Compositions and methods for growth factor modulation

• US 9,758,576 B2
• Filed: 07/09/2015
• Issued: 09/12/2017
• Est. Priority Date: 05/06/2013
• Status: Active Grant

• Current Assignee: Scholar Rock, Inc. (Scholar Rock Holding Corp.)
• Original Assignee: Scholar Rock, Inc. (Scholar Rock Holding Corp.)
• Inventors: Schurpf, Thomas, Mahanthappa, Nagesh K., Straub, Michelle Marie
• Primary Examiner(s): Xie, Xiaozhen
• Application Number:
  US14/795,012
• Publication Number:
  US 20160031980A1
• Time in Patent Office: 796 Days
• Field of Search: None
• CPC Class Codes: 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
• CPC Class Codes: A61K 39/001134 Transforming growth factor [TGF]
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 14/495 : Transforming growth factor [TGF]
• CPC Class Codes: C07K 16/005 : constructed by phage libraries
• CPC Class Codes: C07K 16/22 : against growth factors ; against growth regulators
• CPC Class Codes: C07K 16/28 : against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C07K 16/2863 : against receptors for growth factors, growth regulators
• CPC Class Codes: C07K 2317/21 : from primates, e.g. man
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/31 : multispecific
• CPC Class Codes: C07K 2317/32 : specific for a neo-epitope on a complex, e.g. antibody-antigen or ligand-receptor
• CPC Class Codes: C07K 2317/33 : Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• CPC Class Codes: C07K 2317/55 : Fab or Fab'
• CPC Class Codes: C07K 2317/565 : Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C07K 2317/94 : Stability, e.g. half-life, pH, temperature or enzyme-resistance
• CPC Class Codes: C12N 15/1037 : Screening libraries presented on the surface of microorganisms, e.g. phage display, E. coli display
• CPC Class Codes: G01N 2333/495 : Transforming growth factor [TGF]
• CPC Class Codes: G01N 2333/71 : for growth factors; for growth regulators

Abstract

Provided herein are antibodies that bind growth factor prodomain complexes, for example, growth factor prodomain complexes that include GDF-8 growth factor and GDF-8 prodomain. Also included are antibodies that bind growth factor prodomain complexes that have been altered by proteolytic processing.

Claims

1. An isolated monoclonal antibody, or a fragment thereof, that binds a growth factor prodomain complex (GPC),

wherein said GPC comprises a GDF-8 growth factor and a GDF-8 prodomain (SEQ ID NO:

70),

wherein the antibody or fragment thereof binds the GDF-8 prodomain of said GPC,

wherein the antibody or fragment thereof but does not bind a mature GDF-8 growth factor, a mature GDF-11 growth factor, a GDF-11 prodomain or a complex comprising a GDF-11 prodomain and a GDF-11 growth factor,

wherein said antibody, or fragment thereof, prevents proteolytic cleavage between residues Arg 75 and Asp 76 of GDF-8 prodomain, and

wherein said antibody, or fragment thereof, inhibits the release of said mature GDF-8 growth factor from the GPC.

2. The antibody of claim 1, wherein said antibody recognizes an epitope within the GDF-8 arm region of the GDF-8 prodomain set forth in SEQ ID NO:

77.

3. The antibody of claim 1, wherein said prodomain has not been cleaved at the BMP/tolloid cleavage site between residues Arg 75 and Asp 76 of the GDF-8 prodomain (SEQ ID NO:

70).

4. The antibody of claim 1, wherein said antibody prevents the proteolytic cleavage by at least one metalloproteinase.

5. The antibody of claim 4, wherein said metalloproteinase is mammalian tolloid-like 2 (mTLL2).

6. The antibody of claim 1, wherein said GDF-8 prodomain has not been cleaved at a furin cleavage site.

7. The antibody of claim 1, wherein said GDF-8 prodomain has been cleaved at a furin cleavage site.

8. The antibody of claim 7, wherein said furin cleavage site is Arg-Ser-Arg-Arg set forth in SEQ ID NO:

76.

9. The antibody of claim 1, wherein said antibody is an IgG antibody.

10. The antibody of claim 9, wherein said IgG antibody is a human or humanized antibody.