Mesothelin's minimal MUC16 binding moiety converts TR3 into a potent cancer therapeutic via hierarchical binding events at the plasma membrane.

Yang Su,William G Hawkins,Pratibha Binder,Dirk Spitzer,David G Mutch,Xuejun Wang,Matthew A Powell,Brian Belt,Lindsay Kuroki,Katharina Tatzel

doi:10.18632/oncotarget.8925

Yang Su, William G Hawkins + Show 8 more

Open Access

https://doi.org/10.18632/oncotarget.8925

Copy DOI

Abstract

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.

Highlights

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was discovered in the mid 1990’s as a new member of the large tumor necrosis factor (TNF) superfamily and caught immediate attention as a promising cancer therapeutic [1,2,3,4]
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
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

Summary

Introduction

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was discovered in the mid 1990’s as a new member of the large tumor necrosis factor (TNF) superfamily and caught immediate attention as a promising cancer therapeutic [1,2,3,4]. It turned out that TRAIL acted independently of p53, which suggested that chemotherapy-resistant tumors caused by inactivating mutations of this tumor suppressor were still sensitive to TRAIL-based therapies [11, 20, 21] Based on these features, a number of clinical trials have been initiated, while numerous attempts to develop more potent TRAIL variants were concurrently explored, including www.impactjournals.com/oncotarget stabilization with trimerization domains (leucine zipper [LZ]), formation of higher-order TRAIL complexes and genetic fusions with the constant regions (Fc) of human immunoglobulins [22,23,24]. By taking advantage of the high affinity interaction between mesothelin and MUC16 [27], we recently designed a mesothelin/TR3 fusion protein, designated Meso-TR3, in order to tether our therapeutic to the MUC16 biomarker located on the tumor cell membrane [28]

Methods

Results

Conclusion