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US 9,221,882 B2Granted
Biosynthetic proline/alanine random coil polypeptides and their uses
AssigneesTechnische Universität München, Xl-Protein GmbH
InventorsArne Skerra, Uli Binder, Martin Schlapschy
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Abstract
We discovered that a biosynthetic polypeptide, consisting of at least about 50 proline (Pro) and alanine (Ala) amino acid residues, forms a random coil, and increases the stability of other compounds to which it is conjugated, such as small molecules and polypeptides. We describe such biosynthetic polypeptides, constructs containing such polypeptides, ways of making them, and their use.
Claims34
An isolated drug conjugate comprising
- (i) a random coil polypeptide comprising 50 to 3000 amino acids and consisting solely of proline and alanine,
- wherein said polypeptide forms a random coil, and
- (ii) a drug selected from
- (a) a biologically active polypeptide selected from the group consisting of antibodies, antibody fragments, Fab fragments, F(ab′)2 fragments, CDR-derived peptidomimetics, single chain variable fragments (scFv), domain antibodies, lectins, immunoglobulin domains, fibronectin domains, protein A domains, SH3 domains, ankyrin repeat domains, lipocalins, granulocyte colony stimulating factor, human growth hormone, alpha-interferon, beta-interferon, gamma-interferon, tumor necrosis factor, erythropoietin, coagulation factor VIII, gp120/gp160, soluble tumor necrosis factor I and II receptor, reteplase, exendin-4, anakinra, interleukin-2, neutrophil gelatinase-associated lipocalin, follicle-stimulating hormone, glucocerebrosidase, thymosin alpha 1, glucagon, somatostatin, adenosine deaminase, interleukin 11, coagulation factor VIIa, coagulation factor IX, hematide, lambda-interferon, leptin, interleukin-22 receptor subunit alpha (IL-22ra), interleukin-22, hyaluronidase, fibroblast growth factor 18, fibroblast growth factor 21, glucagon-like peptide 1, osteoprotegerin, IL-18 binding protein, growth hormone releasing factor, soluble TACI receptor, thrombospondin-1, soluble VEGF receptor Flt-1, and IL-4 mutein;
- and
- (b) a small molecule selected from the group consisting of digoxigenin, fluorescein, doxorubicin, calicheamicin, camptothecin, fumagillin, dexamethasone, geldanamycin, paclitaxel, docetaxel, irinotecan, cyclosporine, buprenorphine, naltrexone, naloxone, vindesine, vancomycin, risperidone, aripiprazole, palonosetron, granisetron, cytarabine, NX1838, leuprolide, goserelin, buserelin, octreotide, teduglutide, cilengitide, abarelix, enfuvirtide, ghrelin;
- wherein the drug is conjugated through a covalent link to the N- or C-terminus of the random coil polypeptide.
4 more elements
A method for increasing the stability of a drug comprising conjugating the drug through a covalent link to the N- or C-terminus of a random coil polypeptide, wherein the drug is selected from
- (a) a biologically active polypeptide selected from the group consisting antibodies, antibody fragments, Fab fragments, F(ab′)2 fragments, CDR-derived peptidomimetics, single chain variable fragments (scFv), domain antibodies, lectins, immunoglobulin domains, fibronectin domains, protein A domains, SH3 domains, ankyrin repeat domains, lipocalins, granulocyte colony stimulating factor, human growth hormone, alpha-interferon, beta-interferon, gamma-interferon, tumor necrosis factor, erythropoietin, coagulation factor VIII, gp120/gp160, soluble tumor necrosis factor I and II receptor, reteplase, exendin-4, anakinra, interleukin-2, neutrophil gelatinase-associated lipocalin, follicle-stimulating hormone, glucocerebrosidase, thymosin alpha 1, glucagon, somatostatin, adenosine deaminase, interleukin 11, coagulation factor VIIa, coagulation factor IX, hematide, lambda-interferon, leptin, interleukin-22 receptor subunit alpha (IL-22ra), interleukin-22, hyaluronidase, fibroblast growth factor 18, fibroblast growth factor 21, glucagon-like peptide 1, osteoprotegerin, IL-18 binding protein, growth hormone releasing factor, soluble TACI receptor, thrombospondin-1, soluble VEGF receptor Flt-1, and IL-4 mutein and
- (b) a small molecule selected from the group consisting of digoxigenin, fluorescein, doxorubicin, calicheamicin, camptothecin, fumagillin, dexamethasone, geldanamycin, paclitaxel, docetaxel, irinotecan, cyclosporine, buprenorphine, naltrexone, naloxone, vindesine, vancomycin, risperidone, aripiprazole, palonosetron, granisetron, cytarabine, NX1838, leuprolide, goserelin, buserelin, octreotide, teduglutide, cilengitide, abarelix, enfuvirtide, and ghrelin;
- and the random coil polypeptide comprises 50 to 3000 amino acids and consists solely of proline and alanine, wherein said polypeptide forms a random coil.
Dependencies are inferred from the claim text.