Mesothelin's minimal MUC16 binding moiety converts TR3 into a potent cancer therapeutic via hierarchical binding events at the plasma membrane
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Yang Su1,2, Katharina Tatzel1, Xuejun Wang1, Brian Belt1, Pratibha Binder3, Lindsay Kuroki3, Matthew A. Powell3,4, David G. Mutch3,4, William G. Hawkins1,4, Dirk Spitzer1,4
1Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA
2Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
3Division of Gynecologic Oncology, Washington University School of Medicine, St. Louis, Missouri 63110, USA
4Alvin J. Siteman Cancer Center, St. Louis, Missouri 63110, USA
Dirk Spitzer, email: [email protected]
Yang Su, email: [email protected]
Keywords: TRAIL, Meso64-TR3, mesothelin, MUC16, CA125
Received: March 03, 2016 Accepted: April 10, 2016 Published: April 22, 2016
TRAIL has been extensively explored as a cancer drug based on its tumor-selective activity profile but it is incapable per se of discriminating between death receptors expressed by normal host cells and transformed cancer cells. Furthermore, it is well documented that surface tethering substantially increases its biologic activity. We have previously reported on Meso-TR3, a constitutive TRAIL trimer targeted to the biomarker MUC16 (CA125), in which the entire ectodomain of human mesothelin was genetically fused to the TR3 platform, facilitating attachment to the cancer cells via the MUC16 receptor. Here, we designed a truncation variant, in which the minimal 64 amino acid MUC16 binding domain of mesothelin was incorporated into TR3. It turned out that the dual-domain biologic Meso64-TR3 retained its high MUC16 affinity and bound to the cancer cells quickly, independent of the TR3/death receptor interaction. Furthermore, it was substantially more potent than Meso-TR3 and TR3 in vitro and in a preclinical xenograft model of MUC16-dependent ovarian cancer. Phenotypically, Meso64-TR3 is more closely related to non-targeted TR3, evident by indistinguishable activity profiles on MUC16-deficient cancers and similar thermal stability characteristics. Overall, Meso64-TR3 represents a fully human, MUC16-targetd TRAIL-based biologic, ideally suited for exploring preclinical and clinical evaluation studies in MUC16-dependent malignancies.
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