IL13Ra2-targeted radioimmunotherapy for glioblastoma

University Of Tx Md Anderson Can Ctr, Houston TX

Investigators

Abstract

PROJECT ABSTRACT Interleukin-13 receptor alpha-2 (IL13Rα2) is expressed with high frequency and specificity on some of the most aggressive and deadly cancers such as glioblastoma (GBM), basal-like triple-negative breast cancer, and metastatic colorectal cancer. GBM is a highly aggressive primary brain tumor with dismal prognosis; its infiltrative nature makes it difficult to detect and eliminate disseminated cells, and their high mutagenic potential increases resistance to conventional treatment regimens. In GBM, IL13Rα2 is expressed on bulk and glioma stem cells, which are generally resistant to cytotoxic therapies, leading to treatment failure and tumor recurrence. Radioimmunotherapy (RIT) has the potential to address this critical problem, as it offers specific targeting of cytotoxic radioisotopes while sparing normal tissues, thus enabling delivery of tumoricidal radiation doses to multiple dispersed sites. IL13Rα2 is a cell surface receptor expressed on highly malignant tumors with negligible expression in normal tissues, which limits potential side effects from off-site targeting and makes it an ideal target for RIT. Radiation from RIT induces cell kill when DNA is damaged beyond the capacity of the cell to repair. Beta (β) particles have a long range of deposition in tissues, usually many cell diameters. This is advantageous for killing tumors, which exhibit heterogenous antigen expression. 177Lu is a beta-emitting isotope currently used in commercial products, but 161Tb has demonstrated superior anti-tumor efficacy compared to 177Lu in preclinical and early clinical investigations since its decay results in the release of β-emitter as well as Auger-electrons, which may lead to higher tumor-absorbed doses than with 177Lu. Targeted α-therapy with 225Ac (α-emitter) is ideal for localized cell kill due to its limited range in tissue. It is effective even in hypoxic tumor regions. So far, however, no radiolabeled agent targeting IL13Rα2-positive malignancies is clinically available. To overcome this limitation, we have isolated human monoclonal antibodies that specifically bind IL13Rα2 with picomolar affinity. The primary objectives are to establish a radiotheranostic approach for IL13Rα2-expressing GBM. We will perform in vitro assays including saturation binding assays with the radiolabelled antibodies to validate target specificity, assess binding kinetics, and to determine stability, cell-level radiation toxicity, and dosimetry. Furthermore, we will develop a radiotheranostic approach in orthotopic xenograft mouse models of GBM (including PDX model) and compare RIT with 177Lu vs. 161Tb vs. 225Ac. Systemic and locoregional delivery will be explored. Developing an RIT approach using a human antibody that binds to IL13Rα2-expressing cancer cells with high affinity and specificity will significantly expand the therapeutic potential for the treatment of GBM and other hard-to-treat malignancies, such as basal-like breast and colorectal cancers. MSK’s facilities and team with expertise in the successful development of novel radiopharmaceuticals, clinical translation, and obtaining FDA approval will ensure the feasibility and applicability of this technology.