IL13Rα2-Targeting Antibodies for Immuno-PET in Solid Malignancies

Area of Science:

• Immunology
• Oncology
• Radiochemistry

Background:

• Interleukin-13 receptor α-2 (IL13Rα2) is a promising target for cancer therapy due to its high expression in malignancies like glioblastoma and melanoma, and limited presence in healthy tissues.
• Development of targeted therapies requires specific agents for accurate tumor delineation and effective treatment delivery.

Purpose of the Study:

• To develop and evaluate novel human monoclonal antibodies (mAbs) targeting IL13Rα2 for potential use in cancer imaging and therapy.
• To identify a lead antibody candidate for further development in IL13Rα2-positive solid tumors.

Main Methods:

• Five novel human anti-IL13Rα2 mAbs (KLG-1-5) were generated and characterized for in vitro binding affinity and specificity.
• In vivo studies involved 89Zr-immuno-PET imaging in U-87 MG glioblastoma and A-375 melanoma xenograft mouse models.
• Mass dose titration and biodistribution studies were performed with the lead candidate (KLG-3) to predict dosimetry for 177Lu-labeled radioimmunotherapy.

Main Results:

• In vitro assays confirmed high specificity and low nanomolar binding affinity for all developed mAbs.
• 89Zr-immuno-PET imaging revealed excellent tumor targeting, high tumor-to-normal tissue ratios, and rapid blood pool clearance for KLG-1-5, with KLG-3 showing superior performance.
• KLG-3 demonstrated maximal tumoral uptake of 97 ± 6% injected dose per gram at 144 hours post-injection in glioblastoma models and showed similar efficacy in melanoma models.

Conclusions:

• The lead anti-IL13Rα2 mAb, KLG-3, exhibits high specificity and effectively delineates IL13Rα2-expressing tumors in glioblastoma and melanoma models, producing high-contrast PET images.
• Prospective dosimetry for 177Lu-labeled KLG-3 suggests a favorable therapeutic index, supporting its potential for targeted radioimmunotherapy applications.