Washington University

Dirk Spitzer

William G Hawkins

Robert H Mach

Suwanna Vangveravong

Brian Van Tine

Richard S Hotchkiss

William Hawkins

Robert Mach

The present disclosure provides constructs that comprise (a) a TNF-related apoptosis-inducing ligand (TRAIL) trimer comprising three consecutive extracellular TRAIL domains fused together in a head-to-tail configuration; (b) an epitope binding agent, and (c) optionally one or more additional components, wherein the epitope binding agent competitively inhibits binding of P4-TR3 or HN1-TR3 to cell surface human mesothelin. Constructs of the present disclosure induce apoptosis in cells expressing human mesothelin and a death receptor (DR4 or DR5) on the cell's surface.

Mesothelin-targeted trail trimer

Methods and compositions for treating cancers such as pancreatic cancer and synovial sarcoma are disclosed. Compounds comprising a sigma-2 receptor-binding moiety and a ferroptosis-inducing moiety are described, such as the methanesulfonate salt of a compound of structural Formula IV, , wherein n is an integer chosen from 1, 2, 3, 4, and 5, and Ris H or methyl. At least one described molecular species exhibits an ICvalue below 5 &#x3bc;M against human pancreatic cancer cells in vitro. Administration of this species promoted shrinkage of pancreatic cancer tumors in a murine model system in vivo. It led to a 100% survival of experimental animals over a time course in which control therapies provided only 30% or 40% survival. Methods of synthesis of molecular species are also disclosed.

Sigma-2 receptor ligand drug conjugates as antitumor compounds, methods of synthesis and uses thereof

The present disclosure provides compounds of structural Formula III: or a salt thereof, wherein Y is chosen from Further provided are pharmaceutical compositions comprising these compounds, and methods for treating cancer, such as pancreatic cancer or synovial sarcoma, using the compounds and compositions.

Methods and compositions for treating cancers such as pancreatic cancer and synovial sarcoma are disclosed. Compounds comprising a sigma-2 receptor-binding moiety and a ferroptosis-inducing moiety are described. At least one described molecular species exhibits an ICvalue below 5 &#x3bc;M against human pancreatic cancer cells in vitro. Administration of this species promoted shrinkage of pancreatic cancer tumors in a murine model system in vivo, and led to 100% survival of experimental animals over a time course in which control therapies provided only 30% or 40% survival. Methods of synthesis of molecular species are also disclosed.

Fusion polypeptides comprising a TRAIL trimer and a targeting domain are disclosed. The targeting domain can be, in some embodiments, a sequence that binds MUC16, which is prevalent on some tumor cells such as pancreatic and ovarian tumor cells. A sequence that binds MUC 16 can be mesothelin or a MUC16-binding fragment thereof, such as amino acids 1-64 of mesothelin. A fusion polypeptide of the present teachings can induce apoptosis in a target cell such as a MUC16-expressing cancer cell. Also disclosed are nucleic acids encoding the fusion polypeptides, and methods of use of the fusion polypeptides and nucleic acids.

Tumor targeted TNF-related apoptosis inducing ligand fusion polypeptide, methods and uses therefor

Tumor targeted TNF-related apoptosis inducing ligand fusion polypeptide and nucleic acids encoding the same

Disclosed are TNF-related apoptosis-inducing ligand (TRAIL) trimers (TR3) and nucleic acids encoding covalently linked TRAIL trimers. A TRAIL trimer can have greater stability compared to native TRAIL, and can retain the native killing ability of TRAIL. Target specificity of a TR3 can be shown by blocking its activity with soluble death receptor 5 (DR5-Fc). Also disclosed are modified TRAIL trimers and nucleic. acids encoding them. These modifications include additional functional domains, such as antibody fragments (scFvs). A TR3 comprising an additional functional domain can allow for cell-specific delivery of the TR3. The inventors disclose TR3-decorated RBCs that target cell killing in a model of pancreatic cancer.

Growing community of inventors

Webster Groves, MO, United States of America

Dirk Spitzer