Mesothelin's minimal MUC16 binding moiety converts TR3 into a potent cancer therapeutic via hierarchical binding events at the plasma membrane.
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.
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA.|Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China.
Yang
Y
Su
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Katharina
K
Tatzel
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Xuejun
X
Wang
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Brian
B
Belt
Division of Gynecologic Oncology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Pratibha
P
Binder
Division of Gynecologic Oncology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Lindsay
L
Kuroki
Division of Gynecologic Oncology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.|Alvin J. Siteman Cancer Center, St. Louis, Missouri 63110, USA.
Matthew A
MA
Powell
Division of Gynecologic Oncology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.|Alvin J. Siteman Cancer Center, St. Louis, Missouri 63110, USA.
David G
DG
Mutch
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA.|Alvin J. Siteman Cancer Center, St. Louis, Missouri 63110, USA.
William G
WG
Hawkins
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA.|Alvin J. Siteman Cancer Center, St. Louis, Missouri 63110, USA.
Dirk
D
Spitzer
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D018394:CA-125 Antigen / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D053208:Kaplan-Meier Estimate; D000090204:Mesothelin; D016513:Mice, SCID; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D018394:CA-125 Antigen; D058851:GPI-Linked Proteins; C000715528:Msln protein, mouse; D011993:Recombinant Fusion Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D000090204:Mesothelin
CA125; MUC16; Meso64-TR3; TRAIL; mesothelin