Protein-proteophore complexes

• US 7,879,588 B2
• Filed: 10/01/2004
• Issued: 02/01/2011
• Est. Priority Date: 10/02/2003
• Status: Active Grant

• Current Assignee: Ascendis Pharma GmbH (Ascendis Pharma A/S)
• Original Assignee: Ascendis Pharma A/S
• Inventors: Schnepf, Robert, Vetter, Dirk, Wegge, Thomas, Rau, Harald, Hersel, Ulrich
• Primary Examiner(s): Tate; Christopher R
• Assistant Examiner(s): Kosar; Aaron J
• Application Number:
  US10/574,213
• Publication Number:
  US 20070020224A1
• Time in Patent Office: 2,314 Days
• Field of Search: None
• US Class Current: 435/212
• CPC Class Codes: A61K 47/56 the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
• CPC Class Codes: A61K 47/6949 inclusion complexes, e.g. clathrates, cavitates or fullerenes
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: Y10S 977/70 Nanostructure
• CPC Class Codes: Y10S 977/702 having biological material component
• CPC Class Codes: Y10S 977/705 Protein or peptide
• CPC Class Codes: Y10S 977/754 Dendrimer, i.e. serially branching or "tree-like" structure

Abstract

The application relates to a composition comprising a hyperbranched polymer attached to a core and a biologically active moiety. The biologically active moiety is attached to the core by means of a substantially non-enzymatically cleavable linker L. The composition can be used to deliver the biologically active moiety to its target.

Claims

1. A composition comprising a hyperbranched polymer attached to a core and to a biologically active moiety, wherein the hyperbranched polymer contains at least two molecular chains, which molecular chains are of sufficient length to be so arranged as to form a cavity to accommodate the biologically active moiety, and wherein the molecular chains contain sterically demanding capping groups;

further wherein the composition has the formula (V);

2. The composition of claim 1, wherein the hyperbranched polymer is water soluble.

3. The composition according to claim 1, wherein further groups are present in the polymer chains, the further groups being selected from the groups consisting of S, N, O, (—

S—

S)—

, oxyethylene, oxypropylene, oxybutylene, amide —

C(O)NH—

or —

C(O)NR—

, —

S-succinimido, amino (—

NR—

), carboxylic ester (—

C(O)O—

), sulfonamide (—

S(O)₂—

NR—

), carbamate (—

O—

C(O)—

NR—

), carbonate (—

OC(O)—

O—

), sulfone (—

S(O)₂—

), ether (—

O—

), oxime (—

CR═

N—

O—

), hydrazone (—

CR═

N—

NR—

), urea (—

NR—

C(O)—

NR—

), thiourea (—

NR—

C(S)—

NR—

), carbohydrate, glyceryl, phosphate (—

O—

P(O)(OR)O—

), phosphonate (—

P(O)(OR)O—

), saturated and nonsaturated cyclic groups, and saturated or nonsaturated heterocyclic groups; and

wherein R is selected from the group consisting of H, linear, branched, and cyclical alkyl groups, and which may contain therein additional functional groups or hetero atoms.

4. The composition according to claim 1, wherein the capping groups C contain further groups selected from the groups consisting of S, N, O, (—

S—

S)—

, oxypropylene, oxybutylene, amide (—

C(O)NH—

or C(O)NR—

), —

S-succinimido, amino (—

NR—

), carboxylic ester (—

C(O)O—

), sulfonamide (—

S(O)₂—

NR—

), carbamate (—

O—

C(O)—

NR—

), carbonate (—

O—

C(O)—

O—

), sulfone (—

S(O)₂—

), ether (—

O—

), oxime (—

CR═

N—

O—

), hydrazone (—

CR═

N—

NR—

), urea (—

NR—

C(O)—

NR—

), thiourea (—

NR—

C(S)—

NR—

), carbohydrate, glyceryl, phosphate (—

O—

P(O)(OR)O—

), phosphonate (—

P(O)(OR)O—

), saturated and nonsaturated cyclic groups, and saturated or nonsaturated heterocyclic groups; and

wherein R is selected from the group consisting of H, linear, branched, and cyclical alkyl groups, and which may contain therein additional functional groups or hetero atoms.

5. The composition according to claim 1, wherein the biologically active moiety is a protein or polypeptide selected from the group consisting of ACTH, adenosine deaminase, agalsidase, albumin, alpha-1 antitrypsin (AAT), alpha-1 proteinase inhibitor (API), alteplase, anistreplase, ancrod serine protease, a monoclonal or polyclonal antibody or fragment thereof, antithrombin III, antitrypsins, aprotinin, asparaginases, biphalin, bone-morphogenic proteins, calcitonin, collagenase, DNase, endorphins, enfuvirtide, enkephalins, erythropoietins, factor VIIa, factor VIII, factor VIIIa, factor IX, fibrinolysin, fusion proteins, follicle-stimulating hormones, granulocyte colony stimulating factor (G-CSF), galactosidase, glucagon, glucocerebrosidase, granulocyte macrophage colony stimulating factor (GM-CSF), phospholipase-activating protein (PLAP), gonadotropin chorionic (hCG), hemoglobins, hepatitis B vaccines, hirudin, hyaluronidases, idurnonidase, immune globulins, influenza vaccines, interleukins selected from the group consisting of IL-1α

, IL-1β

, IL-2, IL-3, IL-4, IL-6, IL-10, IL-11, and IL-12, IL-1 receptor antagonists (rhIL-1ra), insulins, interferons selected from the group consisting of IFN-α

2a, IFN-α

2b, IFN-α

2c, IFN-β

1a, IFN-β

1b, IFN-γ

1a, and IFN-γ

1b, keratinocyte growth factor (KGF), transforming growth factors, lactase, leuprolide, levothyroxine, luteinizing hormone, lyme vaccine, natriuretic peptide, pancrelipase, papain, parathyroid hormone, platelet-derived growth factor (PDGF), pepsin, platelet activating factor acetyihydrolase (PAF-AH), prolactin, protein C, octreotide, secretin, sermorelin, superoxide dismutase (SOD), somatropins (growth hormone), somatostatin, streptokinase, sucrase, tetanus toxin fragment, tilactase, thrombins, thymosin, thyroid stimulating hormone, thyrotropin, tumor necrosis factor (TNF), TNF receptor-IgG Fc, tissue plasminogen activator (tPA), thyroid stimulating factor (TSF), urate oxidase, urokinase, vaccines, and plant protein wherein the plant protein is optionally a lectin or a ricin.

6. The composition of claim 1, wherein the biologically active moiety is insulin.

7. The composition of claim 1, wherein the cleavable linker L contains a hydrolysable ester bond and the carbamate.

8. The composition of claim 7, wherein the hydrolysable ester bond is a phenol ester.

9. A drug containing the composition of claim 1.

10. The composition of claim 1, wherein l is 2 or 3 and resulting in a structure of formula (VII) or (VIII):