patent changes the temperature parameter from high-temperature (95°C) processes to room-temperature (20-25°C) labelling. This parameter change is enabled by using THP-mal chelator with mutant IL2 proteins that have enhanced stability and reactivity at lower temperatures, achieving both high labelling efficiency (>95%) and preservation of protein structure and receptor-binding affinity
Solution Approach 2:
The patent replaces thermal energy input (heating to 95°C) with chemical reactivity enhancement through site-directed mutagenesis and optimized chelator selection. The mutant cysteine residues and THP-mal chelator system enable efficient radiolabelling through enhanced chemical reactivity at room temperature, substituting thermal activation with molecular design-driven reactivity
4Ease of manufacture
If rhIL2 is used for radiolabelling, then the protein can be obtained commercially, but its poor solubility in aqueous solvents and tendency to aggregate make labelling difficult and expensive
Solution Approach 1:
The patent uses recombinant IL2 produced through molecular biology techniques (site-directed mutagenesis, expression in E. coli or other systems) as a copy of natural IL2 with improved properties. The recombinant approach allows precise introduction of cysteine mutations and ensures high solubility and stability, avoiding the aggregation problems of commercial rhIL2 while maintaining biological activity
Solution Approach 2:
The patent changes the production method parameter from commercial extraction/purification of rhIL2 to recombinant expression of mutant IL2. This parameter change enables control over protein quality attributes (solubility, stability, purity) through genetic design, eliminating aggregation issues and simplifying downstream processing while maintaining ease of manufacture through scalable recombinant production
5Measurement precision
If 18F-labelled-IL2 is used for PET imaging, then PET imaging capability is achieved, but the in vivo biodistribution is poor and the labelling procedure is cumbersome
Solution Approach 1:
The patent changes the radionuclide parameter from 18F to 68Ga, and the labelling temperature from high to room temperature. This dual parameter change achieves PET imaging capability (superior to gamma-camera) while simplifying the labelling procedure through room-temperature chemistry and improving biodistribution through optimized chelator-protein conjugation that preserves IL2 stability and receptor-binding properties
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 solution provides a stable, high-specific-activity radiopharmaceutical with optimal receptor binding capacity, suitable for PET imaging of IL2R positive cells, reducing production time and costs, and offering favorable biodistribution and stability, enabling effective detection of activated T-lymphocytes in inflammatory diseases and cancer.
Implementation Method 1
a 68Ga-radiolabelled IL2 such as a desalanyl-1, serine-125 human IL2 (dsIL2) radiolabelled with a short-lived PET radioisotope (or radionuclide) gallium-68 (68Ga) by using tris-(hydroxypyridinone-malemide) (THP-mal) as a chelator
Data Source
AI summary
The present invention relates to a radiopharmaceutical compound or composition for Positron Emission Tomography (PET) imaging of interleukin-2 (IL2) receptor positive cells, in particular, 68Ga-radiolabelled interleukin-2 such as a desalanyl-1, serine-125 human interleukin-2 (dsIL2) radiolabelled with a short-lived PET radioisotope (or radionuclide) gallium-68 (68Ga) by using tris-(hydroxypyridinone-maleimide) (THP-mal) as a chelator. The invention concerns also a kit comprising dsIL2 linked to THP-mal which can be added with 68Ga in order to obtain the above mentioned radiopharmaceutical, at room temperature, suitable for PET imaging, a process for the preparation of the radiopharmaceutical and its use in medical and diagnostic field.