# US 2019/0169245 A1 · Ctla4-binding protein peptide-linker masks > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2019/0169245 A1 - Document ID: US20190169245A1 - Status: Published application - Kind: A1 - Application number: 15/543,209 - Filed: 2016-01-13 - Published: 2019-06-06 - Earliest claimed: 2015-01-13 - Assignees: City of Hope; Thomas Jefferson University and Health System, Innovation Pillar - Applicants: City of Hope; Thomas Jefferson University and Health System, Innovation Pillar - Inventors: John WILLIAMS; Ulrich RODECK - Web page: https://patentgrep.com/patent/US20190169245A1 ## CPC - C07K 14/4703: {Inhibitors; Suppressors} - A61K 47/64: Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65) - A61K 47/65: Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers - C07K 14/70521: {CD28, CD152} - A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) - C07K 2319/055: containing a signal for localisation to secretory granules (for exocytosis) - C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto - C07K 2319/50: containing protease site - C07K 2319/70: containing domain for protein-protein interaction - C07K 2319/74: containing a fusion for binding to a cell surface receptor - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) ## Abstract Provided herein are recombinant CTLA-4 binding proteins, which are, inter alia, useful for the treatment of cancer. The recombinant proteins provided herein are, inter alia, capable of binding CTLA-4 proteins on a tumor cell. In a first aspect, there is provided a recombinant CTLA-4 binding protein including (i) a CTLA-4 binding domain; (ii) a CTLA-4 binding domain masking peptide; and (iii) a cleavable peptide linker connecting the CTLA-4 binding domain masking peptide to the CTLA-4 binding domain. In another aspect, there is provided a dimerizing domain covalently attached to the CTLA-4 binding domain, wherein the binding protein domains are bound together. ## Claims ### Claim 1 A recombinant CTLA-4 binding protein comprising: (i) a CTLA-4 binding domain; (ii) a CTLA-4 binding domain masking peptide; and (iii) a cleavable peptide linker connecting said CTLA-4 binding domain masking peptide to said CTLA-4 binding domain. ### Claim 2 (depends on 1) The recombinant CTLA-4 binding protein of claim 1, wherein said CTLA-4 binding domain is a CTLA-4 binding lipocalin 2 (LCN2). ### Claim 3 (canceled) ### Claim 4 (depends on 1) The recombinant CTLA-4 binding protein of claim 1, wherein said sequence has at least 90% homology to SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13 or SEQ ID NO:14. ### Claim 5 (depends on 1) The recombinant CTLA-4 binding protein of claim 1, wherein said sequence has at least 90% homology to SEQ ID NO:12. ### Claim 6 (depends on 1) The recombinant CTLA-4 binding protein of claim 1, wherein said sequence is SEQ ID NO:12. ### Claim 7 (depends on 1) The recombinant CTLA-4 binding protein of claim 1, wherein said sequence has at least 90% homology to SEQ ID NO:9. ### Claim 8 (depends on 1) The recombinant CTLA-4 binding protein of claim 1, wherein said sequence is SEQ ID NO:9. ### Claim 9 (depends on 1) The recombinant CTLA-4 binding protein of claim 1, wherein said CTLA-4 binding domain masking peptide comprises a glycoprotein secretion signal. ### Claim 10 (depends on 9) The recombinant CTLA-4 binding protein of claim 9, wherein said glycoprotein secretion signal is a glycoprotein (gp) 67 secretion signal, pELB signal, human granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR), or an alpha-chain signal sequence (CAR). ### Claim 11 (depends on 1) The recombinant CTLA-4 binding protein of claim 1, wherein said cleavable peptide linker connects said CTLA-4 binding domain masking peptide to the N-terminus of said CTLA-4 binding domain. ### Claim 12 (depends on 1) The recombinant CTLA-4 binding protein of claim 1, wherein said cleavable peptide linker connects said CTLA-4 binding domain masking peptide to the C-terminus of said CTLA-4 binding domain. ### Claim 13 (depends on 1) The recombinant CTLA-4 binding protein of claim 1, wherein said cleavable peptide linker comprises a protease cleavage site. ### Claim 14 (depends on 13) The recombinant CTLA-4 binding protein of claim 13, wherein said protease cleavage site is a tumor-associated protease cleavage site. ### Claim 15 (depends on 13) The recombinant CTLA-4 binding protein of claim 13, wherein said protease cleavage site is a matrix metalloprotease (MMP) cleavage site, a disintegrin and metalloprotease domain-containing (ADAM) metalloprotease cleavage site, a prostate specific antigen (PSA) protease cleavage site, a urokinase-type plasminogen activator (uPA) protease cleavage site, a membrane type serine protease 1 (MT-SP1) protease cleavage site or a legumain protease cleavage site. ### Claim 16 (depends on 15) The recombinant CTLA-4 binding protein of claim 15, wherein said matrix metalloprotease (MMP) cleavage site is a MMP9 cleavage site, a MMP 13 cleavage site or a MMP 2 cleavage site. ### Claim 17 (depends on 15) The recombinant CTLA-4 binding protein of claim 15, wherein said disintegrin and metalloprotease domain-containing (ADAM) metalloprotease cleavage site is a ADAM 9 metalloprotease cleavage site, a ADAM 10 metalloprotease cleavage site or a ADAM 17 metalloprotease cleavage site. ### Claim 18 (depends on 1) The recombinant CTLA-4 binding protein of claim 1, wherein said CTLA-4 binding domain is covalently attached to a dimerizing domain. ### Claim 19 (depends on 18) The recombinant CTLA-4 binding protein of claim 18, wherein said dimerizing domain is a Fc protein domain. ### Claim 20 (depends on 19) The recombinant CTLA-4 binding protein of claim 19, wherein said Fc protein domain is an IgG1 Fc protein. ### Claim 21 (depends on 1) A recombinant nucleic acid encoding the recombinant CTLA-4 binding protein of claim 1. ### Claim at position 22 22-50. (canceled) ### Claim 51 (depends on 1) A method of treating a CTLA-4-mediated disease in a subject in need thereof, said method comprising administering to a subject a therapeutically effective amount of the recombinant CTLA-4 binding protein of claim 1. ### Claim at position 24 52-54. (canceled)