Methods for inhibiting the binding of endosialin to ligands
Inventors
Zhou, Yuhong • Tomkowicz, Brian • Grasso, Luigi • Nicolaides, Nicholas C. • Sass, Philip M.
Assignees
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Publication Number
US-10053509-B2
Publication Date
2018-08-21
Expiration Date
Abstract
The invention provides methods for inhibiting the interaction of endosialin with endosialin ligands. The inhibition is effectuated on the genetic level, by inhibiting endosialin gene expression, and on the protein level, by blocking the interaction of cell-surface expressed endosialin with ligands such as fibronectin and collagen. The invention provides methods for identifying inhibitors of the interaction of endosialin with endosialin ligands. Also provided are methods for inhibiting angiogenesis and neovascularization in vivo and in vitro.
Core Innovation
The disclosure concerns endosialin-targeted therapies and assays that address endosialin-mediated cell–ligand interaction. A central strategy is to inhibit endosialin and thereby reduce endosialin-mediated binding activity between cells and extracellular matrix ligands.
Endosialin inhibition is described through genetic suppression approaches including siRNA/shRNA, antisense nucleic acids, ribozymes, and knockdown. The disclosure also describes inhibiting cell-surface endosialin binding to extracellular matrix ligands such as fibronectin and collagens by using competitive inhibitors and antibodies/antigen-binding fragments.
The endosialin-binding landscape is characterized with recombinant endosialin constructs and with antibodies that block endosialin binding. The document further describes functional pathways affected by endosialin/ECM interactions, including integrin activation/inhibition and matrix metalloproteinase activation with emphasis on MMP-9, supported by binding, adhesion, and migration measurements.
Claims Coverage
The provided material includes two independent claims. Across these claims, the inventive features relate to producing endosialin-binding antibody or antigen-binding fragment via a deposited cell source, and to isolating the corresponding heavy-chain and/or light-chain encoding polynucleotide from that same deposited source.
Recombinant cell expressing an endosialin-binding antibody or antigen-binding fragment from a specified ATCC-deposited source
A recombinant cell that expresses an antibody or antigen-binding fragment thereof that specifically binds endosialin, said antibody or antigen-binding fragment produced by cells having ATCC Access No. PTA-9017.
Isolated polynucleotide encoding heavy and/or light chain from a specified ATCC-deposited source
An isolated polynucleotide encoding the heavy chain and/or the light chain of the antibody or antigen-binding fragment produced by cells having ATCC Access No. PTA-9017.
Together, the independent claims cover a recombinant cell expressing an endosialin-specific antibody or antigen-binding fragment produced by cells identified by ATCC Access No. PTA-9017, and an isolated polynucleotide encoding the corresponding heavy chain and/or light chain from that ATCC-deposited producing cells.
Stated Advantages
Suppresses endosialin-mediated cell–ligand interaction.
Obstructs cell-surface endosialin binding to extracellular matrix ligands.
Suppresses angiogenesis and neovascularization.
Inhibits integrin activation/inhibition effects associated with endosialin/ECM interaction.
Suppresses matrix metalloproteinase activity with emphasis on MMP-9.
Documented Applications
Therapeutic use of endosialin-targeted therapies to suppress angiogenesis and neovascularization.
In vitro/in vivo assays and characterization of endosialin–ECM binding and inhibitor effects, including binding ELISAs, adhesion assays, and migration assays.
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