Abstract
Glioblastoma (GBM) is a complex and heterogeneous tumor that warrants a comprehensive therapeutic approach for treatment. Tumor-associated antigens offer an opportunity to selectively target various components of the GBM microenvironment while sparing the normal cells within the central nervous system. In this study, we conjugated a multivalent vector protein, QUAD 3.0, that can target four receptors: EphA3, EphA2, EphB2, and also IL-13RA2, spanning virtually 100% of the GBM microenvironment, to doxorubicin derivatives. The conjugates effectively bound to all four receptors, although to varying degrees, and delivered cytotoxic loads to both established and patient-derived GBM cell lines, with IC50 values in the low nM range. The conjugates were also non-toxic to animals. We anticipate that the QUAD 3.0 Dox conjugates will be further used in preclinical models and possibly clinics in the foreseeable future.
Highlights
Glioblastoma (GBM) is a stage IV high-grade glioma, a brain tumor that is believed to arise from the glial cells of the central nervous system (CNS) [1]
Our results show that the QUAD 3.0-Dox conjugates were cytotoxic to established and patient-derived GBM cell lines in vitro, with IC50 values in the low nM range
QUAD 3.0 Was Successfully Conjugated to Dox Derivatives
Summary
Glioblastoma (GBM) is a stage IV high-grade glioma, a brain tumor that is believed to arise from the glial cells of the central nervous system (CNS) [1]. The FDA has approved TR1801-ADC(MT_8633) from Tanabe Research Labs that targets cMet-positive solid tumors [66] This investigational new drug (IND) is conjugated with a potent pyrrolobenzodiazepine dimer (PBD) toxin that intercalates the DNA and inhibits cell replication, eventually causing cell death. IL-13.E13K is a modified version of the IL-13 ligand that selectively binds to the GBM-specific IL-13RA2 and not to the physiological IL-4RA/IL-13RA1 receptor complex [77,78] In targeting these four receptors at once, we anticipated that the following would be achieved: (a) Therapeutic coverage of almost 100% of the tumor and its heterogeneous microenvironment; (b) multiple targeting that reduces the chances of antigen loss, allowing significantly less room for therapeutic resistance; and (c) targeting of the mesenchymal subtype along with tumor-associated immune, vascular, infiltrative, and invasive cells within the tumor microenvironment, rendering the tumor less aggressive after therapy. Our results show that the QUAD 3.0-Dox conjugates were cytotoxic to established and patient-derived GBM cell lines in vitro, with IC50 values in the low nM range
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