Abstract 1927: Targeting IL-13RA2 in melanoma and pancreatic cancer
Authors: Zielinski Rafal , Tworowska Izabela , Skora Stanislaw , Rusin Aleksandra , Venugopal Radjendirane , Jayakumar Arumugam , Fokt Izabela , Kang Yaan , Fleming Jason , Huang Yue , Herpai Denise , Debinski Waldemar , Priebe Waldemar 
Published: August 2018

Background. Interleukin receptor alpha 1 (IL-13RA1) is a component of a heterodimeric IL-13 receptor that is shared with IL-4 and it is ubiquitously expressed in normal tissues and also tumors. In contrast, IL-13RA2 is a monomeric receptor which is overexpressed in various solid tumors, but is virtually absent in normal tissues. Ligands specifically targeting IL-13RA2 but not IL-13RA1, such as Pep-1L and IL-13.E13K.D2.Cys, have been developed and validated [1,2].

Objective. To assess the expression of IL-13RA2 in pancreatic ductal adenocarcinoma and metastatic melanoma specimens and to develop tracers for selective recognition of the tumors.

Methods. The expression of IL-13RA2in patient specimens, patient-derived xenografts (PDX) and established cell lines was assessed using Western blot, immunochemistry or immunofluorescence. The ligands were conjugated to a chelator and labeled with Yttrium 86. Ligand specificity was confirmed using IL-13RA2 positive and negative cells and blocking with a “cold” ligand. Biodistribution studies and PET/CT imaging were conducted to assess distribution of the tracer in IL-13RA2 positive tumors models.

Results. IL-13RA2 receptor is overexpressed in melanoma and pancreatic cell lines and tumor tissues. Western blot analysis of 56 patients tumor tissue lysates obtained from pancreatic cancer PDX models showed the presence of IL-13RA2 in over 60% of patients. Similarly, tissue microarray analysis of metastatic melanoma samples identified IL-13RA2 receptor expression in 40% of tumor specimens. Uptake study performed in receptor positive and negative cells confirmed the specificity of radiotracer binding. In vivo experiments indicated fast clearance of 86Y- Pep1L ligand with glomerular filtration as a primary mechanism of the tracer removal. Mice bearing IL-13RA2 positive tumors had up taken the tracer with “tumor to muscle” ratio of 5.6 1 h after probe administration. Yttrium 86-labelled IL-13-E13K.D2.Cys was also taken up by IL-13 RA2 positive tumors.

Conclusion. IL-13RA2 is an attractive target for the development of comprehensive theranostic strategies for melanoma and pancreatic cancer.

References

1. Pandya, H., et al., An interleukin 13 receptor alpha 2-specific peptide homes to human Glioblastoma multiforme xenografts. Neuro Oncol, 2012. 14(1): p. 6-18.

2. Nguyen, V., et al., A novel ligand delivery system to non-invasively visualize and therapeutically exploit the IL13Ralpha2 tumor-restricted biomarker. Neuro Oncol, 2012. 14(10): p. 1239-53.

Citation Format: Rafal Zielinski, Izabela Tworowska, Stanislaw Skora, Aleksandra Rusin, Radjendirane Venugopal, Arumugam Jayakumar, Izabela Fokt, Yaan Kang, Jason Fleming, Yue Huang, Denise Herpai, Waldemar Debinski, Waldemar Priebe. Targeting IL-13RA2 in melanoma and pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1927.