WO2014182676A2 - Compositions and methods for growth factor modulation - Google Patents

Compositions and methods for growth factor modulation Download PDF

Info

Publication number
WO2014182676A2
WO2014182676A2 PCT/US2014/036933 US2014036933W WO2014182676A2 WO 2014182676 A2 WO2014182676 A2 WO 2014182676A2 US 2014036933 W US2014036933 W US 2014036933W WO 2014182676 A2 WO2014182676 A2 WO 2014182676A2
Authority
WO
WIPO (PCT)
Prior art keywords
tgf
protein
antibody
proteins
growth factor
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2014/036933
Other languages
English (en)
French (fr)
Other versions
WO2014182676A3 (en
Inventor
Thomas SCHURPF
Nagesh K. Mahanthappa
Michelle Marie STRAUB
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Scholar Rock Inc
Original Assignee
Scholar Rock Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=51867850&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2014182676(A2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to DK14795041.4T priority Critical patent/DK2981822T3/da
Priority to IL319092A priority patent/IL319092A/en
Priority to ES14795041T priority patent/ES2837042T3/es
Priority to EP20193425.4A priority patent/EP3816625B1/en
Priority to SG11201508681QA priority patent/SG11201508681QA/en
Priority to EP14795041.4A priority patent/EP2981822B1/en
Priority to AU2014262843A priority patent/AU2014262843B2/en
Priority to SI201431717T priority patent/SI2981822T1/sl
Priority to JP2016513010A priority patent/JP2016521283A/ja
Priority to HRP20201914TT priority patent/HRP20201914T1/hr
Priority to SM20210008T priority patent/SMT202100008T1/it
Priority to PL14795041T priority patent/PL2981822T4/pl
Priority to IL301607A priority patent/IL301607B2/en
Priority to EP25202206.6A priority patent/EP4674866A3/en
Priority to CA2911514A priority patent/CA2911514A1/en
Priority to RS20201467A priority patent/RS61778B1/sr
Priority to LTEP14795041.4T priority patent/LT2981822T/lt
Application filed by Scholar Rock Inc filed Critical Scholar Rock Inc
Publication of WO2014182676A2 publication Critical patent/WO2014182676A2/en
Publication of WO2014182676A3 publication Critical patent/WO2014182676A3/en
Priority to US14/795,012 priority patent/US9758576B2/en
Priority to US14/795,007 priority patent/US9573995B2/en
Priority to US14/795,033 priority patent/US9399676B2/en
Priority to US14/795,022 priority patent/US9580500B2/en
Priority to IL242193A priority patent/IL242193B/en
Anticipated expiration legal-status Critical
Priority to US15/187,278 priority patent/US9758577B2/en
Priority to US15/401,386 priority patent/US20170210798A1/en
Priority to US15/404,663 priority patent/US10597443B2/en
Priority to AU2017203611A priority patent/AU2017203611C1/en
Priority to US15/659,974 priority patent/US20180016332A1/en
Priority to US15/671,217 priority patent/US20180022798A1/en
Priority to US16/209,078 priority patent/US10981981B2/en
Priority to AU2019203834A priority patent/AU2019203834A1/en
Priority to US16/736,207 priority patent/US12577296B2/en
Priority to CY20201101140T priority patent/CY1123907T1/el
Priority to US17/196,256 priority patent/US11827698B2/en
Priority to IL281549A priority patent/IL281549B2/en
Priority to AU2021204415A priority patent/AU2021204415B2/en
Priority to US18/488,265 priority patent/US12454570B2/en
Priority to AU2025201228A priority patent/AU2025201228A1/en
Priority to US19/335,639 priority patent/US20260109757A1/en
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/22—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A61K39/00113—Growth factors
    • A61K39/001134—Transforming growth factor [TGF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/475—Growth factors; Growth regulators
    • C07K14/495—Transforming growth factor [TGF]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/005—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies constructed by phage libraries
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2863—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
    • C12N15/1034—Isolating an individual clone by screening libraries
    • C12N15/1037—Screening libraries presented on the surface of microorganisms, e.g. phage display, E. coli display
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/32—Immunoglobulins specific features characterized by aspects of specificity or valency specific for a neo-epitope on a complex, e.g. antibody-antigen or ligand-receptor
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/55—Fab or Fab'
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/475—Assays involving growth factors
    • G01N2333/495—Transforming growth factor [TGF]
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/71—Assays involving receptors, cell surface antigens or cell surface determinants for growth factors; for growth regulators

Definitions

  • Embodiments of the present invention may include recombinant proteins as well as antibodies directed to such proteins.
  • such proteins and antibodies may be related to the field of TGF- ⁇ family member biology.
  • Cell signaling molecules stimulate a variety of cellular activities. Such signaling is often tightly regulated, often through interactions with other biomolecules, the extracellular and/or cellular matrix or within a particular cell environment or niche. Such interactions may be direct or indirect.
  • Cell signaling cascades are involved in a number of diverse biological pathways including, but not limited to modulation of cell growth, modulation of tissue homeostasis, extracellular matrix (ECM) dynamics, modulation of cell migration, invasion and immune modulation/suppression.
  • ECM extracellular matrix
  • proteins involved in cell signaling are synthesized and/or are sequestered in latent form, requiring stimulus of some kind to participate in signaling events.
  • the present invention provides recombinant proteins comprising one or more TGF-P-related proteins comprising one or more protein modules selected from the group consisting of growth factor prodomain complexes (GPCs), latency associated peptides (LAPs), LAP-like domains, straight jacket regions, growth factor domains, fastener regions, furin cleavage site regions, arm regions, fingers regions, N-terminal regions for extracellular associations, latency loops, alpha 1 helical regions, alpha 2 helical regions, RGD sequence regions, trigger loop regions and bowtie regions.
  • recombinant proteins of the present invention may comprise one or more protein modules from a vertebrate species.
  • recombinant proteins of the present invention may comprise one or more protein modules comprising one or more mutations. In some embodiments, recombinant proteins of the present invention may comprise one or more mutations comprising one or more furin cleavage site regions. In some embodiments, such mutations may prevent enzymatic cleavage of recombinant proteins of the present invention. In some embodiments, recombinant proteins of the present invention may comprise one or more mutations comprising a mutation of the amino acid sequence RXXR to the amino acid sequence RXG. In some embodiments, recombinant proteins of the present invention may comprise one or more mutations comprising a mutation of the amino acid sequence RXXR to the amino acid sequence AXXA.
  • recombinant proteins of the present invention may comprise one or more mutations comprising N-terminal regions for extracellular associations. In some embodiments, recombinant proteins of the present invention may comprise one or more mutations comprising substitution and/or deletion of at least one cysteine residue present within about the first 4, 5, 6 or 7 N-terminal amino acid residues. In some embodiments, recombinant proteins of the present invention may comprise one or more substitution of at least one cysteine residue with at least one serine residue.
  • recombinant proteins of the present invention may be complexed with a protein selected from the group consisting of LTBP1, LTBP1S, LTBP2, LTBP3, LTBP4, fibrillin-1, fibrillin-2, fibrillin-3, fibrillin-4, GARP, LRRC33 and a combination or fragment thereof.
  • recombinant proteins of the present invention may comprise one or more detectable labels. Such detectable labels may comprise biotin labels, polyhistidine tags and/or flag tags.
  • the present invention provides chimeric proteins comprising one or more protein modules from at least two TGF-P-related proteins wherein said protein modules may be selected from the group consisting of growth factor prodomain complexes (GPCs), latency associated peptides (LAPs), LAP-like domains, straight jacket regions, growth factor domains, fastener regions, furin cleavage site regions, arm regions, fingers regions, N- terminal regions for extracellular associations, latency loops, alpha 1 helical regions, RGD sequence regions, trigger loop regions, bowtie regions and any of those listed in Tables 2, 3 and 11.
  • chimeric proteins of the present invention may comprise one or more protein modules selected from one or more vertebrate species.
  • chimeric proteins of the present invention may comprise GPCs.
  • such GPCs may comprise at least one LAP or LAP-like domain from a TGF- ⁇ family member and at least one growth factor domain from a TGF- ⁇ family member wherein the LAP or LAP-like domain and the growth factor domain are from different TGF- ⁇ family members.
  • chimeric proteins of the present invention may comprise at least one LAP or LAP-like domain and at least one growth factor domain, each of which is selected from the group consisting of TGF- ⁇ , TGF ⁇ 2, TGF ⁇ 3, GDF-8, GDF-11 and inhibin beta A.
  • chimeric proteins of the present invention may comprise one or more GPC wherein at least one N-terminal region is from a TGF- ⁇ family member, at least one C-terminal region is from a TGF- ⁇ family member and wherein the N-terminal region and C-terminal region are from different TGF- ⁇ family members.
  • chimeric proteins of the present invention may comprise at least one N-terminal region and at least one C-terminal region selected from TGF- ⁇ terminal regions, TGF ⁇ 2 terminal regions, TGF ⁇ 3 terminal regions, GDF-8 terminal regions, GDF-11 terminal regions and inhibin beta A terminal regions.
  • chimeric proteins of the present invention may comprise a GPC from at least one TGF- ⁇ family member comprising at least one arm region from a different TGF- ⁇ family member. In some embodiments, chimeric proteins of the present invention may comprise a GPC comprising at least one TGF- ⁇ family member comprising at least one trigger loop region from a different TGF- ⁇ family member. In some embodiments, chimeric protein of the present invention may comprise any of the protein module combinations listed in Table 12.
  • chimeric protein of the present invention may be complexed with a protein selected from the group consisting of LTBP1, LTBP1S, LTBP2, LTBP3, LTBP4, fibrillin- 1 , fibrillin-2, fibrillin-3, fibrillin-4, GARP and LRRC33 and a combination or fragment thereof.
  • chimeric proteins of the present invention may comprise one or more detectable labels.
  • detectable labels may comprise at least one biotin label, polyhistidine tag and/or flag tag.
  • the present invention provides an antibody directed to any of the recombinant proteins and/or chimeric proteins disclosed herein.
  • such antibodies comprise monoclonal antibodies.
  • antibodies of the present invention are substantially isolated.
  • monoclonal antibodies of the present invention are stabilizing antibodies.
  • stabilizing antibodies of the present invention reduce the level of free growth factor relative to the level of growth factor associated with one or more GPC.
  • stabilizing antibodies may reduce growth factor- dependent cellular signaling.
  • monoclonal antibodies of the present invention may comprise releasing antibodies. Such antibodies may increase the level of free growth factor relative to the level of growth factor associated with one or more GPC.
  • releasing antibodies of the present invention may increase growth factor- dependent cellular signaling.
  • the present invention provides compositions comprising one or more of any of the recombinant proteins, one or more of any of the chimeric proteins and/or one or more of any of the antibodies described herein combined with at least one excipient.
  • the present invention provides methods of modulating the level of free growth factor in a subject or cell niche comprising the use of one or more compositions described herein. In some such methods, the level of growth factor signaling is modulated.
  • the present invention provides methods for selecting a desired antibody comprising the use of one or more assays, wherein such assays comprise one or more recombinant protein of the invention. Some such methods comprise the steps of 1) providing an antibody binding assay, 2) contacting the binding assay with one or more candidate antibodies, 3) obtaining binding data related to candidate antibody affinity for the one or more recombinant protein and 4) selecting a desired antibody based on the binding data. Binding assays according to such methods may include an enzyme-linked immunosorbent assay (ELISA) and/or a fluorescence-associated cell sorting (FACS)-based assay.
  • ELISA enzyme-linked immunosorbent assay
  • FACS fluorescence-associated cell sorting
  • recombinant proteins of such assays may be complexed with a protein selected from the group consisting of SEQ ID NOs: 153-161 and 286-292 or complexed with a protein selected from the group consisting of LTBP1, LTBP1S, LTBP2, LTBP3, LTBP4, fibrillin-1, fibrillin-2, fibrillin-3, fibrillin-4, GARP, LRRC33, perlecan, decorin, elastin and collagen.
  • recombinant proteins may comprise a chimeric protein comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 199-236 and 273.
  • Other methods of selecting a desired antibody may comprise the steps of 1) providing a growth factor activity assay, 2) contacting the growth factor activity assay with one or more candidate antibodies, 3) obtaining growth factor activity data and 4) selecting a desired antibody based on the growth factor activity data.
  • Growth factor activity assays may comprise cell-based assays selected from the group consisting of luciferase-based assays and proliferation assays.
  • Such cell-based assays may comprise one or more expression cells that express one or more recombinant protein of the invention or a complex thereof.
  • Such assays may further comprise one or more responsive cells that yield gene expression data and/or viability data.
  • the present invention provides pharmaceutical compositions comprising one or more of any of the recombinant proteins described herein, one or more of any of the chimeric proteins described herein and/or one or more of any of the antibodies described herein and at least one pharmaceutically excipient.
  • TGF-P-related indications may include fibrotic indications (e.g. lung fibrosis, kidney fibrosis, liver fibrosis, cardiovascular fibrosis, skin fibrosis, and bone marrow fibrosis), myelofibrosis, cancer or cancer- related conditions (e.g. colon cancer, renal cancer, breast cancer, malignant melanoma and glioblastoma) and muscle disorders and/or injuries [e.g.
  • cachexia muscular dystrophy, chronic obstructive pulmonary disease (COPD), motor neuron disease, trauma, neurodegenerative disease, infection, rheumatoid arthritis, immobilization, sarcopenia, inclusion body myositis and diabetes.
  • COPD chronic obstructive pulmonary disease
  • motor neuron disease trauma, neurodegenerative disease, infection, rheumatoid arthritis, immobilization, sarcopenia, inclusion body myositis and diabetes.
  • the invention provides a kit comprising a composition of the invention and instructions for use thereof.
  • Figure 1 is a diagram of the TGF-beta superfamily tree, where divergence is proportional to branch length.
  • Figure 2 is a schematic of one embodiment of a linear representation of a translated growth factor monomer.
  • translated growth factors may comprise secretion signal peptides, prodomains and growth factor domains.
  • translated growth factors may also comprise a cleavage site between prodomain and growth factor regions.
  • FIG. 3 is a schematic of one embodiment of a growth factor-prodomain complex (GPC) as well as an embodiment of a free growth factor dimer and a free latency associated peptide (LAP) dimer.
  • GPC growth factor-prodomain complex
  • LAP free latency associated peptide dimer
  • Figure 4 is a schematic of one embodiment of a free LAP dimer and a free growth factor dimer with labeled features and/or protein modules.
  • Figure 5 is a schematic of an embodiment of a recombinant GPC.
  • Figure 6 is a schematic of embodiments of mutant recombinant GPCs.
  • Figure 7 depicts schematic representations of five recombinant proteins alone or in complex with LTBP or GARP.
  • Figure 8 shows structure-based alignment between TGF- ⁇ family member proteins [adapted from Shi et al (Shi, M. et al, Latent TGF- ⁇ structure and activation. Nature. 2011 Jun 15; 474(7351):343-9, the contents of which are herein incorporated by reference in their entirety.)] Cysteine residues required for interaction with LTBPs and/or GARPs are boxed. Residues mutated in Camurati-Engelmann syndrome are indicated with a star. Protease cleavage sites are indicated with an up arrow. Protein modules and secondary structural elements are indicated with solid bars. Residues underlined at the N-terminus of GDF-8 correspond to alternatively predicted signal peptide processing sites.
  • Figure 10 presents an alignment conducted between GDF-8 (myostatin,) GDF-11, Inhibin A and a GDF-8 dimer. Arrows indicate cleavage sites. Regions involved in internal interactions are boxed. Solid rectangles appear above residues predicted to be involved in steric clashes in chimeric constructs. Stars denote important break points in protein modules.
  • Figure 11 depicts the expression and purification of recombinant antigens and antigen complexes (Coomassie Blue stained SDS-PAGE).
  • Figure 12 presents results from analyses of cell lines stably expressing TGF-pi/GARP complexes.
  • Luciferase assay data is presented in (D) showing TGF- ⁇ signaling activity resulting from co-culture of these cells with cells expressing ⁇ 6 integrin.
  • Figure 13 depicts recombinant histidine -tagged proGDF-8, separated by SDS-PAGE under reducing and non-reducing conditions, as visualized by Coomassie staining.
  • Growth factors are cell signaling molecules that stimulate a variety of cellular activities. Due to their broad-reaching influence within biological systems, growth factor signaling is tightly regulated, often through interactions with other biomolecules, the
  • extracellular and/or cellular matrix or within a particular cell environment or niche may be direct or indirect.
  • TGF- ⁇ transforming growth factor beta
  • type II receptors phosphorylation and activation
  • Activated type I receptors may in turn phosphorylate receptor-associated SMADs (R-SMADs) promoting co- SMAD (e.g. SMAD4) dimer/trimer formation and nuclear translocation.
  • R-SMADs receptor-associated SMADs
  • co- SMAD dimer/trimer formation and nuclear translocation.
  • SMAD complexes collaborate with cofactors to modulate expression of TGF- ⁇ family member target genes.
  • TGF- ⁇ family member signaling cascades are involved in a number of diverse biological pathways including, but not limited to inhibition of cell growth, tissue homeostasis, extracellular matrix (ECM) remodeling, endothelial to mesenchymal transition (EMT) in cell migration and invasion and immune modulation/suppression as well as in mesenchymal to epithelial transition.
  • ECM extracellular matrix
  • EMT endothelial to mesenchymal transition
  • TGF- ⁇ signaling related to growth inhibition and tissue homeostasis may affect epithelial, endothelial, hematopoietic and immune cells through the activation of p21 and pl5 INK to mediate cell cycle arrest and repress myc.
  • TGF- ⁇ signaling may increase fibroblast populations and ECM deposition (e.g. collagen).
  • TGF- ⁇ signaling related to cell migration and invasion may affect epithelial and/or endothelial cells, inducing stem cell-like phenotypes. This aspect of signaling may play a role in smooth muscle cell proliferation following vascular surgery and/or stenting.
  • TGF- ⁇ ligand is necessary for T regulatory cell function and maintenance of immune precursor cell growth and homeostasis. Nearly all immune cells comprise receptors for TGF- ⁇ and TGF- ⁇ knockout mice die postnataly due in part to inflammatory pathologies.
  • TGF- ⁇ suppresses interferon gamma-induced activation of natural killer cells (Wi, J. et al., 2011. Hepatology. 53(4): 1342-51, the contents of which are herein incorporated by reference in their entirety.)
  • TGF-beta The recent solution of the crystal structure of the latent form of TGF-beta is a first for the entire TGF-beta family and offers deep insights into these complexes (Shi, M. et al, Latent TGF- ⁇ structure and activation. Nature. 2011 Jun 15; 474(7351):343-9). Almost all signaling in the TGF-beta family goes through a common pathway whereby a dimeric ligand is recognized by a heterotetrameric receptor complex containing two type I and two type II receptors. Each receptor has a serine-threonine kinase domain. Type II receptors phosphorylate type I receptors, which in turn phosphorylate receptor-regulated Smads that translocate to and accumulate in the nucleus and regulate transcription.
  • TGF- ⁇ family members include the bone morphogenetic proteins (BMP), inhibin, activin, growth and differentiation factor (GDF), myostatin, nodal, anti-Mullerian hormone, and lefty proteins.
  • BMP bone morphogenetic proteins
  • GDF growth and differentiation factor
  • myostatin nodal, anti-Mullerian hormone
  • lefty proteins a review of TGF- ⁇ family members, related signaling molecules as well as their relationships can be found in Massague., 2000. Nature Reviews Molecular Cell Biology. 1 : 169-78, the contents of which are herein incorporated by reference in their entirety.
  • mature growth factors are synthesized along with their prodomains as single polypeptide chains (see Figure 2).
  • such polypeptide chains may comprise cleavage sites for separation of prodomains from mature growth factors.
  • such cleavage sites are furin cleavage sites recognized and cleaved by proprotein convertases.
  • prodomain homology In general, homology among TGF- ⁇ family member growth factor domains is relatively high. Interestingly, prodomain homology is much lower. This lack of homology may be an important factor in altered growth factor regulation among family members. In some cases, prodomains may guide proper folding and/or dimerization of growth factor domains. Prodomains have very recently been recognized, in some cases, to have important functions in directing growth factors (after secretion) to specific locations in the extracellular matrix (ECM) and/or cellular matrix, until other signals are received that cause growth factor release from latency. Release from latency may occur in highly localized environments whereby growth factors may act over short distances (e.g.
  • growth factor-prodomain complexes are secreted as homodimers.
  • prodomain-growth factor complexes may be secreted as heterodimers.
  • TGF-P-related protein refers to a TGF- ⁇ isoform, a TGF- ⁇ family member or a TGF- ⁇ family member-related protein.
  • TGF- ⁇ family members may include, but are not limited to any of those shown in in Figure 1 and/or listed in Table 1. These include, but are not limited to TGF- ⁇ proteins, BMPs, myostatin, GDFs and inhibins. In some
  • the present invention provides tools and/or methods for isolating, characterizing and or modulating TGF ⁇ -related proteins. Aspects of the present invention provide tools and/or methods for characterizing and/or modulating cellular activities related to TGF ⁇ -related protein signaling.
  • tools of the present invention may comprise antigens comprising one or more components of one or more TGF ⁇ -related proteins. Some tools may comprise antibodies directed toward antigens of the present invention.
  • tools of the present invention may comprise assays for the detection and/or characterization of TGF ⁇ -related proteins, the detection and/or characterization of antibodies directed toward TGF-P-related proteins and/or the detection and/or characterization of cellular activities and/or their cellular signaling related to TGF-P-related proteins.
  • TGF-P-related proteins are involved in a number of cellular processes.
  • TGF- ⁇ family of proteins are involved in regulating major developmental processes and the details of the formation of many organs. Much of this regulation occurs before birth; however, the family continues to regulate many processes after birth, including, but not limited to immune responses, wound healing, bone growth, endocrine functions and muscle mass. TGF-P-related proteins are listed and described in U.S. Provisional Patent Applications 61/722,919, filed November 6, 2012; 61/722,969, filed November 6, 2012 and 61/823,552, filed May 15, 2013 the contents of each of which are herein incorporated by reference in their entireties.
  • TGF- ⁇ family pro-proteins i.e. the protein after removal of the secretion signal sequence
  • the pro-protein contains, and is the precursor of, the prodomain and the growth factor. Shown in the Table are the names of the originating TGF- ⁇ family member and the pro-protein sequence. Also identified in "bold” and “underlined” are proprotein convertase cleavage sites. Upon cleavage, the resulting prodomain retains this site, whereas the mature growth factor begins following the cleavage site. It is noted that Leftyl and Lefty2 are not cleaved by proprotein convertases just prior to the start of the mature growth factor.
  • GDF-1 1 AEGPAAAAAAAAAAAAAGVGGERSSRPAPSVAPEPDGCPV 4
  • GDF-8 NENSEQKENVEKEGLCNACTWRQNTKSSRIEAIKIQILSKLRL 5 (myostatin) ETAPNISKDVIRQLLPKAPPLRELIDQYDVQRDDSSDGSLEDD
  • GDF-7 RDGLEAAAVLRAAGAGPVRSPGGGGGGGGRTLAQAAGA 19
  • prodomains may be cleaved by proprotein convertase enzymes.
  • proprotein convertase refers to an enzyme that cleaves a prodomain from a translated protein to facilitate protein maturation.
  • Some proprotein convertases of the present invention include the subtilisin-like proprotein convertase (SPC) family member enzymes.
  • SPC family comprises calcium-dependent serine endoproteases that include, but are not limited to furin/PACE, PCl/3, PC2, PC4, PC5/6, PACE4 and PC7 (Fuller et al, 2009. Invest Ophthalmol Vis Sci.
  • GDF-11 may in, in some cases, be cleaved by PC5/6.
  • proprotein convertases may cleave proproteins at additional sites, other than those indicated in Table 1.
  • pro-proteins may be cleaved at a first cleavage site (the first site being the site closest to the N-terminus).
  • pro-proteins may be cleaved at a cleavage site other than a first cleavage site.
  • proprotein convertase cleavage may occur intracellularly.
  • proprotein convertase cleavage may occur extracellularly.
  • TGF- ⁇ family member proteins are synthesized in conjunction with
  • prodomains Some prodomains may remain associated with growth factors after cleavage. Such associations may form latent growth factor-prodomain complexes (GPCs) that modulate the availability of growth factors for cell signaling. Growth factors may be released from latency in GPCs through associations with one or more extracellular proteins. In some cases, growth factor release may rely on force applied to GPCs through extracellular protein interactions. Such forces may pull from C-terminal and/or N-terminal regions of GPCs resulting in the release of associated growth factors.
  • GPCs latent growth factor-prodomain complexes
  • the prodomain portion of the GPC is responsible for growth factor retention and blocking the interaction of retained growth factors with their receptors.
  • Prodomain portions of GPCs that function in this regard are referred to as latency associated peptides (LAPs).
  • LAPs latency associated peptides
  • TGF- ⁇ , 2 and 3 are know to comprise LAPs.
  • Some prodomains may comprise LAP-like domains.
  • LAP-like domain refers to prodomain portions of GPCs and/or free prodomains that may be structurally similar or synthesized in a similar manner to LAPs, but that may not function to prevent growth factor/receptor interactions.
  • GDF-8 and GDF-11 prodomains comprise LAP-like domains.
  • growth factors may be free or associated with one or more LAP or LAP-like domains.
  • Figure 3 is a schematic depicting an embodiment wherein a growth factor dimer may associate with a LAP dimer.
  • GPCs comprise protein modules necessary for different aspects of growth factor signaling, secretion, latency and/or release from latent GPCs.
  • protein module refers to any component, region and/or feature of a protein. Protein modules may vary in length, comprising one or more amino acids.
  • Protein modules may be from about 2 amino acid residues in length to about 50 amino acid residues in length, from about 5 amino acid residues in length to about 75 amino acid residues in length, from about 10 amino acid residues in length to about 100 amino acid residues in length, from about 25 amino acid residues in length to about 150 amino acid residues in length, from about 125 amino acid residues in length to about 250 amino acid residues in length, from about 175 amino acid residues in length to about 400 amino acid residues in length, from about 200 amino acid residues in length to about 500 amino acid residues in length and/or at least 500 amino acid residues in length.
  • protein modules comprise one or more regions with known functional features (e.g. protein binding domain, nucleic acid binding domain, hydrophobic pocket, etc.) Protein modules may comprise functional protein domains necessary for different aspects of growth factor signaling, secretion, latency and/or release from latent conformations.
  • protein modules may be derived from TGF-P-related proteins.
  • Such protein modules may include, but are not limited to latency-associated peptides (LAPs), LAP-like domains, growth factor domains, fastener regions, proprotein convertase cleavage sites (e.g. furin cleavage sites), B/TP cleavage sites, arm regions, finger regions, residues (such as cysteine residues for example) for extracellular protein [e.g.
  • FIG. 4 is a schematic diagram of an embodiment depicting LAP and growth factor dimers comprising protein modules.
  • protein modules may be derived from one or more TGF- ⁇ isoform (e.g. TGF- ⁇ , TGF-P2 and/or TGF-P3).
  • TGF- ⁇ e.g. TGF- ⁇ , TGF-P2 and/or TGF-P3
  • Such protein modules may comprise the protein modules and/or amino acid sequences listed in Table 2.
  • Some protein modules of the present invention may comprise amino acid sequences similar to those in Table 2, but comprise additional or fewer amino acids than those listed.
  • Such amino acid sequences may comprise about 1 more or fewer amino acids, about 2 more or fewer amino acids, about 3 more or fewer amino acids, about 4 more or fewer amino acids, about 5 more or fewer amino acids, about 6 more or fewer amino acids, about 7 more or fewer amino acids, about 8 more or fewer amino acids, about 9 more or fewer amino acids, about 10 more or fewer amino acids or greater than 10 more or fewer amino acids on N-terminal and/or C-terminal ends.
  • Table 2 TGF- ⁇ protein modules
  • TGF- ⁇ arm region EAVLALYNSTRDRVAGESAEPEPEPEADYYAK 49
  • TGF-P2 arm region PEVISIYNSTRDLLQEKASRRAAACERERSDEE 50
  • TGF- 3 arm region YQVLALYNSTRELLEEMHGEREEGCTQENTES 51
  • TGF- ⁇ fingers region 1 CVRQLYIDFRKDLGWKWIHEPKGYHANFC 52
  • TGF-P3 fingers region 1 C VRPLYIDFRQDLG WKWVHEPKGYYANFC S 54
  • TGF-pi fingers region 2 CVPQALEPLPIVYYVGRKPKVEQLSNMIVRSC 55
  • LAPs or LAP-like domains comprise the prodomain portion of a TGF-P-related protein and/or GPC. Some LAPs or LAP-like domains may associate with growth factors in GPCs. Some LAPs may sterically prevent growth factor association with one or more cellular receptors. LAPs or LAP-like domains may comprise arm regions and/or straight jacket regions. Some LAP or LAP-like domains may comprise C-terminal regions referred to herein as "bowtie regions.” In some LAP or LAP-like domain dimers, bowtie regions of each monomer may associate and/or interact. Such associations may comprise disulfide bond formation, as is found between monomers of TGF- ⁇ isoform LAPs.
  • arm regions may comprise trigger loop regions.
  • Trigger loops may comprise regions that associate with integrins. Such regions may comprise amino acid sequences comprising RGD (Arg-Gly-Asp). Regions comprising RGD sequences are referred to herein as RGD sequence regions.
  • LAPs or LAP-like domains comprise latency loops (also referred to herein as latency lassos). Some latency loops may maintain associations between LAPs or LAP-like domains and growth factors present within GPCs. LAPs or LAP-like domains may also comprise fastener regions. Such fastener regions may maintain associations between LAPs or LAP-like domains and growth factors present within GPCs. Some fastener regions may maintain LAP or LAP-like domain conformations that promote growth factor retention.
  • GPCs may require enzymatic cleavage for dissociation of bound growth factors. Such cleavage may be carried out in some instances by members of the BMP- 1/Tolloid-like proteinase (B/TP) family (Muir et al, 2011. J Biol Chem.
  • metaloproteinases may include, but are not limited to BMP-1, mammalian tolloid protein (mTLD,) mammalian tolloid-like 1 (mTLLl) and mammalian tolloid-like 2 (mTLL2.
  • Exemplary GPCs that may be cleaved by such metalloproteinases may include, but are not limited to GDF-8 and GDF-11.
  • GDF-8 may be cleaved by mTLL2.
  • tolloid cleavage may occur intracellularly. In some cases, tolloid cleavage may occur extracellularly.
  • Straight jacket regions may comprise alpha 1 helical regions.
  • alpha 1 helical regions may be positioned between growth factor monomers.
  • Some alpha 1 helical regions comprise N-terminal regions of LAPs or LAP-like domains.
  • Alpha 1 helical regions may also comprise N-terminal regions for extracellular associations.
  • extracellular associations may comprise extracellular matrix proteins and/or proteins associated with the extracellular matrix.
  • Some extracellular associations may comprise associations with proteins that may include, but are not limited to LTBPs (e.g. LTBP1, LTBP2, LTBP3 and/or LTBP4), fibrillins (e.g.
  • N-terminal extracellular associations may comprise disulfide bonds between cysteine residues.
  • extracellular matrix proteins and/or proteins associated with the extraceullar matrix may comprise bonds with one or more regions of LAPs/LAP-like domains other than N-terminal regions.
  • growth factor domains comprise one or more growth factor monomers. Some growth factor domains comprise growth factor dimers. Such growth factor domains may comprise growth factor homodimers or heterodimers (comprising growth factor monomers from different TGF-P-related proteins.) Some growth factor domains may comprise fingers regions. Such fingers regions may comprise ⁇ -pleated sheets. Fingers regions may associate with LAPs or LAP-like domains. Some fingers regions may maintain association between growth factor domains and LAPs or LAP-like domains.
  • recombinant proteins of the present invention may comprise protein modules from growth differentiation factor (GDF) proteins.
  • GDF protein modules may comprise the protein modules and/or amino acid sequences listed in Table 3.
  • protein modules of the present invention may comprise amino acid sequences similar to those in Table 3, but comprise additional or fewer amino acids than those listed.
  • Some such amino acid sequences may comprise about 1 more or fewer amino acids, about 2 more or fewer amino acids, about 3 more or fewer amino acids, about 4 more or fewer amino acids, about 5 more or fewer amino acids, about 6 more or fewer amino acids, about 7 more or fewer amino acids, about 8 more or fewer amino acids, about 9 more or fewer amino acids, about 10 more or fewer amino acids or greater than 10 more or fewer amino acids on N-terminal and/or C -terminal ends.
  • GDF- 1 1 growth factor NLGLDCDEHSSESRCCRYPLTVDFEAFGWDWI 75 domain IAPKRYKANYCSGQCEYMFMQKYPHTHLVQQ
  • GDF- 11 fastener region residues 1 10- 1 12, EYH —
  • GDF-8 fingers region 1 CRYPLTVDFEAFGWDWIIAPKRYKANYCS 79
  • GDF- 11 fingers region 1 CRYPLTVDFEAFGWDWIIAPKRYKANYCS 79
  • Some recombinant proteins of the present invention may comprise GDF-15, GDF-15 signaling pathway-related proteins and/or modules and/or portions thereof.
  • GDF-15 is a TGF- ⁇ family protein that is highly expressed in liver. Expression of GDF-15 is dramatically upregulated following liver injury (Hsiao et al. 2000. Mol Cell Biol. 20(10):3742-51.)
  • GDF-15 levels in circulation have been found to negatively correlate with hepcidin levels, suggesting a role for GDF-15 in iron load and/or metabolism (Finkenstedt et al., 2008. British Journal of Haematology. 144:789-93.) Elevated GDF-15 in the blood is also associated with ineffective and/or apoptotic erythropoiesis, such as in subjects suffering from beta- thalassemia or dyserythropoietic anemias.
  • recombinant proteins of the present invention may comprise protein modules from activin subunits.
  • Such protein modules may comprise the protein modules and/or amino acid sequences of the activin subunit inhibin beta A, listed in Table 4.
  • protein modules of the present invention may comprise amino acid sequences similar to those in Table 4, but comprise additional or fewer amino acids than those listed.
  • Some such amino acid sequences may comprise about 1 more or fewer amino acids, about 2 more or fewer amino acids, about 3 more or fewer amino acids, about 4 more or fewer amino acids, about 5 more or fewer amino acids, about 6 more or fewer amino acids, about 7 more or fewer amino acids, about 8 more or fewer amino acids, about 9 more or fewer amino acids, about 10 more or fewer amino acids or greater than 10 more or fewer amino acids on N-terminal and/or C -terminal ends.
  • Prodomains may vary in length from about 50 to about 200, from about 100 to about 400 or from about 300 to about 500 amino acids residues. In some embodiments, prodomains range from about 169 to about 433 residues. Prodomains may be unrelated in sequence and/or low in homology. Some prodomains may have similar folds and/or three dimensional structures. Prodomains of TGF- ⁇ family members may comprise latency loops. Such loops may be pro line- rich. Latency loop length may determine the ability of such loops to encircle growth factor finger regions.
  • protein modules from some TGF- ⁇ family members comprise low sequence identity with protein modules from other TGF- ⁇ family members. Such low sequence identity may indicate specialized roles for such family members with distinct protein modules.
  • GPCs Association of GPCs with extracellular proteins may strengthen prodomain-growth factor interactions.
  • extracellular proteins may include, but are not limited to LTBPs, fibrillins and/or GARP.
  • extracellular protein associations are required to keep growth factors latent in GPCs.
  • GARP expression has been shown to be required for surface expression of GPCs on the surface of cells of hematopoietic origin (Tran, D.Q. et al., GARP (LRRC32) is essential for the surface expression of latent TGF- ⁇ on platelets and activated FOXP3+ regulatory T cells. PNAS. 2009, Jun 2. 106(32): 13445-50.) GARP may act as a tether to hold GPCs in place on the surface of these cells, including, but not limited to regulatory T-cells and/or platelets.
  • recombinant proteins of the present invention may comprise bone morphogenetic proteins (BMPs), a family of TGF ⁇ -related proteins.
  • BMPs bone morphogenetic proteins
  • Protein modules comprising sequences from BMPs may comprise sequences from any of those BMP modules disclosed in Figure 8. While related to other TGF- ⁇ family member proteins, BMPs generally signal through SMADl, 5 and 8 proteins while TGF- ⁇ isoforms (e.g. TGF- ⁇ , TGF ⁇ 2 and TGF- ⁇ 3) signal through SMAD2 and SMAD3.
  • Some BMP receptors and/or co-receptors are also distinct from other TGF- ⁇ family member proteins.
  • RGM repulsive guidance molecule
  • RGM proteins act as co-receptors for BMP signaling.
  • RGMA, RGMB and RGMC also known as hemojuvelin (Hjv.)
  • Recombinant proteins of the present invention comprising one or more BMP protein module may be useful for the
  • CTCK domain-containing proteins may act antagonistically with regard to GDF/BMP signal transduction.
  • CTCK domain-containing proteins include, but are not limited to Cerberus, Connective tissue growth factor (CTGF), DAN domain family member 5 (DAND5), Gremlin- 1 (GREM1), Gremlin-2 (GREM2), Mucin- 19 (MUC19), Mucin-2 (MUC2), Mucin-5AC (MUC5AC), Mucin-5B (MUC5B), Mucin-6 (MUC6), Neuroblastoma suppressor of tumorigenicity 1 (NBL1), Norrin (NDP), Otogelin (OTOG), Otogelin-like protein (OTOGL), Protein CYR61 (CYR61), Protein NOV homolog (NOV), Sclerostin (SOST), Sclerostin domain-containing protein 1 (SOSTDC1), SCO-spondin (SSPO), Slit homolog 1 protein (SLITl), Slit homolog 2 protein (SLIT2), Slit homolog 3 protein (SLIT3), von Willebrand factor (VWF), WNTl-inducible
  • the present invention provides recombinant proteins.
  • the term "recombinant protein” refers to a protein produced by an artificial gene and/or process (e.g. genetic engineering). Such recombinant proteins may comprise one or more protein modules from one or more TGF-P-related proteins. Some recombinant proteins disclosed herein may be useful as recombinant antigens.
  • the term "recombinant antigen” refers to a recombinant protein that may be used to immunize one or more hosts for the production of antibodies directed toward one or more epitopes present on such recombinant antigens. Some recombinant antigens may be cell-based antigens.
  • cell-based antigen refers to recombinant antigens that are expressed in cells for presentation of such antigens on the cell surface. Such cells may be used to immunize hosts for the production of antibodies directed to such cell-based antigens.
  • recombinant proteins disclosed herein may be used as therapeutics.
  • Recombinant proteins disclosed herein may modulate growth factor (e.g. growth factors comprising TGF-P-related proteins) levels and/or activity (e.g. signaling) upon administration and/or introduction to one or more subjects and/or niches.
  • growth factor e.g. growth factors comprising TGF-P-related proteins
  • activity e.g. signaling
  • recombinant proteins disclosed herein may be used to assay growth factor (e.g. growth factors comprising TGF-P-related proteins) levels and/or activity (e.g. signaling). Some recombinant proteins disclosed herein may be used in the isolation of antibodies directed to TGF-P-related proteins. Recombinant proteins of the present invention may also be used as recombinant antigens in the development of stabilizing [reducing or preventing dissociation between two agents, (e.g. growth-factor release from GPCs, GPC release from one or more protein interactions)] and/or releasing [enhancing the dissociation between two agents (e.g. growth-factor release from GPCs, GPC release from one or more protein
  • Recombinant proteins of the present invention may include TGF- ⁇ family member proteins as well as components and/or protein modules thereof.
  • recombinant proteins of the present invention may comprise prodomains without associated growth factors, furin cleavage-deficient mutants, mutants deficient in extracellular protein associations and/or combinations thereof.
  • recombinant proteins may comprise detectable labels.
  • Detectable labels may be used to allow for detection and/or isolation of recombinant proteins.
  • Some detectable labels may comprise biotin labels, polyhistidine tags and/or flag tags. Such tags may be used to isolate tagged proteins.
  • Proteins produced may comprise additional amino acids encoding one or more 3C protease cleavage site. Such sites allow for cleavage at the 3C protease cleavage site upon treatment with 3C protease, including, but not limited to rhino virus 3C protease. Such cleavage sites are introduced to allow for removal of detectable labels from recombinant proteins.
  • FIG. 5 is a schematic depicting an embodiment of a recombinant GPC.
  • Recombinant proteins according to Figure 5 comprising TGF-P-family member proteins may comprise features including, but not limited to C-terminal regions of the mature growth factor, N-terminal regions of the prodomain and/or proprotein cleavage sites.
  • the proprotein cleavage site of recombinant TGF- ⁇ GPCs may, for example, comprise the furin consensus sequence RXXR wherein R is arginine and X indicates amino acid residues that may vary among TGF- ⁇ family members.
  • Furin cleavage site sequences (although not limited to cleavage by furin alone and may include cleavage by other proprotein convertase enzymes) for each TGF- ⁇ family member are indicated in Table 1.
  • Recombinant GPCs according to the embodiment depicted in Figure 5 may also comprise one or more cysteine residues within and/or near the N-terminal region of the prodomain. Such cysteine residues may be from about 1 to about 10 amino acids, from about 4 to about 15 amino acids, from about 5 to about 20 amino acids and/or from about 7 to about 50 amino acids from the N-terminus of the prodomain.
  • Recombinant GPCs may also comprise detectable labels. Such detectable labels may be useful for detection and/or isolation of recombinant GPCs.
  • Detectable labels may comprise 2 or more histidine (His) residues. Such detectable labels may also be referred to herein as polyhistidine tags.
  • Polyhistidine tags may include hexa histidine tags or HIS-TAGTM (EMD Biosciences, Darmstadt, Germany) comprising a chain of six histidine residues. Some polyhistidine tags may be present at the N-terminus of recombinant proteins disclosed herein. Some polyhistidine tags may be present at the C-terminus of recombinant proteins disclosed herein. Proteins produced may comprise additional amino acids encoding one or more 3C protease cleavage site.
  • Such sites allow for cleavage at the 3C protease cleavage site upon treatment with 3C protease, including, but not limited to rhino virus 3C protease. Some cleavage sites may be introduced to allow for removal of detectable labels from recombinant proteins.
  • recombinant GPCs may comprise mutations in one or more amino acids as compared to wild type sequences.
  • one or more regions of proteolytic processing may be mutated. Such regions may comprise proprotein convertase cleavage sites.
  • Proprotein convertase e.g. furin
  • cleavage site mutations prevent enzymatic cleavage at that site and/or prevent enzymatic cleavage of growth factors from their prodomains (see Figure 6.)
  • Some proprotein convertase cleavage sites comprising RXXR sequences may be mutated to RXG (wherein X indicates a site where amino acid residues may be variable).
  • Such mutations are herein abbreviated as "D2G” mutations and may be resistant to enzymatic cleavage.
  • furin cleavage sites comprising RXXR sequences are mutated to AXXA.
  • AXXA sequences may also be resistant to enzymatic cleavage.
  • regions of proteolytic processing by tolloid and/or tolloid-like proteins may be mutated to prevent such proteolytic processing.
  • tolloid processing regions on GDF-8 and/or GDF-11 may be mutated.
  • mutation of aspartic acid residues to alanine residues within tolloid processing regions prevents tolloid processing. Mutation of aspartic acid residue 76 (D76) of the GDF-8 (myostatin) proprotein has been shown to prevent proteolytic activation of latent GDF-8 (Wolfman, N.M. et al.,PNAS. 2003, Oct 6.
  • Asp 120 (D120, residue number counted from the translated protein, D98 from the proprotein of SEQ ID NO: 4) in GDF-11 may be mutated to prevent tolloid processing (Ge et al, 2005. Mol Cell Biol. 25(14):5846-58, the contents of which are herein incorporated by reference in their entirety.)
  • one or more amino acids may be mutated in order to form recombinant GPCs with reduced latency. Such mutations are referred to herein as "activating mutations.” These mutations may introduce one or more regions of steric clash between complex prodomains and growth factor domains.
  • steric clash when referring to the interaction between two proteins or between two domains and/or epitopes within the same protein, refers to a repulsive interaction between such proteins, domains and/or epitopes due to overlapping position in three-dimensional space.
  • Steric clash within GPCs may reduce the affinity between prodomains and growth factor domains, resulting in elevated ratios of free growth factor to latent growth factor.
  • one or more amino acids may be mutated in order to form recombinant GPCs with increased latency. Such mutations are referred to herein as "stabilizing mutations.” These mutations may increase the affinity between prodomains and growth factor domains, resulting in decreased ratios of free growth factor to latent growth factor.
  • recombinant proteins of the present invention may comprise any of the sequences listed in Table 6 or fragments thereof.
  • proTGF- ⁇ C4S LSTSKTIDMELVKRKRIEAIRGQILSKLRLASPPSQGEVPPGP 99 (LAP) LPEAVLALYNSTRDRVAGESAEPEPEADYYAKEVTRVL
  • proTGF- ⁇ D2G LSTCKTIDMELVKRKRIEAIRGQILSKLRLASPPSQGEVPPGP 100
  • proTGF- ⁇ C4S D2G LSTSKTIDMELVKRKRIEAIRGQILSKLRLASPPSQGEVPPGP 101
  • proTGF- ⁇ LAP LSTCKTIDMELVKRKRIEAIRGQILSKLRLASPPSQGEVPPGP 38
  • proTGF-p2 C5S SLSTSSTLDMDQFMRKRIEAIRGQILSKLKLTSPPEDYPEPEE 102
  • proTGF- 3 SLSLSTCTTLDFGHIKKKRVEAIRGQILSKLRLTSPPEPTVMT 3
  • activating mutations may comprise residues critical for LAP or LAP-like protein dimerization.
  • Some activating mutations may comprise TGF- ⁇ isoforms (TGF- ⁇ , TGF-P2 and/or TGF-P3).
  • Mutant GPCs with activating mutations may comprise mutations that correspond to mutations identified in Camurati-Engelmann disease (CED).
  • Subjects suffering from CED typically have genetic defects in TGF- ⁇ . Mutations identified in such subjects include, but are not limited to mutations in residues Y81, R218, H222, C223 and C225. Residues C223 and C225 are necessary for disulfide bond formation in LAP dimerization.
  • Mutations to R218, H222, C223 and/or C225 may lead to weakened or disrupted disulfide bond formation and LAP dimerization.
  • CED mutations lead to elevated release of TGF- ⁇ and/or increased TGF- ⁇ activity.
  • recombinant GPCs comprising TGF- ⁇ with CED mutations comprise sequences listed in Table 7. The amino acid substitutions indicated in these proteins reflect the residue number as counted from the start of the translated protein (before removal of the secretion signal sequence).
  • proTGF- ⁇ C223R LSTCKTIDMELVKRKRIEAIRGQILSKLRLASPPSQGEVPPGP 1 13
  • proTGF- ⁇ C225R LSTCKTIDMELVKRKRIEAIRGQILSKLRLASPPSQGEVPPGP 1 14
  • GPCs comprising CED mutations may find several uses in the context of the present invention.
  • such GPCs may be used to produce recombinant proteins comprising LAPs or LAP-like domains complexed with GARP. Coexpression of the entire GPC with GARP may be necessary in some embodiments, for proper association and folding.
  • GPCs comprising CED mutations
  • growth factors may be able to dissociate leaving the desired GARP-LAP complex.
  • Y81H mutations may be useful in this regard. Y81H mutations lead to growth factor release, but do not disrupt disulfide bonding between LAP monomers at residues C223 and C225. Therefore, GARP-LAP complexes formed through expression of Y81H GPC mutants may comprise intact LAP dimers wherein growth factors have become dissociated. In some embodiments, additional co-expression or addition of excess furin during the production process may enhance growth factor dissociation as well.
  • GPCs comprising CED mutations may be expressed to allow for the production and release of mature growth factor. Some GPC-free growth factors expressed according to this method may be used to assess antibody reactivity, for example in enzyme-linked immunosorbent assays (ELISAs.) Some GPCs comprising CED mutations may be expressed to allow for the production and release of GPC-bound growth factors. GPCs comprising CED mutations may be expressed to allow for the production and release of chimeric proteins comprising the TGF- ⁇ LAP (or protein modules or fragments thereof) expressed with one or more protein modules from other TGF- ⁇ family members. Such chimeric proteins may comprise TGF- ⁇ LAP and TGF-P2 or TGF-P3 growth factor domains.
  • Furin cleavage of recombinant proteins of the invention may in some cases occur intracellularly. In some cases furin cleavage of recombinant proteins of the invention may occur extracellularly.
  • recombinant GPCs of the present invention may comprise mutations in one or more N-terminal regions for extracellular associations.
  • N-terminal region for extracellular association refers to regions at or near protein N- termini that may be necessary for extracellular associations with one or more N-terminal regions. Such regions may comprise at least the first N-terminal residue, at least the first 5 N-terminal residues, at least the first 10 N-terminal residues, at least the first 20 amino acid residues and/or at least the first 50 amino acid residues.
  • Some mutations may comprise from about 1 amino acid residue to about 30 amino acid residues, from about 5 amino acid residues to about 40 amino acid residues and/or from about 10 amino acid residues to about 50 amino acid residues at or near protein N-termini.
  • Such regions may comprise residues for LTBP, fibrillin and/or GARP association.
  • one or more cysteine residues present within and/or near N-terminal regions for extracellular associations may be necessary for such associations.
  • cysteine residues present within and/or near N-terminal regions for extracellular associations are present within about the first 2 N-terminal residues, about the first 3 N-terminal residues, about the first 4 N-terminal residues, about the first 5 N-terminal residues, about the first 6 N-terminal residues, about the first 7 N-terminal residues and/or at least the first 30 N- terminal residues.
  • Some mutations in one or more N-terminal regions for extracellular associations comprise substitution and/or deletion of such cysteine residues. Such mutations may modulate the association of GPCs and/or prodomains with one or more extracellular proteins, including, but not limited to LTBPs, fibrillins and/or GARP.
  • These mutations may also comprise substitution of one or more cysteine with another amino acid.
  • Cysteine residue substitutions are abbreviated herein as "C#X" wherein # represents the residue number [counting from the N- terminus of the pro-protein (without the signal peptide)] of the original cysteine residue and X represents the one letter amino acid code for the amino acid that is used for substitution. Any amino acid may be used for such substitutions.
  • serine (S) residues are used to substitute cysteine residues.
  • Nonlimiting examples of such mutations may include C4S, C5S and/or C7S.
  • cysteine residues residing at amino acid position number 4 may be mutated.
  • cysteine residues residing at amino acid position number 5 may be mutated.
  • cysteine residues at position 7 may be mutated.
  • cysteine in one or more other region of GPCs may be substituted or deleted.
  • GPC modifications may promote the release of mature growth factor from prodomains.
  • cysteines may include those present in one or more of mature growth factors, alpha 2 helices, fasteners, latency lassos and/or bow-tie regions.
  • recombinant proteins of the present invention may comprise protein modules derived from one or more species, including mammals, including, but not limited to mice, rats, rabbits, pigs, monkeys and/or humans.
  • Recombinant proteins may comprise one or more amino acids from one or more amino acid sequences derived from one or more non- human protein sequences listed in Table 8.
  • recombinant proteins of the present invention may comprise such sequences with or without the native signal peptide.
  • proGDF-8 Mouse NEGSEREENVEKEGLCNACAWRQNTRYSRIEAIKIQILS 125
  • GCS proGDF-8 Mouse NEGSEREENVEKEGLCNACAWRQNTRYSRIEAIKIQILS 126 AxxA KLRLETAPNISKDAIRQLLPRAPPLRELIDQYDVQRDDSS
  • proGDF-8 Mouse NEGSEREENVEKEGLCNACAWRQNTRYSRIEAIKIQILS 127 D76A KLRLETAPNISKDAIRQLLPRAPPLRELIDQYDVQRADSS
  • proGDF-8 Mouse NEGSEREENVEKEGLCNACAWRQNTRYSRIEAIKIQILS 128 AxxA D76A KLRLETAPNISKDAIRQLLPRAPPLRELIDQYDVQRADSS
  • proGDF- 1 Mouse AEGPAAAAAAAAAGVGGERSSRPAPSAPPEPDGCPV 138 AxxA CVWRQHSRELRLESIKSQILSKLRLKEAPNISREVVKQLL
  • proGDF- 1 Mouse AEGPAAAAAAAAAGVGGERSSRPAPSAPPEPDGCPV 139 AxxA D96A CVWRQHSRELRLESIKSQILSKLRLKEAPNISREVVKQLL
  • proGDF- 1 Mouse AEGPAAAAAAAAAGVGGERSSRPAPSAPPEPDGCPV 140 D96A CVWRQHSRELRLESIKSQILSKLRLKEAPNISREVVKQLL
  • GDF-1 1 Mouse AEGPAAAAAAAAAGVGGERSSRPAPSAPPEPDGCPV 141 prodomain CVWRQHSRELRLESIKSQILSKLRLKEAPNISREVVKQLL
  • GDF-1 1 Mouse AEGPAAAAAAAAAGVGGERSSRPAPSAPPEPDGCPV 142 prodomain CVWRQHSRELRLESIKSQILSKLRLKEAPNISREVVKQLL D96A PKAPPLQQILDLHDFQGAALQPEDFLEEDEYHATTETVIS

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Immunology (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Zoology (AREA)
  • Biomedical Technology (AREA)
  • Microbiology (AREA)
  • Diabetes (AREA)
  • Oncology (AREA)
  • Wood Science & Technology (AREA)
  • General Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Epidemiology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Neurology (AREA)
  • Virology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Mycology (AREA)
  • Endocrinology (AREA)
  • Pain & Pain Management (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Rheumatology (AREA)
PCT/US2014/036933 2013-05-06 2014-05-06 Compositions and methods for growth factor modulation Ceased WO2014182676A2 (en)

Priority Applications (38)

Application Number Priority Date Filing Date Title
AU2014262843A AU2014262843B2 (en) 2013-05-06 2014-05-06 Compositions and methods for growth factor modulation
SM20210008T SMT202100008T1 (it) 2013-05-06 2014-05-06 Composizioni e metodi per la modulazione di fattore di crescita
ES14795041T ES2837042T3 (es) 2013-05-06 2014-05-06 Composiciones y métodos para la modulación del factor de crecimiento
EP20193425.4A EP3816625B1 (en) 2013-05-06 2014-05-06 Compositions and methods for growth factor modulation
SG11201508681QA SG11201508681QA (en) 2013-05-06 2014-05-06 Compositions and methods for growth factor modulation
EP14795041.4A EP2981822B1 (en) 2013-05-06 2014-05-06 Compositions and methods for growth factor modulation
PL14795041T PL2981822T4 (pl) 2013-05-06 2014-05-06 Kompozycje i sposoby modulacji czynnika wzrostu
SI201431717T SI2981822T1 (sl) 2013-05-06 2014-05-06 Sestavki in postopki za modulacijo rastnega dejavnika
JP2016513010A JP2016521283A (ja) 2013-05-06 2014-05-06 成長因子モジュレーションのための組成物および方法
HRP20201914TT HRP20201914T1 (hr) 2013-05-06 2014-05-06 Sastavi i postupci za modulaciju faktora rasta
LTEP14795041.4T LT2981822T (lt) 2013-05-06 2014-05-06 Kompozicijos ir būdai, skirti augimo faktoriaus moduliacijai
DK14795041.4T DK2981822T3 (da) 2013-05-06 2014-05-06 Sammensætninger og fremgangsmåder til vækstfaktormodulation
IL319092A IL319092A (en) 2013-05-06 2014-05-06 Compositions and methods for growth factor modulation
EP25202206.6A EP4674866A3 (en) 2013-05-06 2014-05-06 Compositions and methods for growth factor modulation
CA2911514A CA2911514A1 (en) 2013-05-06 2014-05-06 Compositions and methods for growth factor modulation
RS20201467A RS61778B1 (sr) 2013-05-06 2014-05-06 Kompozicije i postupci za modulaciju faktora rasta
IL301607A IL301607B2 (en) 2013-05-06 2014-05-06 Compositions and methods for growth factor modulation
US14/795,022 US9580500B2 (en) 2013-05-06 2015-07-09 Compositions and methods for growth factor modulation
US14/795,012 US9758576B2 (en) 2013-05-06 2015-07-09 Compositions and methods for growth factor modulation
US14/795,007 US9573995B2 (en) 2013-05-06 2015-07-09 Compositions and methods for growth factor modulation
US14/795,033 US9399676B2 (en) 2013-05-06 2015-07-09 Compositions and methods for growth factor modulation
IL242193A IL242193B (en) 2013-05-06 2015-10-21 Preparations and methods for growth factor modulation
US15/187,278 US9758577B2 (en) 2013-05-06 2016-06-20 Compositions and methods for growth factor modulation
US15/401,386 US20170210798A1 (en) 2013-05-06 2017-01-09 Compositions and methods for growth factor modulation
US15/404,663 US10597443B2 (en) 2013-05-06 2017-01-12 Compositions and methods for growth factor modulation
AU2017203611A AU2017203611C1 (en) 2013-05-06 2017-05-30 Compositions and methods for growth factor modulation
US15/659,974 US20180016332A1 (en) 2013-05-06 2017-07-26 Compositions and methods for growth factor modulation
US15/671,217 US20180022798A1 (en) 2013-05-06 2017-08-08 Compositions and methods for growth factor modulation
US16/209,078 US10981981B2 (en) 2013-05-06 2018-12-04 Compositions and methods for growth factor modulation
AU2019203834A AU2019203834A1 (en) 2013-05-06 2019-05-31 Compositions and methods for growth factor modulation
US16/736,207 US12577296B2 (en) 2013-05-06 2020-01-07 Compositions and methods for growth factor modulation
CY20201101140T CY1123907T1 (el) 2013-05-06 2020-12-02 Συνθεσεις και μεθοδοι για ρυθμιση αυξητικων παραγοντων
US17/196,256 US11827698B2 (en) 2013-05-06 2021-03-09 Compositions and methods for growth factor modulation
IL281549A IL281549B2 (en) 2013-05-06 2021-03-16 Preparations and methods for growth factor modulation
AU2021204415A AU2021204415B2 (en) 2013-05-06 2021-06-28 Compositions and methods for growth factor modulation
US18/488,265 US12454570B2 (en) 2013-05-06 2023-10-17 Compositions and methods for growth factor modulation
AU2025201228A AU2025201228A1 (en) 2013-05-06 2025-02-21 Compositions and methods for growth factor modulation
US19/335,639 US20260109757A1 (en) 2013-05-06 2025-09-22 Compositions and methods for growth factor modulation

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US201361819840P 2013-05-06 2013-05-06
US61/819,840 2013-05-06
US201361823552P 2013-05-15 2013-05-15
US61/823,552 2013-05-15
US201361900438P 2013-11-06 2013-11-06
US61/900,438 2013-11-06

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US201361819840P Continuation 2013-05-06 2013-05-06

Related Child Applications (4)

Application Number Title Priority Date Filing Date
US14/795,022 Continuation US9580500B2 (en) 2013-05-06 2015-07-09 Compositions and methods for growth factor modulation
US14/795,033 Continuation US9399676B2 (en) 2013-05-06 2015-07-09 Compositions and methods for growth factor modulation
US14/795,007 Continuation US9573995B2 (en) 2013-05-06 2015-07-09 Compositions and methods for growth factor modulation
US14/795,012 Continuation US9758576B2 (en) 2013-05-06 2015-07-09 Compositions and methods for growth factor modulation

Publications (2)

Publication Number Publication Date
WO2014182676A2 true WO2014182676A2 (en) 2014-11-13
WO2014182676A3 WO2014182676A3 (en) 2015-02-05

Family

ID=51867850

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2014/036933 Ceased WO2014182676A2 (en) 2013-05-06 2014-05-06 Compositions and methods for growth factor modulation

Country Status (19)

Country Link
US (14) US9580500B2 (https=)
EP (3) EP4674866A3 (https=)
JP (6) JP2016521283A (https=)
AU (5) AU2014262843B2 (https=)
CA (1) CA2911514A1 (https=)
CY (1) CY1123907T1 (https=)
DK (1) DK2981822T3 (https=)
ES (2) ES2837042T3 (https=)
HR (2) HRP20251426T1 (https=)
HU (1) HUE052232T2 (https=)
IL (4) IL319092A (https=)
LT (1) LT2981822T (https=)
PL (2) PL2981822T4 (https=)
PT (1) PT2981822T (https=)
RS (1) RS61778B1 (https=)
SG (3) SG10201800800YA (https=)
SI (1) SI2981822T1 (https=)
SM (1) SMT202100008T1 (https=)
WO (1) WO2014182676A2 (https=)

Cited By (61)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015015003A1 (en) 2013-08-01 2015-02-05 Université Catholique de Louvain Anti-garp protein and uses thereof
WO2016073879A3 (en) * 2014-11-06 2016-06-23 Scholar Rock, Inc. Transforming growth factor-related antibodies and uses thereof
WO2016098357A1 (en) 2014-12-19 2016-06-23 Chugai Seiyaku Kabushiki Kaisha Anti-myostatin antibodies, polypeptides containing variant fc regions, and methods of use
US9399676B2 (en) 2013-05-06 2016-07-26 Scholar Rock, Inc. Compositions and methods for growth factor modulation
WO2016125017A1 (en) * 2015-02-03 2016-08-11 Universite Catholique De Louvain Anti-garp protein and uses thereof
WO2016186575A1 (en) * 2015-05-15 2016-11-24 Agency For Science, Technology And Research Native protein purification technology
WO2017015622A3 (en) * 2015-07-22 2017-03-02 Scholar Rock, Inc Gdf11 binding proteins and uses thereof
WO2017046229A1 (en) * 2015-09-17 2017-03-23 Histide Ag Pharmaceutical association of growth factor receptor agonist and adhesion protein inhibitor for converting a neoplastic cell into a non-neoplastic cell and uses thereof
WO2017049011A1 (en) * 2015-09-15 2017-03-23 Scholar Rock, Inc. Anti-pro/latent-myostatin antibodies and uses thereof
WO2017088027A1 (en) * 2015-11-26 2017-06-01 Prince Henry's Institute Of Medical Research Trading As The Hudson Institute Of Medical Research Inhibin analogs
WO2017046227A3 (en) * 2015-09-17 2017-06-29 Histide Ag Pharmaceutical association of growth factor receptor agonist and adhesion protein inhibitor for converting a neoplastic cell into a non-neoplastic cell and uses thereof
WO2017046226A3 (en) * 2015-09-17 2017-06-29 Histide Ag Pharmaceutical association for converting a neoplastic cell into a non-neoplastic cell and uses thereof
WO2017046228A3 (en) * 2015-09-17 2017-06-29 Histide Ag Pharmaceutical association of growth factor receptor agonist and adhesion protein inhibitor for converting a neoplastic cell into a non-neoplastic cell and uses thereof
WO2017120523A3 (en) * 2016-01-08 2017-08-17 Scholar Rock, Inc. Anti-pro/latent myostatin antibodies and methods of use thereof
WO2017156500A1 (en) * 2016-03-11 2017-09-14 Scholar Rock, Inc. Tgfb1-binding immunoglobulins and use thereof
US9828429B2 (en) 2007-09-26 2017-11-28 Chugai Seiyaku Kabushiki Kaisha Method of modifying isoelectric point of antibody via amino acid substitution in CDR
US9868948B2 (en) 2008-04-11 2018-01-16 Chugai Seiyaku Kabushiki Kaisha Antigen-binding molecule capable of binding to two or more antigen molecules repeatedly
US9969800B2 (en) 2015-02-05 2018-05-15 Chugai Seiyaku Kabushiki Kaisha IL-8 antibodies
WO2018112362A1 (en) * 2016-12-16 2018-06-21 Biogen Ma Inc. Stabilized proteolytically activated growth differentiation factor 11
US10017567B2 (en) 2015-01-14 2018-07-10 The Brigham And Women's Hospital, Inc. Treatment of cancer with anti-LAP monoclonal antibodies
WO2018129329A1 (en) * 2017-01-06 2018-07-12 Scholar Rock, Inc. ISOFORM-SPECIFIC, CONTEXT-PERMISSIVE TGFβ1 INHIBITORS AND USE THEREOF
WO2018129395A1 (en) 2017-01-06 2018-07-12 Scholar Rock, Inc. Methods for treating metabolic diseases by inhibiting myostatin activation
WO2018208888A1 (en) 2017-05-09 2018-11-15 Scholar Rock, Inc. Lrrc33 inhibitors and use thereof
EP3366306A3 (en) * 2016-12-23 2018-11-28 Istanbul Universitesi Rektorlugu Use of some peptides in diagnosis and treatment of diabetes, obesity and metabolic diseases associated thereto
WO2019023661A1 (en) * 2017-07-28 2019-01-31 Scholar Rock, Inc. SPECIFIC INHIBITORS OF TGF-BETA 1 LTBP COMPLEX AND USES THEREOF
KR20190034560A (ko) * 2016-07-14 2019-04-02 스칼러 락, 인크. TGFβ 항체, 방법 및 용도
US10307480B2 (en) 2014-11-06 2019-06-04 Scholar Rock, Inc. Anti-pro/latent-myostatin antibodies and uses thereof
EP3390443A4 (en) * 2015-12-18 2019-11-13 Chugai Seiyaku Kabushiki Kaisha ANTI-MYOSTATIN ANTIBODIES, POLYPEPTIDES WITH DEVIANT FC REGIONS AND METHOD OF USE
US10479829B2 (en) 2017-05-11 2019-11-19 Argenx Bvba GARP-TGF-beta 1 antibodies
WO2020014460A1 (en) 2018-07-11 2020-01-16 Scholar Rock, Inc. HIGH-AFFINITY, ISOFORM-SELECTIVE TGFβ1 INHIBITORS AND USE THEREOF
WO2020014473A1 (en) 2018-07-11 2020-01-16 Scholar Rock, Inc. TGFβ1 INHIBITORS AND USE THEREOF
US10588980B2 (en) 2014-06-23 2020-03-17 Novartis Ag Fatty acids and their use in conjugation to biomolecules
EP3532494A4 (en) * 2016-10-26 2020-06-03 The Children's Medical Center Corporation METHOD AND COMPOSITIONS FOR MODULATING TRANSFORMATION GROWTH FACTOR BETA-REGULATED FUNCTIONS
EP3677278A1 (en) 2018-07-11 2020-07-08 Scholar Rock, Inc. Isoform selective tgfbeta1 inhibitors and use thereof
EP3689905A2 (en) 2019-01-30 2020-08-05 Scholar Rock, Inc. Ltbp complex-specific inhibitors of tgf-beta and uses thereof
US10844115B2 (en) 2017-01-20 2020-11-24 Genzyme Corporation Bone-targeting antibodies
WO2020245264A1 (en) * 2019-06-05 2020-12-10 Io Biotech Aps Tgf-beta vaccine
US10919953B2 (en) 2012-08-24 2021-02-16 Chugai Seiyaku Kabushiki Kaisha FcgammaRIIB-specific Fc region variant
US10946036B2 (en) 2016-06-13 2021-03-16 Scholar Rock, Inc. Use of myostatin inhibitors and combination therapies
US11046784B2 (en) 2006-03-31 2021-06-29 Chugai Seiyaku Kabushiki Kaisha Methods for controlling blood pharmacokinetics of antibodies
US11053308B2 (en) 2016-08-05 2021-07-06 Chugai Seiyaku Kabushiki Kaisha Method for treating IL-8-related diseases
WO2021142448A2 (en) 2020-01-11 2021-07-15 Scholar Rock,Inc. Tgf-beta inhibitors and use thereof
WO2021142427A1 (en) 2020-01-11 2021-07-15 Scholar Rock, Inc. TGFβ INHIBITORS AND USE THEREOF
US11130802B2 (en) 2018-10-10 2021-09-28 Tilos Therapeutics, Inc. Anti-lap antibody variants
US11155611B2 (en) 2017-01-06 2021-10-26 Scholar Rock, Inc. Compositions and methods for making and using anti-myostatin antibodies
WO2021231732A1 (en) 2020-05-15 2021-11-18 Bristol-Myers Squibb Company Antibodies to garp
US11230601B2 (en) 2017-10-10 2022-01-25 Tilos Therapeutics, Inc. Methods of using anti-lap antibodies
US11236168B2 (en) 2012-08-24 2022-02-01 Chugai Seiyaku Kabushiki Kaisha Mouse FcγammaRII-specific Fc antibody
US11267868B2 (en) 2013-04-02 2022-03-08 Chugai Seiyaku Kabushiki Kaisha Fc region variant
US11312767B2 (en) 2019-08-28 2022-04-26 Chugai Seiyaku Kabushiki Kaisha Cross-species anti-latent TGF-beta 1 antibodies
US11359009B2 (en) 2015-12-25 2022-06-14 Chugai Seiyaku Kabushiki Kaisha Anti-myostatin antibodies and methods of use
WO2022204581A2 (en) 2021-03-26 2022-09-29 Scholar Rock, Inc. Tgf-beta inhibitors and use thereof
WO2022256723A2 (en) 2021-06-03 2022-12-08 Scholar Rock, Inc. Tgf-beta inhibitors and therapeutic use thereof
WO2022271867A1 (en) 2021-06-23 2022-12-29 Scholar Rock, Inc. A myostatin pathway inhibitor in combination with a glp-1 pathway activator for use in treating metabolic disorders
WO2023288277A1 (en) 2021-07-14 2023-01-19 Scholar Rock, Inc. Ltbp complex-specific inhibitors of tgfb1 and uses thereof
US11578110B2 (en) 2015-08-25 2023-02-14 Histide Ag Compounds for inducing tissue formation and uses thereof
WO2023170241A1 (en) * 2022-03-09 2023-09-14 Universite Catholique De Louvain TGF-β ANTIBODIES
US11891434B2 (en) 2010-11-30 2024-02-06 Chugai Seiyaku Kabushiki Kaisha Antigen-binding molecule capable of binding to plurality of antigen molecules repeatedly
US12049496B2 (en) 2017-01-20 2024-07-30 Sanofi Anti-TGF-beta antibodies and their use
US12338279B2 (en) 2022-12-22 2025-06-24 Scholar Rock, Inc. Selective and potent inhibitory antibodies of myostatin activation
TWI923549B (zh) 2019-01-30 2026-05-01 美商供石公司 TGFβ之LTBP複合物專一性抑制劑及其用途

Families Citing this family (57)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8755053B2 (en) 2005-10-14 2014-06-17 Applied Research Associates Nz Limited Method of monitoring a surface feature and apparatus therefor
US9179844B2 (en) 2011-11-28 2015-11-10 Aranz Healthcare Limited Handheld skin measuring or monitoring device
US10967298B2 (en) 2012-03-15 2021-04-06 Flodesign Sonics, Inc. Driver and control for variable impedence load
US9752113B2 (en) 2012-03-15 2017-09-05 Flodesign Sonics, Inc. Acoustic perfusion devices
US9458450B2 (en) 2012-03-15 2016-10-04 Flodesign Sonics, Inc. Acoustophoretic separation technology using multi-dimensional standing waves
US9950282B2 (en) 2012-03-15 2018-04-24 Flodesign Sonics, Inc. Electronic configuration and control for acoustic standing wave generation
US9745548B2 (en) 2012-03-15 2017-08-29 Flodesign Sonics, Inc. Acoustic perfusion devices
US10689609B2 (en) 2012-03-15 2020-06-23 Flodesign Sonics, Inc. Acoustic bioreactor processes
US10704021B2 (en) 2012-03-15 2020-07-07 Flodesign Sonics, Inc. Acoustic perfusion devices
US10322949B2 (en) 2012-03-15 2019-06-18 Flodesign Sonics, Inc. Transducer and reflector configurations for an acoustophoretic device
US10737953B2 (en) 2012-04-20 2020-08-11 Flodesign Sonics, Inc. Acoustophoretic method for use in bioreactors
US9745569B2 (en) 2013-09-13 2017-08-29 Flodesign Sonics, Inc. System for generating high concentration factors for low cell density suspensions
WO2015105955A1 (en) 2014-01-08 2015-07-16 Flodesign Sonics, Inc. Acoustophoresis device with dual acoustophoretic chamber
WO2015138385A1 (en) * 2014-03-10 2015-09-17 H. Lee Moffitt Cancer Center And Research Institute, Inc. Radiologically identifed tumor habitats
US9744483B2 (en) 2014-07-02 2017-08-29 Flodesign Sonics, Inc. Large scale acoustic separation device
CA2962859A1 (en) * 2014-09-30 2016-04-07 Universiteit Gent A method of treating joint disease
TW201628649A (zh) 2014-10-09 2016-08-16 再生元醫藥公司 減少醫藥調配物中微可見顆粒之方法
US10603359B2 (en) * 2014-10-30 2020-03-31 Acceleron Pharma Inc. Methods and compositions using GDF15 polypeptides for increasing red blood cells
US11708572B2 (en) 2015-04-29 2023-07-25 Flodesign Sonics, Inc. Acoustic cell separation techniques and processes
US11021699B2 (en) 2015-04-29 2021-06-01 FioDesign Sonics, Inc. Separation using angled acoustic waves
US11377651B2 (en) 2016-10-19 2022-07-05 Flodesign Sonics, Inc. Cell therapy processes utilizing acoustophoresis
US11474085B2 (en) 2015-07-28 2022-10-18 Flodesign Sonics, Inc. Expanded bed affinity selection
US11459540B2 (en) 2015-07-28 2022-10-04 Flodesign Sonics, Inc. Expanded bed affinity selection
US11046782B2 (en) 2016-03-30 2021-06-29 Musc Foundation For Research Development Methods for treatment and diagnosis of cancer by targeting glycoprotein A repetitions predominant (GARP) and for providing effective immunotherapy alone or in combination
US10013527B2 (en) 2016-05-02 2018-07-03 Aranz Healthcare Limited Automatically assessing an anatomical surface feature and securely managing information related to the same
US11085035B2 (en) 2016-05-03 2021-08-10 Flodesign Sonics, Inc. Therapeutic cell washing, concentration, and separation utilizing acoustophoresis
US11214789B2 (en) 2016-05-03 2022-01-04 Flodesign Sonics, Inc. Concentration and washing of particles with acoustics
KR102369014B1 (ko) 2016-08-16 2022-03-02 리제너론 파아마슈티컬스, 인크. 혼합물로부터 개별 항체들을 정량하는 방법
EP3516063A4 (en) * 2016-09-20 2020-05-13 University of Pittsburgh- Of the Commonwealth System of Higher Education USE OF PROTEIN-BASED MEDICINES WITH AN ANCHOR DOMAIN FOR USE ON THE EYE SURFACE
CA3041517A1 (en) 2016-10-19 2018-04-26 Flodesign Sonics, Inc. Affinity cell extraction by acoustics
EA201990986A1 (ru) 2016-10-25 2019-09-30 Ридженерон Фармасьютикалз, Инк. Способы и системы анализа хроматографических данных
CN110430890B (zh) 2016-11-10 2024-09-10 科乐斯疗法公司 激活素受体iia型变体及其使用方法
US11116407B2 (en) 2016-11-17 2021-09-14 Aranz Healthcare Limited Anatomical surface assessment methods, devices and systems
US10900786B2 (en) 2017-03-31 2021-01-26 International Business Machines Corporation Refining an ecological niche model
US11903723B2 (en) 2017-04-04 2024-02-20 Aranz Healthcare Limited Anatomical surface assessment methods, devices and systems
US20210087240A1 (en) * 2017-07-19 2021-03-25 Musc Foundation For Research Development Blocking garp cleavage and methods of use thereof
AU2018306149B2 (en) * 2017-07-26 2021-09-16 Ftf Pharma Private Limited Liquid dosage forms of imatinib
WO2019060062A1 (en) 2017-09-19 2019-03-28 Regeneron Pharmaceuticals Inc. METHODS OF REDUCING PARTICLE FORMATION AND COMPOSITIONS FORMED THEREFROM
EP3706777B1 (en) 2017-11-09 2024-05-22 Keros Therapeutics, Inc. Activin receptor type iia variants and methods of use thereof
WO2019118921A1 (en) 2017-12-14 2019-06-20 Flodesign Sonics, Inc. Acoustic transducer drive and controller
IL320014A (en) 2018-01-12 2025-06-01 Keros Therapeutics Inc Activin receptor type iib variants and methods of use thereof
WO2019173829A1 (en) * 2018-03-09 2019-09-12 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Delivering biological drugs to tissues
JP7405772B2 (ja) 2018-05-09 2023-12-26 ケロス セラピューティクス インコーポレイテッド アクチビンｉｉａ型受容体変異体および同変異体を含む医薬組成物
TWI853823B (zh) 2018-07-02 2024-09-01 美商里珍納龍藥品有限公司 自混合物製備多肽之系統及方法
EA202192422A1 (ru) 2019-03-05 2021-12-09 Ридженерон Фармасьютикалз, Инк. Человеческий сывороточный альбумин в составах
WO2020234653A1 (en) 2019-05-20 2020-11-26 Aranz Healthcare Limited Automated or partially automated anatomical surface assessment methods, devices and systems
JP7350242B2 (ja) * 2019-07-19 2023-09-26 国立研究開発法人理化学研究所 ヒトＴＧＦ－βのＬＡＰ断片に対する抗体及びその利用
CN114761013A (zh) * 2019-09-27 2022-07-15 迪斯克医药公司 治疗骨髓纤维化和相关病症的方法
US20220372136A1 (en) * 2019-09-27 2022-11-24 Disc Medicine, Inc. Methods for treating anemia of chronic disease
CN111072764A (zh) * 2019-12-13 2020-04-28 东莞市东阳光生物药研发有限公司 一种重组人Activin A的制备方法
US11801304B2 (en) 2020-02-19 2023-10-31 Nammi Therapeutics, Inc. Formulated and/or co-formulated liposome compositions containing TFGB antagonist prodrugs useful in the treatment of cancer and methods thereof
WO2021189006A1 (en) * 2020-03-20 2021-09-23 Keros Therapeutics, Inc. Methods of using activin receptor type iia variants
IL296394A (en) 2020-03-20 2022-11-01 Keros Therapeutics Inc Type ii activin receptor chimeras and methods of using them
WO2021189010A1 (en) 2020-03-20 2021-09-23 Keros Therapeutics, Inc. Methods of using activin receptor type iib variants
WO2021231798A1 (en) 2020-05-13 2021-11-18 Disc Medicine, Inc. Anti-hemojuvelin (hjv) antibodies for treating myelofibrosis
WO2023206188A1 (en) * 2022-04-28 2023-11-02 Wenzhou Prarucom Bio-Chemical Technology Co. Method for alleviating pulmonary fibrosis using epidermal growth factor
WO2025049960A1 (en) * 2023-08-30 2025-03-06 University Of Cincinnati Enhancing the production of anti-mullerian hormone through modification of its prodomain

Citations (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4179337A (en) 1973-07-20 1979-12-18 Davis Frank F Non-immunogenic polypeptides
US4301144A (en) 1979-07-11 1981-11-17 Ajinomoto Company, Incorporated Blood substitute containing modified hemoglobin
US4485045A (en) 1981-07-06 1984-11-27 Research Corporation Synthetic phosphatidyl cholines useful in forming liposomes
US4496689A (en) 1983-12-27 1985-01-29 Miles Laboratories, Inc. Covalently attached complex of alpha-1-proteinase inhibitor with a water soluble polymer
US4544545A (en) 1983-06-20 1985-10-01 Trustees University Of Massachusetts Liposomes containing modified cholesterol for organ targeting
US4640835A (en) 1981-10-30 1987-02-03 Nippon Chemiphar Company, Ltd. Plasminogen activator derivatives
US4670417A (en) 1985-06-19 1987-06-02 Ajinomoto Co., Inc. Hemoglobin combined with a poly(alkylene oxide)
US4791192A (en) 1986-06-26 1988-12-13 Takeda Chemical Industries, Ltd. Chemically modified protein with polyethyleneglycol
EP0404097A2 (de) 1989-06-22 1990-12-27 BEHRINGWERKE Aktiengesellschaft Bispezifische und oligospezifische, mono- und oligovalente Rezeptoren, ihre Herstellung und Verwendung
US5013556A (en) 1989-10-20 1991-05-07 Liposome Technology, Inc. Liposomes with enhanced circulation time
US5024947A (en) 1987-07-24 1991-06-18 Cetus Corporation Serum free media for the growth on insect cells and expression of products thereby
US5116964A (en) 1989-02-23 1992-05-26 Genentech, Inc. Hybrid immunoglobulins
US5208020A (en) 1989-10-25 1993-05-04 Immunogen Inc. Cytotoxic agents comprising maytansinoids and their therapeutic use
WO1993011161A1 (en) 1991-11-25 1993-06-10 Enzon, Inc. Multivalent antigen-binding proteins
JPH05336990A (ja) 1992-02-19 1993-12-21 Kyowa Hakko Kogyo Co Ltd 抗ＴＧＦ−βマスキングプロテインモノクローナル抗体
US5475092A (en) 1992-03-25 1995-12-12 Immunogen Inc. Cell binding agent conjugates of analogues and derivatives of CC-1065
US5541087A (en) 1994-09-14 1996-07-30 Fuji Immunopharmaceuticals Corporation Expression and export technology of proteins as immunofusins
US6348584B1 (en) 1996-10-17 2002-02-19 John Edward Hodgson Fibronectin binding protein compounds
US6492497B1 (en) 1999-04-30 2002-12-10 Cambridge Antibody Technology Limited Specific binding members for TGFbeta1
US6673901B2 (en) 1997-06-12 2004-01-06 Research Corporation Technologies, Inc. Artificial antibody polypeptides
US7572599B2 (en) 2002-09-16 2009-08-11 The Johns Hopkins University School Of Medicine Metalloprotease activation of myostatin, and methods of modulating myostatin activity
US20100009424A1 (en) 2008-07-14 2010-01-14 Natasha Forde Sonoporation systems and methods
US7723486B2 (en) 2005-02-08 2010-05-25 Optein, Inc. Antibodies to TGF-β
US20100196983A1 (en) 2009-02-05 2010-08-05 Ut-Battelle, Llc Transformation of gram positive bacteria by sonoporation
US20110053221A1 (en) 2008-03-14 2011-03-03 Humanzyme Limited Recombinant production of authentic human proteins using human cell expression systems
WO2011034935A2 (en) 2009-09-16 2011-03-24 Switchgear Genomics Transcription biomarkers of biological responses and methods
US20110135570A1 (en) 2006-03-23 2011-06-09 Mary Jo Janatpour Anti-Tumor Cell Antigen Antibody Therapeutics
WO2011102483A1 (ja) 2010-02-19 2011-08-25 独立行政法人理化学研究所 ヒトTGF-βのLAPに結合する抗体
WO2011151432A1 (en) 2010-06-03 2011-12-08 Glaxo Group Limited Humanised antigen binding proteins to myostatin6
US8415459B2 (en) 2007-11-01 2013-04-09 Pfizer Inc. Antibody to GDF8 and uses thereof
US20130122007A1 (en) 2011-11-14 2013-05-16 Regeneron Pharmaceuticals, Inc. Compositions and Methods for Increasing Muscle Mass and Muscle Strength by Specifically Antagonizing GDF8 and or Activin A
US8637637B2 (en) 2010-01-12 2014-01-28 Bill Nai-Chau Sun Fc fusion proteins of human growth hormone
WO2014074532A2 (en) 2012-11-06 2014-05-15 Scholar Rock Inc. Compositions and methods for modulating cell signaling

Family Cites Families (168)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4444887A (en) 1979-12-10 1984-04-24 Sloan-Kettering Institute Process for making human antibody producing B-lymphocytes
US4714681A (en) 1981-07-01 1987-12-22 The Board Of Reagents, The University Of Texas System Cancer Center Quadroma cells and trioma cells and methods for the production of same
US4474893A (en) 1981-07-01 1984-10-02 The University of Texas System Cancer Center Recombinant monoclonal antibodies
US4716111A (en) 1982-08-11 1987-12-29 Trustees Of Boston University Process for producing human antibodies
GB8308235D0 (en) 1983-03-25 1983-05-05 Celltech Ltd Polypeptides
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US5807715A (en) 1984-08-27 1998-09-15 The Board Of Trustees Of The Leland Stanford Junior University Methods and transformed mammalian lymphocyte cells for producing functional antigen-binding protein including chimeric immunoglobulin
US5262319A (en) 1985-04-19 1993-11-16 Oncogene Science, Inc. Method for obtaining bone marrow free of tumor cells using transforming growth factor β3
GB8607679D0 (en) 1986-03-27 1986-04-30 Winter G P Recombinant dna product
US5225539A (en) 1986-03-27 1993-07-06 Medical Research Council Recombinant altered antibodies and methods of making altered antibodies
US4946778A (en) 1987-09-21 1990-08-07 Genex Corporation Single polypeptide chain binding molecules
US5001225A (en) 1986-12-08 1991-03-19 Georgetown University Monoclonal antibodies to a pan-malarial antigen
US5258498A (en) 1987-05-21 1993-11-02 Creative Biomolecules, Inc. Polypeptide linkers for production of biosynthetic proteins
US5091513A (en) 1987-05-21 1992-02-25 Creative Biomolecules, Inc. Biosynthetic antibody binding sites
US5266683A (en) 1988-04-08 1993-11-30 Stryker Corporation Osteogenic proteins
US4925648A (en) 1988-07-29 1990-05-15 Immunomedics, Inc. Detection and treatment of infectious and inflammatory lesions
US5601819A (en) 1988-08-11 1997-02-11 The General Hospital Corporation Bispecific antibodies for selective immune regulation and for selective immune cell binding
US5223409A (en) 1988-09-02 1993-06-29 Protein Engineering Corp. Directed evolution of novel binding proteins
EP0436597B1 (en) 1988-09-02 1997-04-02 Protein Engineering Corporation Generation and selection of recombinant varied binding proteins
US5530101A (en) 1988-12-28 1996-06-25 Protein Design Labs, Inc. Humanized immunoglobulins
ES2096590T3 (es) 1989-06-29 1997-03-16 Medarex Inc Reactivos biespecificos para la terapia del sida.
US5413923A (en) 1989-07-25 1995-05-09 Cell Genesys, Inc. Homologous recombination for universal donor cells and chimeric mammalian hosts
JPH03180192A (ja) * 1989-12-07 1991-08-06 Kirin Brewery Co Ltd 遺伝子組換えによるヒトプロＴＧＦ―β１の製造
GB8928874D0 (en) 1989-12-21 1990-02-28 Celltech Ltd Humanised antibodies
WO1991010737A1 (en) 1990-01-11 1991-07-25 Molecular Affinities Corporation Production of antibodies using gene libraries
US5780225A (en) 1990-01-12 1998-07-14 Stratagene Method for generating libaries of antibody genes comprising amplification of diverse antibody DNAs and methods for using these libraries for the production of diverse antigen combining molecules
EP1690934A3 (en) 1990-01-12 2008-07-30 Abgenix, Inc. Generation of xenogeneic antibodies
US6075181A (en) 1990-01-12 2000-06-13 Abgenix, Inc. Human antibodies derived from immunized xenomice
US5427908A (en) 1990-05-01 1995-06-27 Affymax Technologies N.V. Recombinant library screening methods
GB9015198D0 (en) 1990-07-10 1990-08-29 Brien Caroline J O Binding substance
US5625126A (en) 1990-08-29 1997-04-29 Genpharm International, Inc. Transgenic non-human animals for producing heterologous antibodies
US5633425A (en) 1990-08-29 1997-05-27 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
US5545806A (en) 1990-08-29 1996-08-13 Genpharm International, Inc. Ransgenic non-human animals for producing heterologous antibodies
US5814318A (en) 1990-08-29 1998-09-29 Genpharm International Inc. Transgenic non-human animals for producing heterologous antibodies
ATE300615T1 (de) 1990-08-29 2005-08-15 Genpharm Int Transgene mäuse fähig zur produktion heterologer antikörper
US5661016A (en) 1990-08-29 1997-08-26 Genpharm International Inc. Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
US5698426A (en) 1990-09-28 1997-12-16 Ixsys, Incorporated Surface expression libraries of heteromeric receptors
AU667460B2 (en) 1990-10-05 1996-03-28 Medarex, Inc. Targeted immunostimulation with bispecific reagents
EP0557300B1 (en) 1990-10-29 1997-11-19 Chiron Corporation Bispecific antibodies, method of production, and uses thereof
CA2405246A1 (en) 1990-12-03 1992-06-11 Genentech, Inc. Enrichment method for variant proteins with alterred binding properties
DE69209734T2 (de) 1991-01-30 1996-08-08 Ihara Chemical Ind Co Dithiocarbaminsäure salze, verfahren zur herstellung und verfahren zur herstellung von isothiocyanaten aus diesen salzen
DK0580737T3 (da) 1991-04-10 2004-11-01 Scripps Research Inst Heterodimere receptorbiblioteker ved anvendelse af phagemider
IE921342A1 (en) 1991-04-26 1992-11-04 Surface Active Ltd Novel antibodies, and methods for their use
EP0519596B1 (en) 1991-05-17 2005-02-23 Merck & Co. Inc. A method for reducing the immunogenicity of antibody variable domains
ES2136092T3 (es) 1991-09-23 1999-11-16 Medical Res Council Procedimientos para la produccion de anticuerpos humanizados.
US5932448A (en) 1991-11-29 1999-08-03 Protein Design Labs., Inc. Bispecific antibody heterodimers
ES2341666T3 (es) 1991-12-02 2010-06-24 Medimmune Limited Produccion de autoanticuerpos de repertorios de segmentos de anticue rpos expresados en la superficie de fagos.
EP1306095A3 (en) 1992-03-05 2003-06-25 Board Of Regents, The University Of Texas System Methods and compositions for targeting the vasculature of solid tumors
US5733743A (en) 1992-03-24 1998-03-31 Cambridge Antibody Technology Limited Methods for producing members of specific binding pairs
US5639641A (en) 1992-09-09 1997-06-17 Immunogen Inc. Resurfacing of rodent antibodies
AU5587094A (en) 1992-10-26 1994-05-24 Kirin Brewery Company, Limited Method for producing large latent transforming growth factor-beta complexes and large latency associated peptide
US5951983A (en) 1993-03-05 1999-09-14 Universite Catholique De Louvain Methods of inhibiting T cell mediated immune responses with humanized LO-CD2A-specific antibodies
US5994618A (en) 1997-02-05 1999-11-30 Johns Hopkins University School Of Medicine Growth differentiation factor-8 transgenic mice
DK0690873T3 (da) 1993-03-19 2003-09-29 Univ Johns Hopkins Med Vækstdifferentieringsfaktor-8
US7393682B1 (en) * 1993-03-19 2008-07-01 The Johns Hopkins University School Of Medicine Polynucleotides encoding promyostatin polypeptides
US6465239B1 (en) 1993-03-19 2002-10-15 The John Hopkins University School Of Medicine Growth differentiation factor-8 nucleic acid and polypeptides from aquatic species and non-human transgenic aquatic species
DE69434520T3 (de) 1993-07-30 2009-10-15 Affymax, Inc., Palo Alto Biotinylierung von proteinen
EP0733070A1 (en) 1993-12-08 1996-09-25 Genzyme Corporation Process for generating specific antibodies
PT1231268E (pt) 1994-01-31 2005-11-30 Univ Boston Bancos de anticorpos policlonais
US5972335A (en) 1994-03-29 1999-10-26 The Victoria University Of Manchester Wound healing
US5516637A (en) 1994-06-10 1996-05-14 Dade International Inc. Method involving display of protein binding pairs on the surface of bacterial pili and bacteriophage
US5786464C1 (en) 1994-09-19 2012-04-24 Gen Hospital Corp Overexpression of mammalian and viral proteins
US5919652A (en) 1994-11-09 1999-07-06 The Regents Of The University Of California Nucleic acid molecules comprising the prostate specific antigen (PSA) promoter and uses thereof
US5616561A (en) 1995-03-31 1997-04-01 Regents Of The University Of California TGF-β antagonists as mitigators of radiation-induced tissue damage
CA2219361C (en) 1995-04-27 2012-02-28 Abgenix, Inc. Human antibodies derived from immunized xenomice
EP0823941A4 (en) 1995-04-28 2001-09-19 Abgenix Inc HUMAN ANTIBODIES DERIVED FROM IMMUNIZED XENO MOUSES
US5967979A (en) 1995-11-14 1999-10-19 Verg, Inc. Method and apparatus for photogrammetric assessment of biological tissue
JP2978435B2 (ja) 1996-01-24 1999-11-15 チッソ株式会社 アクリロキシプロピルシランの製造方法
KR20000064752A (ko) 1996-03-22 2000-11-06 더 제네랄 호스피탈 코포레이션 중추신경계허혈또는외상의발현후폴리펩티드성장인자를투여하는방법
US6114148C1 (en) 1996-09-20 2012-05-01 Gen Hospital Corp High level expression of proteins
US5916771A (en) 1996-10-11 1999-06-29 Abgenix, Inc. Production of a multimeric protein by cell fusion method
EP1500329B1 (en) 1996-12-03 2012-03-21 Amgen Fremont Inc. Human antibodies that specifically bind human TNF alpha
BRPI9809391B8 (pt) 1997-04-14 2021-05-25 Amgen Res Munich Gmbh processo para a produção de um receptor de antígeno anti-humano, anticorpo humano e composição farmacêutica
US6235883B1 (en) 1997-05-05 2001-05-22 Abgenix, Inc. Human monoclonal antibodies to epidermal growth factor receptor
DE69841139D1 (de) 1997-07-14 2009-10-22 Univ Liege Mutationen im myostatingen steigern muskelmasse in säugetieren
US6656475B1 (en) * 1997-08-01 2003-12-02 The Johns Hopkins University School Of Medicine Growth differentiation factor receptors, agonists and antagonists thereof, and methods of using same
US6891082B2 (en) * 1997-08-01 2005-05-10 The Johns Hopkins University School Of Medicine Transgenic non-human animals expressing a truncated activintype II receptor
CA2304208A1 (en) 1997-09-19 1999-03-25 Dana-Farber Cancer Institute, Inc. Intrabody-mediated control of immune reactions
ES2330062T3 (es) 1998-05-06 2009-12-03 Metamorphix, Inc. Procedimientos para tratar la diabetes por inhibicion de gdf-8.
JP3762222B2 (ja) 1998-10-07 2006-04-05 ストライカー・コーポレーション 改変型ＴＧＦ−βスーパーファミリータンパク質
AU772694B2 (en) 1999-01-21 2004-05-06 Metamorphix International, Inc. Growth differentiation factor inhibitors and uses therefor
GB2344886B (en) 1999-03-10 2000-11-01 Medical Res Council Selection of intracellular immunoglobulins
EP1181041A2 (en) 1999-04-30 2002-02-27 Curis, Inc. Morphogen-induced enhancement of fertility
US6784999B1 (en) 1999-05-17 2004-08-31 The Florida International University Board Of Trustees Surface plasmon resonance detection with high angular resolution and fast response time
US7056512B1 (en) 1999-07-20 2006-06-06 Pharmexa A/S Method for down-regulating GDF-8 activity
US7358056B1 (en) 1999-08-30 2008-04-15 Signal Pharmaceuticals Methods for modulating signal transduction mediated by TGF-β and related proteins
IT1317922B1 (it) 2000-10-24 2003-07-15 S I S S A Scuola Internaz Supe Metodo per identificare in vivo epitopi intracellulari.
US20030104402A1 (en) 2001-01-23 2003-06-05 University Of Rochester Methods of producing or identifying intrabodies in eukaryotic cells
DE10108240B4 (de) 2001-02-21 2018-06-28 Leica Microsystems Cms Gmbh Verfahren zur Abbildung und Vermessung mikroskopischer dreidimensionaler Strukturen
US20040047891A1 (en) 2001-02-26 2004-03-11 Sabina Glozman Systems devices and methods for intrabody targeted delivery and reloading of therapeutic agents
GB0108165D0 (en) 2001-03-31 2001-05-23 Univ Manchester Intracellular analysis
CA2453662A1 (en) 2001-07-19 2003-01-30 Stefan Ewert Modification of human variable domains
AU2002355477B2 (en) 2001-08-03 2008-09-25 Medical Research Council Method of identifying a consensus sequence for intracellular antibodies
US7320789B2 (en) 2001-09-26 2008-01-22 Wyeth Antibody inhibitors of GDF-8 and uses thereof
US7241444B2 (en) 2002-01-18 2007-07-10 Pierre Fabre Medicament Anti-IGF-IR antibodies and uses thereof
GB0201611D0 (en) 2002-01-24 2002-03-13 Grosveld Frank Transgenic animal
GB0226723D0 (en) 2002-11-15 2002-12-24 Medical Res Council Antibodies for in vitro use
GB0226727D0 (en) 2002-11-15 2002-12-24 Medical Res Council Intrabodies
AU2003219277A1 (en) 2002-03-14 2003-09-29 Medical Research Council Intracellular antibodies
SI2332989T1 (sl) 2002-05-22 2015-06-30 Esbatech, An Alcon Biomedical Research Unit Llc Imunoglobulinski bralni okvirji, ki kaĺ˝ejo izboljĺ ano stabilnost v intraceliäśnem okolju, in postopki za njihovo identifikacijo
AR047392A1 (es) 2002-10-22 2006-01-18 Wyeth Corp Neutralizacion de anticuerpos contra gdf 8 y su uso para tales fines
US20040223966A1 (en) 2002-10-25 2004-11-11 Wolfman Neil M. ActRIIB fusion polypeptides and uses therefor
JP2006521088A (ja) 2002-11-15 2006-09-21 メディカル リサーチ カウンシル 抗活性化ｒａｓ抗体
GB0226729D0 (en) 2002-11-15 2002-12-24 Medical Res Council Intracellular antibodies
EP1482309A1 (en) 2003-05-07 2004-12-01 Institut Curie Means for detecting protein conformation and applications thereof
BRPI0410927A (pt) 2003-06-02 2006-06-27 Wyeth Corp métodos terapêuticos e profiláticos para distúrbios neuromusculares
WO2005010049A2 (en) 2003-07-09 2005-02-03 Eli Lilly And Company Tgf-beta1 ligands
WO2005016254A2 (en) * 2003-07-16 2005-02-24 The Ohio State University Research Foundation Methods and reagents for treating inflammation and fibrosis
WO2005013915A2 (en) 2003-08-08 2005-02-17 The Regents Of The University Of California Novel indications for transforming growth factor-beta regulators
JP4653660B2 (ja) * 2003-09-04 2011-03-16 独立行政法人理化学研究所 ＴＧＦ−β活性化制御領域の切断面を認識する抗体
EP1677735B1 (en) 2003-10-17 2014-07-23 Joslin Diabetes Center, Inc. Methods and compositions for modulating adipocyte function
KR100500610B1 (ko) 2003-10-29 2005-07-11 한국전기연구원 형광 현미경 및 이를 사용한 관측 방법
CA2550933A1 (en) 2003-12-22 2005-07-14 Amgen Inc. Methods for identifying functional antibodies
CA2551877A1 (en) 2003-12-31 2005-07-21 Schering-Plough Ltd. Neutralizing epitope-based growth enhancing vaccine
EP1729793B1 (en) 2004-03-02 2015-07-22 Acceleron Pharma Inc. Alk7 and myostatin inhibitors for muscle wasting disorders
ATE557042T1 (de) 2004-03-23 2012-05-15 Lilly Co Eli Anti-myostatin-antikörper
AU2005247508A1 (en) 2004-05-27 2005-12-08 Acceleron Pharma Inc. Cerberus/coco derivatives and uses thereof
AU2005272646A1 (en) 2004-08-12 2006-02-23 Wyeth Combination therapy for diabetes, obesity, and cardiovascular diseases using GDF-8 inhibitors
JP4974892B2 (ja) 2004-09-15 2012-07-11 ザ・トラステイーズ・オブ・ザ・ユニバーシテイ・オブ・ペンシルベニア 臍帯血由来のｔ調節性細胞の単離および増殖の方法
EA011879B1 (ru) 2004-09-24 2009-06-30 Эмджин Инк. МОЛЕКУЛЫ С МОДИФИЦИРОВАННЫМ Fc ФРАГМЕНТОМ
US20080118487A1 (en) 2004-09-30 2008-05-22 Orico Limited Myostatin Isoform
US20060121042A1 (en) 2004-10-27 2006-06-08 Medimmune, Inc. Modulation of antibody specificity by tailoring the affinity to cognate antigens
JP2008526201A (ja) 2004-12-30 2008-07-24 シェーリング−プラウ・リミテッド 中和エピトープベースの成長増強ワクチン
NZ538097A (en) 2005-02-07 2006-07-28 Ovita Ltd Method and compositions for improving wound healing
WO2006106599A1 (ja) 2005-03-01 2006-10-12 Kyoto University 細胞外ドメインシェディングの異常亢進に起因する疾患の予防及び／又は治療のための医薬
WO2006103639A2 (en) * 2005-03-31 2006-10-05 Case Western Reserve University Methods and reagents for identifying/isolating t regulatory (treg) cells and for treating individuals
ATE505489T1 (de) 2005-04-22 2011-04-15 Lilly Co Eli Tgf-beta-1-spezifische antikörper
NL1031674C2 (nl) 2005-04-25 2007-04-26 Pfizer Antilichamen tegen myostatine.
ES2534760T3 (es) 2005-08-19 2015-04-28 Wyeth Llc Anticuerpos antagonistas contra GDF-8 y sus usos en el tratamiento de ELA y otros trastornos asociados con GDF-8
BRPI0616923A2 (pt) * 2005-10-06 2011-07-05 Lilly Co Eli anticorpos monoclonais, seus usos e composição farmacêutica
UA92504C2 (en) 2005-10-12 2010-11-10 Эли Лилли Энд Компани Anti-myostatin monoclonal antibody
EP1948675B1 (en) 2005-10-25 2014-07-30 The Johns Hopkins University Methods and compositions for the treatment of marfan syndrome and associated disorders
CA2661836A1 (en) 2006-09-05 2008-03-13 Eli Lilly And Company Anti-myostatin antibodies
JP2008102117A (ja) 2006-09-21 2008-05-01 Fujifilm Corp 表面プラズモン増強蛍光センサおよび蛍光検出方法
DK2083863T3 (da) 2006-10-03 2015-06-22 Genzyme Corp Antistoffer mod tgf-beta til anvendelse til behandling af spædbørn med risiko for udvikling af bronkopulmonal dysplasi
WO2009018438A1 (en) 2007-07-31 2009-02-05 Cornell Research Foundation, Inc. Protein discovery using intracellular ribosome display
KR100988471B1 (ko) 2007-07-06 2010-10-18 전자부품연구원 실시간 세포 분석 장치 및 이를 이용한 세포의 대사 측정방법
US20100266577A1 (en) 2007-07-25 2010-10-21 Felipe Samaniego Method of Cancer Treatment with Antagonists of FAS Inhibitors
EP3178496A1 (en) 2007-08-24 2017-06-14 Keio University Fstl1 suppressor for use in the treatment of tumours
GB0809592D0 (en) 2008-05-27 2008-07-02 Imp Innovations Ltd Biomaterials
EP2143735A1 (en) 2008-07-10 2010-01-13 Institut Pasteur Variable domains of camelid heavy-chain antibodies directed against glial fibrillary acidic proteins
AR074777A1 (es) 2008-12-19 2011-02-09 Glaxo Group Ltd Proteinas de union a antigeno
BRPI1010587A2 (pt) 2009-06-08 2019-04-09 Acceleron Pharma Inc. métodos para aumentar adipócitos termogênicos
US8399624B1 (en) 2009-06-25 2013-03-19 Esbatech, An Alcon Biomedical Research Unit Llc Acceptor framework for CDR grafting
EP3818988A1 (en) 2009-11-03 2021-05-12 Acceleron Pharma Inc. Methods for treating fatty liver disease
US8956828B2 (en) 2009-11-10 2015-02-17 Sangamo Biosciences, Inc. Targeted disruption of T cell receptor genes using engineered zinc finger protein nucleases
JP6267425B2 (ja) 2009-11-17 2018-01-24 アクセルロン ファーマ， インコーポレイテッド 筋ジストロフィー治療のためのユートロフィン誘導に関するａｃｔｒｉｉｂタンパク質およびその改変体およびその使用
JO3340B1 (ar) 2010-05-26 2019-03-13 Regeneron Pharma مضادات حيوية لـعامل تمايز النمو 8 البشري
EP2407487A1 (en) 2010-07-14 2012-01-18 F-Star Biotechnologische Forschungs - und Entwicklungsges. M.B.H. Multispecific modular antibody
US8999343B2 (en) 2010-08-16 2015-04-07 Amgen Inc. Antibodies that bind myostatin, compositions and methods
CN103501815B (zh) 2010-10-08 2016-09-28 希望之城公司 针对中间位的单克隆抗体框架结合界面、中间位投递系统及其使用方法
EP2703485B1 (en) 2011-03-30 2018-12-26 National University Corporation University Of Toyama Method for selecting plasma cells and plasmablasts, and method for producing target antigen-specific antibody
SG195253A1 (en) * 2011-06-03 2013-12-30 Xoma Technology Ltd Antibodies specific for tgf-beta
US9505763B2 (en) 2011-07-25 2016-11-29 Vanderbilt University Cancer treatment using BMP inhibitor
CN103890246A (zh) 2011-08-18 2014-06-25 亲和生物科学公司 可溶性多肽
WO2013033420A1 (en) 2011-08-30 2013-03-07 Whitehead Institute For Biomedical Research Methods of downregulating translocated oncogene expression using bromodomain inhibitors
KR102056932B1 (ko) 2011-10-10 2019-12-17 시티 오브 호프 메디토프와 메디토프-결합 항체 및 이들의 용도
LT2794658T (lt) 2011-12-19 2017-05-10 Synimmune Gmbh Bispecifinė antikūno molekulė
EP2861617A1 (en) 2012-06-15 2015-04-22 Pfizer Inc. Improved antagonist antibodies against gdf-8 and uses therefor
EP3165535B1 (en) 2012-08-22 2019-05-15 Mogam Biotechnology Research Institute Screening and engineering method of super-stable immunoglobulin variable domains and their uses
TWI633117B (zh) 2012-09-13 2018-08-21 必治妥美雅史谷比公司 結合至肌肉生長抑制素（ｍｙｏｓｔａｔｉｎ）以纖維連接蛋白爲主之支架結構域蛋白質
US20150328249A1 (en) 2012-12-11 2015-11-19 Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center Modulation of myofiber repair by anti-myostatin strategies and/or ppar gamma ligands, alone or in combination with stem cells, for the therapy of critical limb ischemia and other ischemic processes affecting the skeletal muscle
RU2714733C2 (ru) 2013-03-15 2020-02-19 Мемориал Слоан-Кеттеринг Кэнсер Сентер Технологии мультимеризации
HRP20251426T1 (hr) 2013-05-06 2026-01-02 Scholar Rock, Inc. Sastavi i postupci za modulaciju faktora rasta
WO2015015003A1 (en) 2013-08-01 2015-02-05 Université Catholique de Louvain Anti-garp protein and uses thereof
EP2832747A1 (en) 2013-08-01 2015-02-04 Université Catholique de Louvain Anti-GARP protein and uses thereof
US20170073406A1 (en) 2014-05-06 2017-03-16 Scholar Rock, Inc. Compositions and methods for growth factor modulation
HK1243940A1 (zh) 2014-11-06 2018-07-27 Scholar Rock, Inc. 抗原肌肉生长抑制素/潜在肌肉生长抑制素的抗体及其用途

Patent Citations (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4179337A (en) 1973-07-20 1979-12-18 Davis Frank F Non-immunogenic polypeptides
US4301144A (en) 1979-07-11 1981-11-17 Ajinomoto Company, Incorporated Blood substitute containing modified hemoglobin
US4485045A (en) 1981-07-06 1984-11-27 Research Corporation Synthetic phosphatidyl cholines useful in forming liposomes
US4640835A (en) 1981-10-30 1987-02-03 Nippon Chemiphar Company, Ltd. Plasminogen activator derivatives
US4544545A (en) 1983-06-20 1985-10-01 Trustees University Of Massachusetts Liposomes containing modified cholesterol for organ targeting
US4496689A (en) 1983-12-27 1985-01-29 Miles Laboratories, Inc. Covalently attached complex of alpha-1-proteinase inhibitor with a water soluble polymer
US4670417A (en) 1985-06-19 1987-06-02 Ajinomoto Co., Inc. Hemoglobin combined with a poly(alkylene oxide)
US4791192A (en) 1986-06-26 1988-12-13 Takeda Chemical Industries, Ltd. Chemically modified protein with polyethyleneglycol
US5024947A (en) 1987-07-24 1991-06-18 Cetus Corporation Serum free media for the growth on insect cells and expression of products thereby
US5116964A (en) 1989-02-23 1992-05-26 Genentech, Inc. Hybrid immunoglobulins
EP0404097A2 (de) 1989-06-22 1990-12-27 BEHRINGWERKE Aktiengesellschaft Bispezifische und oligospezifische, mono- und oligovalente Rezeptoren, ihre Herstellung und Verwendung
US5013556A (en) 1989-10-20 1991-05-07 Liposome Technology, Inc. Liposomes with enhanced circulation time
US5208020A (en) 1989-10-25 1993-05-04 Immunogen Inc. Cytotoxic agents comprising maytansinoids and their therapeutic use
WO1993011161A1 (en) 1991-11-25 1993-06-10 Enzon, Inc. Multivalent antigen-binding proteins
JPH05336990A (ja) 1992-02-19 1993-12-21 Kyowa Hakko Kogyo Co Ltd 抗ＴＧＦ−βマスキングプロテインモノクローナル抗体
US5846545A (en) 1992-03-25 1998-12-08 Immunogen, Inc. Targeted delivery of cyclopropylbenzindole-containing cytotoxic drugs
US5585499A (en) 1992-03-25 1996-12-17 Immunogen Inc. Cyclopropylbenzindole-containing cytotoxic drugs
US5475092A (en) 1992-03-25 1995-12-12 Immunogen Inc. Cell binding agent conjugates of analogues and derivatives of CC-1065
US5541087A (en) 1994-09-14 1996-07-30 Fuji Immunopharmaceuticals Corporation Expression and export technology of proteins as immunofusins
US6348584B1 (en) 1996-10-17 2002-02-19 John Edward Hodgson Fibronectin binding protein compounds
US6673901B2 (en) 1997-06-12 2004-01-06 Research Corporation Technologies, Inc. Artificial antibody polypeptides
US7151169B2 (en) 1999-04-30 2006-12-19 Cambridge Antibody Technology Limited Specific binding members for TGFβ1
US6492497B1 (en) 1999-04-30 2002-12-10 Cambridge Antibody Technology Limited Specific binding members for TGFbeta1
US7572599B2 (en) 2002-09-16 2009-08-11 The Johns Hopkins University School Of Medicine Metalloprotease activation of myostatin, and methods of modulating myostatin activity
US7723486B2 (en) 2005-02-08 2010-05-25 Optein, Inc. Antibodies to TGF-β
US20110008364A1 (en) 2005-02-08 2011-01-13 Genzyme Corporation Antibodies to tgf-beta
US20110135570A1 (en) 2006-03-23 2011-06-09 Mary Jo Janatpour Anti-Tumor Cell Antigen Antibody Therapeutics
US8415459B2 (en) 2007-11-01 2013-04-09 Pfizer Inc. Antibody to GDF8 and uses thereof
US20110053221A1 (en) 2008-03-14 2011-03-03 Humanzyme Limited Recombinant production of authentic human proteins using human cell expression systems
US20100009424A1 (en) 2008-07-14 2010-01-14 Natasha Forde Sonoporation systems and methods
US20100196983A1 (en) 2009-02-05 2010-08-05 Ut-Battelle, Llc Transformation of gram positive bacteria by sonoporation
WO2011034935A2 (en) 2009-09-16 2011-03-24 Switchgear Genomics Transcription biomarkers of biological responses and methods
US8637637B2 (en) 2010-01-12 2014-01-28 Bill Nai-Chau Sun Fc fusion proteins of human growth hormone
WO2011102483A1 (ja) 2010-02-19 2011-08-25 独立行政法人理化学研究所 ヒトTGF-βのLAPに結合する抗体
WO2011151432A1 (en) 2010-06-03 2011-12-08 Glaxo Group Limited Humanised antigen binding proteins to myostatin6
US20130122007A1 (en) 2011-11-14 2013-05-16 Regeneron Pharmaceuticals, Inc. Compositions and Methods for Increasing Muscle Mass and Muscle Strength by Specifically Antagonizing GDF8 and or Activin A
WO2014074532A2 (en) 2012-11-06 2014-05-15 Scholar Rock Inc. Compositions and methods for modulating cell signaling

Non-Patent Citations (143)

* Cited by examiner, † Cited by third party
Title
"Biocomputing: Informatics and Genome Projects", 1993, ACADEMIC PRESS
"Bioreversible Carriers in Drug Design", 1987, AMERICAN PHARMACEUTICAL ASSOCIATION AND PERGAMON PRESS
"Computer Analysis of Sequence Data", 1994, HUMANA PRESS
"Pharmaceutical Salts: Properties, Selection, and Use", 2008, WILEY-VCH
"Remington: The Science and Practice of Pharmacy", 2006, LIPPINCOTT, WILLIAMS & WILKINS
"Remington's Pharmaceutical Sciences", 1985, MACK PUBLISHING COMPANY, pages: 1418
"Sequence Analysis Primer", 1991, M STOCKTON PRESS
ABE, M. ET AL.: "An assay for transforming growth factor-β using cells transfected with a plasminogen activator inhibitor-1 promoter-luciferase construct", ANALYTICAL BIOCHEMISTRY, vol. 216, 1994, pages 276 - 84, XP024763357, DOI: 10.1006/abio.1994.1042
ALDERSON, K.L. ET AL., J BIOMED BIOTECHNOL., 2011, pages 379123
ALTSCHUL, S. F. ET AL., J. MOLEC. BIOL., vol. 215, 1990, pages 403
ANDERSON ET AL., J BIOL CHEM., vol. 283, no. 11, 2007, pages 25852 - 35
ANDRE, F.M. ET AL.: "Nucleic acids electrotransfer in vivo: mechanisms and practical aspects", CURR GENE THER., vol. 10, 2010, pages 267 - 80
AURIGEMMA, N ENGL J MED., vol. 355, no. 3, 2006, pages 308 - 10
BAZIGOU, E. ET AL.: "Integrin- a9 is required for fibronectin matrix assembly during lymphatic valve morphogenesis", DEV CELL, vol. 17, no. 2, August 2009 (2009-08-01), pages 175 - 86
BENOIT, D.S. ET AL.: "Synthesis of folate-functionalized RAFT polymers for targeted siRNA delivery", BIOMACROMOLECULES, vol. 12, 2011, pages 2708 - 14
BERGE ET AL., JOURNAL OF PHARMACEUTICAL SCIENCE, vol. 66, 1977, pages 1 - 19
BISWAS ET AL., J CLIN INVEST, vol. 117, no. 5, May 2007 (2007-05-01), pages 1305 - 1313
BLOBE, G.C. ET AL.: "Role of transforming growth factor beta in human disease", N ENGL J MED., vol. 342, no. 18, 4 May 2000 (2000-05-04), pages 1350 - 8
BOILEAU ET AL., NATURE GENETICS LETTERS, vol. 44, no. 8, 2012, pages 916 - 23
CARILLO, H.LIPMAN, D., SIAM J APPLIED MATH., vol. 48, 1988, pages 1073
CARON, N.J. ET AL.: "Intracellular delivery of a Tat-eGFP fusion protein into muscle cells", MOL THER., vol. 3, no. 3, 2001, pages 310 - 8
CARRINGTON, L.M. ET AL.: "Differential regulation of key stages in early corneal wound healing by TGF-beta isoforms and their inhibitors", INVEST OPHTHALMOL VIS SCI., vol. 47, no. 5, May 2006 (2006-05-01), pages 1886 - 94, XP055504563, DOI: 10.1167/iovs.05-0635
CASH, J.N ET AL.: "The structure of myostatin:follistatin 288: insights into receptor utilization and heparin binding", THE EMBO JOURNAL, vol. 28, 2009, pages 2662 - 76, XP055183670, DOI: 10.1038/emboj.2009.205
CECO, E. ET AL., FEBS J., vol. 280, no. 17, 2013, pages 4198 - 209
CHIARELLA, P. ET AL.: "Application of electroporation in DNA vaccination protocols", CURR GENE THER., vol. 10, 2010, pages 281 - 6
COIN, P.G. ET AL., AM J RESPIR CRIT CARE MED., vol. 154, no. 5, 1996, pages 1511 - 9
CRONICAN, J.J. ET AL.: "Potent delivery of functional proteins into mammalian cells in vitro and in vivo using a supercharged protein", ACS CHEM BIOL., vol. 5, 2010, pages 747 - 52, XP055242284, DOI: 10.1021/cb1001153
CZAJKOWSKY, D.M. ET AL., EMBO MOL MED., vol. 4, no. 10, 2012, pages 1015 - 28
DAOPIN, S. ET AL.: "Crystal structure of transforming growth factor-Ø2: an unusual fold for the superfamily", SCIENCE, vol. 257, no. 5068, 1992, pages 369 - 73, XP000857489, DOI: 10.1126/science.1631557
DAUGHERTY ET AL.: "Formulation and delivery issues for monoclonal antibody therapeutics", ADV DRUG DELIV REV., vol. 58, no. 5-6, 7 August 2006 (2006-08-07), pages 686 - 706, XP024892149, DOI: 10.1016/j.addr.2006.03.011
DAVIS, M.E. ET AL.: "Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles", NATURE, vol. 464, 2010, pages 1067 - 70, XP055094641, DOI: 10.1038/nature08956
DAVIS, M.E. ET AL.: "The first targeted delivery of siRNA in humans via a self-assembling, cyclodextrin polymer-based nanoparticle: from concept to clinic", MOL PHARM., vol. 6, 2009, pages 659 - 668, XP055144106, DOI: 10.1021/mp900015y
DENICOURT, C. ET AL.: "Another twist in the transforming growth factor β-induced cell-cycle arrest chronicle", PNAS, vol. 100, no. 26, 2003, pages 15290 - 1
DESHAYES, S. ET AL.: "Cell-penetrating peptides: tools for intracellular delivery of therapeutics", CELL MOL LIFE SCI., vol. 62, no. 16, 2005, pages 1839 - 49, XP019200807, DOI: 10.1007/s00018-005-5109-0
DEVEREUX, J. ET AL., NUCLEIC ACIDS RESEARCH, vol. 12, no. 1, 1984, pages 387
EL-ANDALOUSSI, S. ET AL.: "Cell-penetrating peptides: mechanisms and applications", CURR PHARM DES., vol. 11, no. 28, 2003, pages 3597 - 611, XP008081641, DOI: 10.2174/138161205774580796
EPPSTEIN, D.A. ET AL.: "Biological activity of liposome-encapsulated murine interferon gamma is mediated by a cell membrane receptor", PROC NATL ACAD SCI USA., vol. 82, no. 11, June 1985 (1985-06-01), pages 3688 - 92
FINKENSTEDT ET AL., BRITISH JOURNAL OF HAEMATOLOGY, vol. 144, 2008, pages 789 - 93
FUJII, T. ET AL., BMC GASTROENTEROLOGY, vol. 10, 2010, pages 79
FULLER ET AL., INVEST OPHTHALMOL VIS SCI., vol. 50, no. 12, 2009, pages 5759 - 68
G. S. BANKER: "Modern Pharmaceutics, Drugs and the Pharmaceutical Sciences", vol. 72, 1996, MARCEL DEKKER
GARDENGHI ET AL., JCI, vol. 120, no. 12, 2010, pages 4466 - 77
GE ET AL., MOL CEL BIOL., vol. 25, no. 14, 2005, pages 5846 - 58
GE ET AL., MOL CELL BIOL., vol. 25, no. 14, 2005, pages 5846 - 58
GREENBERG, CURR OPIN NEUROL., vol. 25, no. 5, 2012, pages 630 - 9
GUO ET AL., DIABETES, vol. 61, no. 10, 2012, pages 2414 - 23
HAHM, K. ET AL., AM J PATHOL., vol. 170, no. 1, 2007, pages 110 - 5
HAN ET AL., INT J BIOCHEM CELL BIOL., vol. 45, no. 10, 2013, pages 2333 - 47
HILL, J.J. ET AL., JBC, vol. 277, no. 43, 2002, pages 40735 - 41
HILL, J.J. ET AL., MOL ENDOCRINOLOGY., vol. 17, no. 6, 2003, pages 1144 - 54
HOJMAN, P.: "Basic principles and clinical advancements of muscle electrotransfer", CURR GENE THER., vol. 10, 2010, pages 128 - 38, XP009185948, DOI: 10.2174/156652310791110994
HOLLINGER, P. ET AL.: "Diabodies'':Small bivalent and bispecific antibody fragments", PNAS, vol. 90, 1993, pages 6444 - 8
HORAN G.S. ET AL., AM J RESPIR CRIT CARE MED., vol. 177, no. 1, 4 October 2007 (2007-10-04), pages 56 - 65
HSIAO ET AL., MOL CELL BIOL., vol. 20, no. 10, 2000, pages 3742 - 51
HUH, M.I. ET AL.: "Distribution of TGF-β isoforms and signaling intermediates in corneal fibrotic wound repair", J CELL BIOCHEM., vol. 108, no. 2, 1 October 2009 (2009-10-01), pages 476 - 88
HWANG, K.J. ET AL.: "Hepatic uptake and degradation of unilamellar sphingomyelin/cholesterol liposomes: a kinetic study", PROC NATL ACAD SCI USA., vol. 77, no. 7, July 1980 (1980-07-01), pages 4030 - 4
IREDALE, J.P, J CLIN INVEST., vol. 117, no. 3, 2007, pages 539 - 48
JANSSENS, K. ET AL.: "Transforming growth factor-beta 1 mutations in Camurati-Engelmann disease lead to increased signaling by altering either activation or secretion of the mutant protein", J BIOL CHEM., vol. 278, no. 9, 18 December 2002 (2002-12-18), pages 7718 - 24
KATSIMPARDI, L. ET AL., SCIENCE EXPRESS, 2014, pages 2 - 6
KLAMPF ET AL., NEJM, vol. 369, 2013, pages 2379 - 90
KOEPKE, M.L. ET AL., NEPHROL DIAL TRANSPLANT., vol. 22, no. 4, 2007, pages 1062 - 9
LACOUT, C. ET AL., BLOOD, vol. 107, no. 5, 2006, pages 2952 - 60
LANGEL, U.: "Cell-Penetrating Peptides: Processes and Applications", 2002, CRC PRESS
LEE ET AL., PNAS, vol. 110, no. 39, 2013, pages E3713 - 22
LEE, IMMUNOL ENDOCR METAB AGENTS MED CHEM., vol. 10, 2010, pages 183 - 94
LEE, S-J. ET AL., MOL ENDOCRINOL., vol. 24, no. 10, 2010, pages 1998 - 2008
LING, H. ET AL., J AM SOC NEPHROL., vol. 14, 2003, pages 377 - 88
LOFFREDO ET AL., CELL, vol. 153, 2013, pages 828 - 39
MA ET AL., J CLIN INVEST., vol. 115, 2005, pages 3460 - 72
MA, L.J. ET AL., AMERICAN JOURNAL OF PATHOLOGY, vol. 163, no. 4, 2003, pages 1261 - 73
MARCINKIEWICZ, C. ET AL.: "Inhibitory effects of MLDG-containing heterodimeric disintegrins reveal distinct structural requirements for interaction of the integrin α β with VCAM-1, tenascin-C, and osteopontin", JBC, vol. 275, no. 41, 2000, pages 31930 - 7, XP001020781, DOI: 10.1074/jbc.M003209200
MARTIN, F.J. ET AL.: "Irreversible coupling of immunoglobulin fragments to preformed vesicles. An improved method for liposome targeting", J BIOL CHEM., vol. 257, no. l, 10 January 1982 (1982-01-10), pages 286 - 8, XP001098117
MARVIN, J.S. ET AL., ACTA PHARMACOLOGICA SINICA, vol. 26, no. 6, 2005, pages 649 - 58
MASCARENHAS, J. ET AL., LEUKEMIA AND LYMPHOMA, vol. 55, 2014, pages 450 - 2
MASSAGUE, NATURE REVIEWS MOLECULAR CELL BIOLOGY, vol. 1, 2000, pages 169 - 78
MASSIGNANI, M. ET AL.: "Cellular delivery of antibodies: effective targeted subcellular imaging and new therapeutic tool", NATURE PROCEEDINGS, 2010, pages l-17
MCNAUGHTON, B.R. ET AL.: "Mammalian cell penetration, siRNA transfection, and DNA transfection by supercharged proteins", PROC NATL ACAD SCI, USA, vol. 106, 2009, pages 6111 - 6
MCPHERRON ET AL., ADIPOCYTE, vol. 2, no. 2, 2013, pages 92 - 8
MEAD, A.L. ET AL.: "Evaluation of anti-TGF-beta2 antibody as a new postoperative anti-scarring agent in glaucoma surgery", INVEST OPHTHALMOL VIS SCI., vol. 44, no. 8, August 2003 (2003-08-01), pages 3394 - 401, XP002977767, DOI: 10.1167/iovs.02-0978
MENG, X.M. ET AL.: "Smad2 Protects against TGF-beta/Smad3-Mediated Renal Fibrosis", J AM SOC NEPHROL., vol. 21, no. 9, 1 July 2010 (2010-07-01), pages 1477 - 87
MEYERSMILLER, CABIOS, vol. 4, 1989, pages 11 - 17
MOHAMMAD, K.S. ET AL.: "Pharmacologic inhibition of the TGF-beta type I receptor kinase has anabolic and anti-catabolic effects on bone", PLOS ONE, vol. 4, no. 4, 16 April 2008 (2008-04-16), pages e5275, XP055315063, DOI: 10.1371/journal.pone.0005275
MORELY, FAMILY PRACTICE, vol. 29, 2012, pages i44 - i48
MULLALLY, A. ET AL., CANCER CELL, vol. 17, 2010, pages 584 - 96
NEWMAN, C.M. ET AL.: "Gene therapy progress and prospects: ultrasound for gene transfer", GENE THER., vol. 14, no. 6, 2007, pages 465 - 75
NIALS, A.T. ET AL., DISEASE MODELS AND MECHANISMS, vol. 1, 2008, pages 213 - 20
ODENIKE, O., HEMATOLOGY, vol. 1, no. 545-52, 2013
OIDA, T. ET AL.: "TGF-β induces surface LAP expression on Murine CD4 T cells independent of FoxP3 induction", PLOS ONE, vol. 5, no. ll, 2010, pages el5523
OKLU, R. ET AL.: "The latent transforming growth factor beta binding protein (LTBP) family", BIOCHEM J., vol. 352, 15 December 2000 (2000-12-15), pages 601 - 10, XP009010129, DOI: 10.1042/0264-6021:3520601
OLIVA, B. ET AL.: "An automated classification of the structure of protein loops", J MOL BIOL., vol. 266, no. 4, 1997, pages 814 - 30, XP004462194, DOI: 10.1006/jmbi.1996.0819
OOMMEN, S. ET AL.: "Vacular endothelial growth factor A (VEGF-A) induces endothelial and cancer cell migration through direct binding to integrin α β", JBC, vol. 286, no. 2, 2011, pages 1083 - 92, XP055472312, DOI: 10.1074/jbc.M110.175158
PALMER, E.L. ET AL.: "Sequence and tissue distribution of the integrin a subunit, a novel partner of β1 that is widely distributed in epithelia and muscle", JOURNAL OF CELL BIOLOGY, vol. 123, no. 5, 1993, pages 1289 - 97, XP002305856
PAULUHN, J. ET AL., TOXICOLOGY, vol. 161, 2001, pages 153 - 63
PICHT, G. ET AL.: "Transforming growth factor beta 2 levels in the aqueous humor in different types of glaucoma and the relation to filtering bleb development", GRAEFES ARCH CLIN EXP OPHTHALMOL., vol. 9, no. 3, 23 March 2001 (2001-03-23), pages 199 - 207
PITELLA, F. ET AL.: "Enhanced endosomal escape of siRNA-incorporating hybrid nanoparticles from calcium phosphate and PEG-block charge-conversional polymer for efficient gene knockdown with negligible cytotoxicity", BIOMATERIALS, vol. 32, 2011, pages 3106 - 14, XP028145194, DOI: 10.1016/j.biomaterials.2010.12.057
POSTEMA, M. ET AL.: "Ultrasound-directed drug delivery", CURR PHARM BIOTECHNOL., vol. 8, 2007, pages 355 - 61
PREUSCH ET AL., EUR J MED RES., vol. 18, 2013, pages 19
RIETHMULLER, G., CANCER IMMUNITY, vol. 12, 2012, pages 12 - 18
ROBERTS, S.N. ET AL., J PATHOL., vol. 176, no. 3, 1995, pages 309 - 18
RODINO-KLAPAC, L.R. ET AL., MUSCLE NERVE, vol. 39, no. 3, 2009, pages 283 - 96
ROZEMA, D.B. ET AL.: "Dynamic polyconjugates for targeted in vivo delivery of siRNA to hepatocytes", PROC NATL ACAD SCI USA., vol. 104, 2007, pages 12982 - 12887
SASU ET AL., BLOOD, vol. 115, no. 17, 2010, pages 3616 - 24
SATO-NISHIUCHI, R. ET AL.: "Polydom/SVEPI is a ligand for integrin α β", JBC, vol. 287, no. 30, 2012, pages 25615 - 30, XP055261550, DOI: 10.1074/jbc.M112.355016
SCHAEFER, D.W. ET AL., EUR RESPIR REV., vol. 20, no. 120, 2011, pages 85 - 97
SCHAEFER, W. ET AL., PNAS, vol. 108, no. 27, 2011, pages 11187 - 92
SCHEIFFELE, F. ET AL., CURR PROTOC IMMUNOL., 2002
See also references of EP2981822A4
SENGLE ET AL., J BIOL CHEM., vol. 286, no. 49, 2011, pages 41905 - 99
SENGLE ET AL., J MOL BIOL., vol. 381, no. 4, 2008, pages 1025 - 39
SHERWOOD, J.K. ET AL.: "Controlled antibody delivery systems", NATURE BIOTECHNOLOGY, vol. 10, 1992, pages 1446 - 9
SHI, M. ET AL.: "Latent TGF-beta structure and activation", NATURE, vol. 474, no. 7351, 15 June 2011 (2011-06-15), pages 343 - 9, XP055167968, DOI: 10.1038/nature10152
SHI, M. ET AL.: "Latent TGF-fJ structure and activation", NATURE, vol. 474, no. 7351, 15 June 2011 (2011-06-15), pages 343 - 9, XP055167968, DOI: 10.1038/nature10152
SHI, M. ET AL.: "Latent TGF-P structure and activation", NATURE, vol. 474, no. 7351, 15 June 2011 (2011-06-15), pages 343 - 9, XP055167968, DOI: 10.1038/nature10152
SIEGWART, D.J. ET AL.: "Combinatorial synthesis of chemically diverse core-shell nanoparticles for intracellular delivery", PROC NATL ACAD SCI USA., vol. 108, 2011, pages 12996 - 3001, XP055454058, DOI: 10.1073/pnas.1106379108
SMITH ET AL., CIRC RES., vol. 84, no. 10, 1999, pages 1212 - 22
STANISZEWSKA, I. ET AL.: "Integrin α β is a receptor for nerve growth factor and other neurotrophins", JOURNAL OF CELL SCIENCE, vol. 121, 2007, pages 504 - 13
SUMIOKA, T. ET AL.: "Inhibitory effect of blocking TGF-beta/Smad signal on injury-induced fibrosis of corneal endothelium", MOL VIS., vol. 14, 11 December 2008 (2008-12-11), pages 2272 - 81, XP008148116
T. E. CREIGHTON: "Proteins: Structure and Molecular Properties", 1983, W.H. FREEMAN & CO., pages: 79 - 86
T. HIGUCHIV. STELLA: "Pro-drugs as Novel Delivery Systems", A.C.S. SYMPOSIUM SERIES, vol. 14
TAKEHARA-KASAMATSU, Y. ET AL., J MED INVEST., vol. 54, no. 3-4, 2007, pages 276 - 88
TANNO ET AL., CURR OPIN HEMATOL., vol. 17, no. 3, 2010, pages 184 - 90
TAYLOR, R.G. ET AL., LAB INVEST., vol. 52, no. l, 1985, pages 61 - 70
THIES, R.S. ET AL.: "GDF-8 propeptide binds to GDF-8 and antagonizes biological activity by inhibiting GDF-8 receptor binding", GROWTH FACTORS, vol. 18, 2001, pages 251 - 9, XP008013942
THOMAS, M. ET AL., MYOSTATIN, A NEGATIVE REGULATOR OF MUSCLE GROWTH, FUNCTIONS BY INHIBITING MYOBLAST PROLIFERATION, vol. 275, no. 51, 2000, pages 40235 - 43
THRALL, R.S. ET AL., AM J PATHOL., vol. 95, 1979, pages 117 - 30
TRAN, D.Q. ET AL.: "GARP (LRRC32) is essential for the surface expression of latent TGF-β on platelets and activated FOXP3+ regulatory T cells", PNAS, vol. 106, no. 32, 2 June 2009 (2009-06-02), pages 13445 - 50, XP055021925, DOI: 10.1073/pnas.0901944106
TRAN, D.Q. ET AL.: "GARP (LRRC32) is essential for the surface expression of latent TGF-β on platelets and activated FOXP3+ regulatory T cells", PNAS, vol. 106, no. 32, 2009, pages 13445 - 50, XP055021925, DOI: 10.1073/pnas.0901944106
TRIPATHI, R.C. ET AL.: "Aqueous humor in glaucomatous eyes contains an increased level of TGF-Ø2", EXP EYE RES., vol. 9, no. 6, 5 December 1994 (1994-12-05), pages 723 - 7
TSANG, M. ET AL., CYTOKINE, vol. 7, no. 5, 1995, pages 389 - 97
VANNUCCHI, A.M. ET AL., BLOOD, vol. 100, no. 10, 2002, pages 3495 - 503
VERDINE, G.L. ET AL.: "Stapled peptides for intracellular drug targets", METHODS ENZYMOL., vol. 503, 2012, pages 3 - 33, XP055042537, DOI: 10.1016/B978-0-12-396962-0.00001-X
VLAHOS, R. ET AL., CLIN SCI., vol. 126, 2014, pages 253 - 65
WANG, A. ET AL., EXPRESSION OF THE INTEGRIN SUBUNIT A IN THE MURINE EMBRYO. DEVELOPMENTAL DYNAMICS, vol. 204, 1995, pages 421 - 31
WANG, R. ET AL.: "GARP regulates the bioavailability and activation of TGF-β", MOL BIOL CELL., vol. 23, no. 6, 25 January 2012 (2012-01-25), pages 1129 - 39
WHO DRUG INFORMATION, vol. 23, no. 2, 2009
WI, J. ET AL., HEPATOLOGY, vol. 53, no. 4, 2011, pages 1342 - 51
WOLFMAN, N.M. ET AL., PNAS, vol. 100, no. 26, 6 October 2003 (2003-10-06), pages 15842 - 6
WOODSAKAGUCHI, NATURE REVIEWS, 2003
XU ET AL., MATRIX BIOL., vol. 29, no. 6, 2010, pages 461 - 70
YOKASAKI, Y. ET AL.: "Identification of the ligand binding site for the integrin α β in the third fibronectin type III repeat of tenascin C", THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 273, no. 19, 1998, pages 11423 - 8, XP055032169, DOI: 10.1074/jbc.273.19.11423
YOKOSAKI, Y. ET AL.: "The integrin α β binds to a novel recognition sequence (SVVYGLR) in the thrombin-cleaved amino-terminal fragment of osteopontin", JBC, vol. 274, no. 51, 1999, pages 36328 - 34, XP002953833, DOI: 10.1074/jbc.274.51.36328
YOON, C.S. ET AL.: "Ultrasound-mediated gene delivery", EXPERT OPIN DRUG DELIV., vol. 7, 2010, pages 321 - 30
YU, A.L. ET AL.: "TGF-Ø2 induces senescence-associated changes in human trabecular meshwork cells", INVEST OPHTHALMOL VIS SCI., vol. 1, no. 11, 5 November 2010 (2010-11-05), pages 5718 - 23

Cited By (168)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11046784B2 (en) 2006-03-31 2021-06-29 Chugai Seiyaku Kabushiki Kaisha Methods for controlling blood pharmacokinetics of antibodies
US12473375B2 (en) 2006-03-31 2025-11-18 Chugai Seiyaku Kabushiki Kaisha Methods for controlling blood pharmacokinetics of antibodies
US12116414B2 (en) 2007-09-26 2024-10-15 Chugai Seiyaku Kabushiki Kaisha Method of modifying isoelectric point of antibody via amino acid substitution in CDR
US12122840B2 (en) 2007-09-26 2024-10-22 Chugai Seiyaku Kabushiki Kaisha Method of modifying isoelectric point of antibody via amino acid substitution in CDR
US9828429B2 (en) 2007-09-26 2017-11-28 Chugai Seiyaku Kabushiki Kaisha Method of modifying isoelectric point of antibody via amino acid substitution in CDR
US11248053B2 (en) 2007-09-26 2022-02-15 Chugai Seiyaku Kabushiki Kaisha Method of modifying isoelectric point of antibody via amino acid substitution in CDR
US9868948B2 (en) 2008-04-11 2018-01-16 Chugai Seiyaku Kabushiki Kaisha Antigen-binding molecule capable of binding to two or more antigen molecules repeatedly
US9890377B2 (en) 2008-04-11 2018-02-13 Chugai Seiyaku Kabushiki Kaisha Antigen-binding molecule capable of binding to two or more antigen molecules repeatedly
US10472623B2 (en) 2008-04-11 2019-11-12 Chugai Seiyaku Kabushiki Kaisha Antigen-binding molecule capable of binding two or more antigen molecules repeatedly
US11359194B2 (en) 2008-04-11 2022-06-14 Chugai Seiyaku Kabushiki Kaisha Antigen-binding molecule capable of binding two or more antigen molecules repeatedly
US11371039B2 (en) 2008-04-11 2022-06-28 Chugai Seiyaku Kabushiki Kaisha Antigen-binding molecule capable of binding to two or more antigen molecules repeatedly
US11891434B2 (en) 2010-11-30 2024-02-06 Chugai Seiyaku Kabushiki Kaisha Antigen-binding molecule capable of binding to plurality of antigen molecules repeatedly
US11236168B2 (en) 2012-08-24 2022-02-01 Chugai Seiyaku Kabushiki Kaisha Mouse FcγammaRII-specific Fc antibody
US10919953B2 (en) 2012-08-24 2021-02-16 Chugai Seiyaku Kabushiki Kaisha FcgammaRIIB-specific Fc region variant
US11267868B2 (en) 2013-04-02 2022-03-08 Chugai Seiyaku Kabushiki Kaisha Fc region variant
US10981981B2 (en) 2013-05-06 2021-04-20 Scholar Rock, Inc. Compositions and methods for growth factor modulation
US9758576B2 (en) 2013-05-06 2017-09-12 Scholar Rock, Inc. Compositions and methods for growth factor modulation
US9573995B2 (en) 2013-05-06 2017-02-21 Scholar Rock, Inc. Compositions and methods for growth factor modulation
US11827698B2 (en) 2013-05-06 2023-11-28 Scholar Rock, Inc. Compositions and methods for growth factor modulation
US12577296B2 (en) 2013-05-06 2026-03-17 Scholar Rock, Inc. Compositions and methods for growth factor modulation
US12454570B2 (en) 2013-05-06 2025-10-28 Scholar Rock, Inc. Compositions and methods for growth factor modulation
US9399676B2 (en) 2013-05-06 2016-07-26 Scholar Rock, Inc. Compositions and methods for growth factor modulation
US10597443B2 (en) 2013-05-06 2020-03-24 Scholar Rock, Inc. Compositions and methods for growth factor modulation
EP3027650B1 (en) * 2013-08-01 2021-01-13 Université catholique de Louvain Antibody binding a complex of human glycoprotein a repetitions predominant (garp) and latent tgf-beta-1
US10822424B2 (en) 2013-08-01 2020-11-03 Université Catholique de Louvain Method of screening for anti-GARP antibodies
WO2015015003A1 (en) 2013-08-01 2015-02-05 Université Catholique de Louvain Anti-garp protein and uses thereof
US10000572B2 (en) 2013-08-01 2018-06-19 Université Catholique de Louvain Method for inhibiting the immune suppressive function of human T regulatory cells by administering an anti-GARP monoclonal antibody
US11230603B2 (en) 2013-08-01 2022-01-25 Ludwig Institute For Cancer Research Ltd Anti-GARP protein
EP3786187A1 (en) * 2013-08-01 2021-03-03 Université catholique de Louvain Antibody binding a complex of human glycoprotein a repetitions predominant (garp) and latent tgf-beta-1
AU2014298373B2 (en) * 2013-08-01 2019-12-05 Ludwig Institute For Cancer Research Ltd Anti-GARP protein and uses thereof
US10588980B2 (en) 2014-06-23 2020-03-17 Novartis Ag Fatty acids and their use in conjugation to biomolecules
US10786576B2 (en) 2014-06-23 2020-09-29 Novartis Ag Fatty acids and their use in conjugation to biomolecules
US11752211B2 (en) 2014-06-23 2023-09-12 Novartis Ag Fatty acids and their use in conjugation to biomolecules
US10307480B2 (en) 2014-11-06 2019-06-04 Scholar Rock, Inc. Anti-pro/latent-myostatin antibodies and uses thereof
US11925683B2 (en) 2014-11-06 2024-03-12 Scholar Rock, Inc. Compositions for making and using anti-Myostatin antibodies
US11135291B2 (en) 2014-11-06 2021-10-05 Scholar Rock, Inc. Methods for making and using anti-myostatin antibodies
WO2016073879A3 (en) * 2014-11-06 2016-06-23 Scholar Rock, Inc. Transforming growth factor-related antibodies and uses thereof
US10000560B2 (en) 2014-12-19 2018-06-19 Chugai Seiyaku Kabushiki Kaisha Anti-myostatin antibodies, polypeptides containing variant Fc regions, and methods of use
IL251319B2 (en) * 2014-12-19 2023-07-01 Chugai Pharmaceutical Co Ltd Anti-myostatin antibodies, polypeptides containing variable fc regions and methods of use
IL251319B1 (en) * 2014-12-19 2023-03-01 Chugai Pharmaceutical Co Ltd Anti-myostatin antibodies, polypeptides containing variable fc regions and methods of use
JP7011438B2 (ja) 2014-12-19 2022-01-26 中外製薬株式会社 抗ミオスタチン抗体、変異Ｆｃ領域を含むポリペプチド、および使用方法
US12169205B2 (en) 2014-12-19 2024-12-17 Chugai Seiyaku Kabushiki Kaisha Anti-myostatin antibodies, polypeptides containing variant fc regions, and methods of use
WO2016098357A1 (en) 2014-12-19 2016-06-23 Chugai Seiyaku Kabushiki Kaisha Anti-myostatin antibodies, polypeptides containing variant fc regions, and methods of use
US10738111B2 (en) 2014-12-19 2020-08-11 Chugai Seiyaku Kabushiki Kaisha Anti-myostatin antibodies, polypeptides containing variant Fc regions, and methods of use
EP4600372A3 (en) * 2014-12-19 2025-11-19 Chugai Seiyaku Kabushiki Kaisha Anti-myostatin antibodies, polypeptides containing variant fc regions, and methods of use
US11454633B2 (en) 2014-12-19 2022-09-27 Chugai Seiyaku Kabushiki Kaisha Anti-myostatin antibodies, polypeptides containing variant Fc regions, and methods of use
EP3240804A4 (en) * 2014-12-19 2019-01-09 Chugai Seiyaku Kabushiki Kaisha ANTI-MYOSTATIN ANTIBODIES, POLYPEPTIDES WITH DEVIANT FC REGIONS AND METHOD OF USE
AU2015365168B2 (en) * 2014-12-19 2021-08-05 Chugai Seiyaku Kabushiki Kaisha Anti-myostatin antibodies, polypeptides containing variant Fc regions, and methods of use
US10287347B2 (en) 2015-01-14 2019-05-14 The Brigham And Women's Hospital, Inc. Treatment of cancer with anti-lap monoclonal antibodies
US10017567B2 (en) 2015-01-14 2018-07-10 The Brigham And Women's Hospital, Inc. Treatment of cancer with anti-LAP monoclonal antibodies
US11407823B2 (en) 2015-01-14 2022-08-09 The Brigham And Women's Hospital, Inc. Treatment of cancer with anti-LAP monoclonal antibodies
WO2016125017A1 (en) * 2015-02-03 2016-08-11 Universite Catholique De Louvain Anti-garp protein and uses thereof
US10519229B2 (en) 2015-02-05 2019-12-31 Chugai Seiyaku Kabushiki Kaisha Nucleic acids encoding IL-8 antibodies
US12595299B2 (en) 2015-02-05 2026-04-07 Chugai Seiyaku Kabushiki Kaisha FC variants
US9969800B2 (en) 2015-02-05 2018-05-15 Chugai Seiyaku Kabushiki Kaisha IL-8 antibodies
US11180548B2 (en) 2015-02-05 2021-11-23 Chugai Seiyaku Kabushiki Kaisha Methods of neutralizing IL-8 biological activity
WO2016186575A1 (en) * 2015-05-15 2016-11-24 Agency For Science, Technology And Research Native protein purification technology
US20180208648A1 (en) * 2015-07-22 2018-07-26 Scholar Rock, Inc. Gdf11 binding proteins and uses thereof
WO2017015622A3 (en) * 2015-07-22 2017-03-02 Scholar Rock, Inc Gdf11 binding proteins and uses thereof
US11578110B2 (en) 2015-08-25 2023-02-14 Histide Ag Compounds for inducing tissue formation and uses thereof
US11439704B2 (en) 2015-09-15 2022-09-13 Scholar Rock, Inc. Methods for using anti-myostatin antibodies
WO2017049011A1 (en) * 2015-09-15 2017-03-23 Scholar Rock, Inc. Anti-pro/latent-myostatin antibodies and uses thereof
AU2016323447B2 (en) * 2015-09-15 2023-03-30 Scholar Rock, Inc. Anti-pro/latent-Myostatin antibodies and uses thereof
EP3922645A1 (en) * 2015-09-15 2021-12-15 Scholar Rock, Inc. Anti-pro/latent-myostatin antibodies and uses thereof
US12582712B2 (en) 2015-09-15 2026-03-24 Scholar Rock, Inc. Method of making anti-pro/latent myostatin antibodies
IL258121B1 (en) * 2015-09-15 2023-09-01 Scholar Rock Inc Anti-pro/latent-myostatin antibodies and uses thereof
US10751413B2 (en) 2015-09-15 2020-08-25 Scholar Rock, Inc. Anti-pro/latent-Myostatin antibodies and uses thereof
EP4461312A3 (en) * 2015-09-15 2025-01-22 Scholar Rock, Inc. Anti-pro/latent-myostatin antibodies and uses thereof
IL258121B2 (en) * 2015-09-15 2024-01-01 Scholar Rock Inc Anti-pro/latent-myostatin antibodies and uses thereof
EA038146B1 (ru) * 2015-09-15 2021-07-13 Сколар Рок, Инк. Антитела к про-/латентному миостатину и их применения
EP3949975A1 (en) * 2015-09-17 2022-02-09 Histide AG Pharmaceutical association of growth factor receptor agonist and adhesion protein inhibitor for converting a neoplastic cell into a non-neoplastic cell and uses thereof
WO2017046226A3 (en) * 2015-09-17 2017-06-29 Histide Ag Pharmaceutical association for converting a neoplastic cell into a non-neoplastic cell and uses thereof
WO2017046229A1 (en) * 2015-09-17 2017-03-23 Histide Ag Pharmaceutical association of growth factor receptor agonist and adhesion protein inhibitor for converting a neoplastic cell into a non-neoplastic cell and uses thereof
WO2017046227A3 (en) * 2015-09-17 2017-06-29 Histide Ag Pharmaceutical association of growth factor receptor agonist and adhesion protein inhibitor for converting a neoplastic cell into a non-neoplastic cell and uses thereof
EP3998076A1 (en) * 2015-09-17 2022-05-18 Histide AG Pharmaceutical association of growth factor receptor agonist and adhesion protein inhibitor for converting a neoplastic cell into a non-neoplastic cell and uses thereof
EP3906932A3 (en) * 2015-09-17 2021-12-01 Histide AG Pharmaceutical association of growth factor receptor agonist and adhesion protein inhibitor for converting a neoplastic cell into a non-neoplastic cell and uses thereof
WO2017046228A3 (en) * 2015-09-17 2017-06-29 Histide Ag Pharmaceutical association of growth factor receptor agonist and adhesion protein inhibitor for converting a neoplastic cell into a non-neoplastic cell and uses thereof
EP3875102A1 (en) * 2015-09-17 2021-09-08 Histide AG Pharmaceutical association of growth factor receptor agonist and adhesion protein inhibitor for converting a neoplastic cell into a non-neoplastic cell and uses thereof
WO2017088027A1 (en) * 2015-11-26 2017-06-01 Prince Henry's Institute Of Medical Research Trading As The Hudson Institute Of Medical Research Inhibin analogs
US11230583B2 (en) 2015-11-26 2022-01-25 Hudson Institute of Medical Research Inhibin analogs
EP3390443A4 (en) * 2015-12-18 2019-11-13 Chugai Seiyaku Kabushiki Kaisha ANTI-MYOSTATIN ANTIBODIES, POLYPEPTIDES WITH DEVIANT FC REGIONS AND METHOD OF USE
AU2016372934B2 (en) * 2015-12-18 2023-10-05 Chugai Seiyaku Kabushiki Kaisha Anti-myostatin antibodies, polypeptides containing variant Fc regions, and methods of use
US11359009B2 (en) 2015-12-25 2022-06-14 Chugai Seiyaku Kabushiki Kaisha Anti-myostatin antibodies and methods of use
US12252532B2 (en) 2015-12-25 2025-03-18 Chugai Seiyaku Kabushiki Kaisha Anti-myostatin antibodies and methods of use
JP2019504064A (ja) * 2016-01-08 2019-02-14 スカラー ロック インコーポレイテッドＳｃｈｏｌａｒ Ｒｏｃｋ，Ｉｎｃ． 抗プロ／潜在型ミオスタチン抗体およびその使用方法
US10882904B2 (en) 2016-01-08 2021-01-05 Scholar Rock, Inc. Methods for inhibiting myostatin activation by administering anti-pro/latent myostatin antibodies
US12006359B2 (en) 2016-01-08 2024-06-11 Scholar Rock, Inc. Methods for altering body composition by administering anti-pro/latent myostatin antibodies
WO2017120523A3 (en) * 2016-01-08 2017-08-17 Scholar Rock, Inc. Anti-pro/latent myostatin antibodies and methods of use thereof
US10287345B2 (en) 2016-01-08 2019-05-14 Scholar Rock, Inc. Methods for inhibiting myostatin activation by administering anti-pro/latent myostatin antibodies
JP2023018053A (ja) * 2016-01-08 2023-02-07 スカラー ロック インコーポレイテッド 抗プロ／潜在型ミオスタチン抗体およびその使用方法
JP2023108057A (ja) * 2016-03-11 2023-08-03 スカラー ロック インコーポレイテッド ＴＧＦβ１結合性免疫グロブリンおよびその使用
JP2022031403A (ja) * 2016-03-11 2022-02-18 スカラー ロック インコーポレイテッド ＴＧＦβ１結合性免疫グロブリンおよびその使用
WO2017156500A1 (en) * 2016-03-11 2017-09-14 Scholar Rock, Inc. Tgfb1-binding immunoglobulins and use thereof
CN109071646A (zh) * 2016-03-11 2018-12-21 供石公司 TGFβ1-结合免疫球蛋白及其用途
EP3365368B1 (en) 2016-03-11 2023-05-17 Scholar Rock, Inc. Tgfbeta1-binding immunoglobulins and use thereof
US11643459B2 (en) 2016-03-11 2023-05-09 Scholar Rock, Inc. TGFβ1-binding immunoglobulins and use thereof
EP4169942A1 (en) * 2016-03-11 2023-04-26 Scholar Rock, Inc. Tgfbeta1-binding immunoglobulins and use thereof
JP7794630B2 (ja) 2016-03-11 2026-01-06 スカラー ロック インコーポレイテッド ＴＧＦβ１結合性免疫グロブリンおよびその使用
JP2022028680A (ja) * 2016-03-11 2022-02-16 スカラー ロック インコーポレイテッド ＴＧＦβ１結合性免疫グロブリンおよびその使用
JP2019509737A (ja) * 2016-03-11 2019-04-11 スカラー ロック インコーポレイテッドＳｃｈｏｌａｒ Ｒｏｃｋ，Ｉｎｃ． ＴＧＦβ１結合性免疫グロブリンおよびその使用
US10946036B2 (en) 2016-06-13 2021-03-16 Scholar Rock, Inc. Use of myostatin inhibitors and combination therapies
KR102577551B1 (ko) * 2016-07-14 2023-09-11 스칼러 락, 인크. TGFβ 항체, 방법 및 용도
AU2017294772B2 (en) * 2016-07-14 2024-05-02 Scholar Rock, Inc. TGFB antibodies, methods, and uses
JP2019524094A (ja) * 2016-07-14 2019-09-05 スカラー ロック インコーポレイテッドＳｃｈｏｌａｒ Ｒｏｃｋ，Ｉｎｃ． Ｔｇｆｂ抗体、方法、及び使用
KR20190034560A (ko) * 2016-07-14 2019-04-02 스칼러 락, 인크. TGFβ 항체, 방법 및 용도
JP7128801B2 (ja) 2016-07-14 2022-08-31 スカラー ロック インコーポレイテッド Ｔｇｆｂ抗体、方法、及び使用
US12281159B2 (en) 2016-07-14 2025-04-22 Scholar Rock, Inc. TGFβ antibodies, methods and uses
EP3484499A4 (en) * 2016-07-14 2020-05-13 Scholar Rock, Inc. TGFB ANTIBODIES, METHODS AND USE
US12516115B2 (en) 2016-08-05 2026-01-06 Chugai Seiyaku Kabushiki Kaisha Composition for prophylaxis or treatment of IL-8 related diseases
US11780912B2 (en) 2016-08-05 2023-10-10 Chugai Seiyaku Kabushiki Kaisha Composition for prophylaxis or treatment of IL-8 related diseases
US11053308B2 (en) 2016-08-05 2021-07-06 Chugai Seiyaku Kabushiki Kaisha Method for treating IL-8-related diseases
EP3532494A4 (en) * 2016-10-26 2020-06-03 The Children's Medical Center Corporation METHOD AND COMPOSITIONS FOR MODULATING TRANSFORMATION GROWTH FACTOR BETA-REGULATED FUNCTIONS
US11136383B2 (en) 2016-10-26 2021-10-05 The Children's Medical Center Corporation Methods and compositions for modulaton of transforming growth factor beta-regulated functions
WO2018112362A1 (en) * 2016-12-16 2018-06-21 Biogen Ma Inc. Stabilized proteolytically activated growth differentiation factor 11
EP3366306A3 (en) * 2016-12-23 2018-11-28 Istanbul Universitesi Rektorlugu Use of some peptides in diagnosis and treatment of diabetes, obesity and metabolic diseases associated thereto
WO2018129329A1 (en) * 2017-01-06 2018-07-12 Scholar Rock, Inc. ISOFORM-SPECIFIC, CONTEXT-PERMISSIVE TGFβ1 INHIBITORS AND USE THEREOF
WO2018129395A1 (en) 2017-01-06 2018-07-12 Scholar Rock, Inc. Methods for treating metabolic diseases by inhibiting myostatin activation
JP2020503362A (ja) * 2017-01-06 2020-01-30 スカラー ロック インコーポレイテッドＳｃｈｏｌａｒ Ｒｏｃｋ，Ｉｎｃ． アイソフォーム特異的な、コンテクスト寛容ＴＧＦβ１阻害剤およびその使用
CN110382530A (zh) * 2017-01-06 2019-10-25 供石公司 亚型特异性、背景许可性TGFβ1抑制剂及其用途
JP7157744B2 (ja) 2017-01-06 2022-10-20 スカラー ロック インコーポレイテッド アイソフォーム特異的な、コンテクスト寛容ＴＧＦβ１阻害剤およびその使用
US11155611B2 (en) 2017-01-06 2021-10-26 Scholar Rock, Inc. Compositions and methods for making and using anti-myostatin antibodies
EP4218817A2 (en) 2017-01-06 2023-08-02 Scholar Rock, Inc. Methods for treating metabolic diseases by inhibiting myostatin activation
US10844115B2 (en) 2017-01-20 2020-11-24 Genzyme Corporation Bone-targeting antibodies
US12049496B2 (en) 2017-01-20 2024-07-30 Sanofi Anti-TGF-beta antibodies and their use
US12098194B2 (en) 2017-01-20 2024-09-24 Genzyme Corporation Bone-targeting antibodies
EP4286013A2 (en) 2017-05-09 2023-12-06 Scholar Rock, Inc. Lrrc33 inhibitors and use thereof
WO2018208888A1 (en) 2017-05-09 2018-11-15 Scholar Rock, Inc. Lrrc33 inhibitors and use thereof
US10875914B2 (en) 2017-05-11 2020-12-29 Argenx Bvba Nucleic acids encoding GARP-TGF-beta 1 antibodies
US10793627B2 (en) 2017-05-11 2020-10-06 Argenx Bvba GARP-TGF-β 1 IGG antibodies
US10479829B2 (en) 2017-05-11 2019-11-19 Argenx Bvba GARP-TGF-beta 1 antibodies
WO2019023661A1 (en) * 2017-07-28 2019-01-31 Scholar Rock, Inc. SPECIFIC INHIBITORS OF TGF-BETA 1 LTBP COMPLEX AND USES THEREOF
US12358992B2 (en) 2017-07-28 2025-07-15 Scholar Rock, Inc. LTBP complex-specific inhibitors of TGF-beta 1 and uses thereof
EP3658583A1 (en) * 2017-07-28 2020-06-03 Scholar Rock, Inc. Ltbp complex-specific inhibitors of tgf-beta 1 and uses thereof
US11230601B2 (en) 2017-10-10 2022-01-25 Tilos Therapeutics, Inc. Methods of using anti-lap antibodies
US12252531B2 (en) 2018-07-11 2025-03-18 Scholar Rock, Inc. Methods of screening for high-affinity, isoform-selective TGFβ1 inhibitors
US12122823B2 (en) 2018-07-11 2024-10-22 Scholar Rock, Inc. Isoform-selective TGFB1 inhibitors and use thereof
WO2020014473A1 (en) 2018-07-11 2020-01-16 Scholar Rock, Inc. TGFβ1 INHIBITORS AND USE THEREOF
WO2020014460A1 (en) 2018-07-11 2020-01-16 Scholar Rock, Inc. HIGH-AFFINITY, ISOFORM-SELECTIVE TGFβ1 INHIBITORS AND USE THEREOF
EP3677278A1 (en) 2018-07-11 2020-07-08 Scholar Rock, Inc. Isoform selective tgfbeta1 inhibitors and use thereof
EP4019046A1 (en) 2018-07-11 2022-06-29 Scholar Rock, Inc. Isoform selective tgfbeta1 inhibitors and use thereof
CN112996535B (zh) * 2018-07-11 2026-04-24 供石公司 高亲和性、亚型选择性TGFβ1抑制剂及其用途
CN112996535A (zh) * 2018-07-11 2021-06-18 供石公司 高亲和性、亚型选择性TGFβ1抑制剂及其用途
US11130803B2 (en) 2018-07-11 2021-09-28 Scholar Rock, Inc. Isoform-selective TGFβ1 inhibitors and use thereof
US11130802B2 (en) 2018-10-10 2021-09-28 Tilos Therapeutics, Inc. Anti-lap antibody variants
WO2020160291A2 (en) 2019-01-30 2020-08-06 Scholar Rock, Inc. LTBP COMPLEX-SPECIFIC INHIBITORS OF TGFβ AND USES THEREOF
TWI923549B (zh) 2019-01-30 2026-05-01 美商供石公司 TGFβ之LTBP複合物專一性抑制劑及其用途
EP3689905A3 (en) * 2019-01-30 2021-02-24 Scholar Rock, Inc. Ltbp complex-specific inhibitors of tgf-beta and uses thereof
US12173059B2 (en) 2019-01-30 2024-12-24 Scholar Rock, Inc. LTBP complex-specific inhibitors of TGFβ and uses thereof
WO2020160291A3 (en) * 2019-01-30 2020-09-10 Scholar Rock, Inc. LTBP COMPLEX-SPECIFIC INHIBITORS OF TGFβ AND USES THEREOF
US11365245B2 (en) 2019-01-30 2022-06-21 Scholar Rock, Inc. LTBP complex-specific inhibitors of TGFβ and uses thereof
EP3689905A2 (en) 2019-01-30 2020-08-05 Scholar Rock, Inc. Ltbp complex-specific inhibitors of tgf-beta and uses thereof
US11214614B2 (en) 2019-01-30 2022-01-04 Scholar Rock, Inc. LTBP complex-specific inhibitors of TGFβ and uses thereof
AU2020287902B9 (en) * 2019-06-05 2025-10-30 Io Biotech Aps TGF-beta vaccine
WO2020245264A1 (en) * 2019-06-05 2020-12-10 Io Biotech Aps Tgf-beta vaccine
AU2020287902B2 (en) * 2019-06-05 2025-10-16 Io Biotech Aps TGF-beta vaccine
US11312767B2 (en) 2019-08-28 2022-04-26 Chugai Seiyaku Kabushiki Kaisha Cross-species anti-latent TGF-beta 1 antibodies
US12371483B2 (en) 2019-08-28 2025-07-29 Chugai Seiyaku Kabushiki Kaisha Cross-species anti-latent TGF-beta 1 antibodies and methods of use
WO2021142448A2 (en) 2020-01-11 2021-07-15 Scholar Rock,Inc. Tgf-beta inhibitors and use thereof
WO2021142427A1 (en) 2020-01-11 2021-07-15 Scholar Rock, Inc. TGFβ INHIBITORS AND USE THEREOF
WO2021231732A1 (en) 2020-05-15 2021-11-18 Bristol-Myers Squibb Company Antibodies to garp
WO2022204581A2 (en) 2021-03-26 2022-09-29 Scholar Rock, Inc. Tgf-beta inhibitors and use thereof
WO2022256723A2 (en) 2021-06-03 2022-12-08 Scholar Rock, Inc. Tgf-beta inhibitors and therapeutic use thereof
EP4714494A2 (en) 2021-06-23 2026-03-25 Scholar Rock, Inc. A myostatin pathway inhibitor in combination with a glp-1 pathway activator for use in treating metabolic disorders
WO2022271867A1 (en) 2021-06-23 2022-12-29 Scholar Rock, Inc. A myostatin pathway inhibitor in combination with a glp-1 pathway activator for use in treating metabolic disorders
WO2023288277A1 (en) 2021-07-14 2023-01-19 Scholar Rock, Inc. Ltbp complex-specific inhibitors of tgfb1 and uses thereof
WO2023170242A1 (en) * 2022-03-09 2023-09-14 Universite Catholique De Louvain Bispecific antibodies
WO2023170241A1 (en) * 2022-03-09 2023-09-14 Universite Catholique De Louvain TGF-β ANTIBODIES
US12338279B2 (en) 2022-12-22 2025-06-24 Scholar Rock, Inc. Selective and potent inhibitory antibodies of myostatin activation

Also Published As

Publication number Publication date
IL301607B2 (en) 2025-08-01
US20150337034A1 (en) 2015-11-26
JP6796695B2 (ja) 2020-12-09
US10981981B2 (en) 2021-04-20
US20200131259A1 (en) 2020-04-30
IL301607A (en) 2023-05-01
AU2025201228A1 (en) 2025-05-08
SMT202100008T1 (it) 2021-03-15
HRP20201914T1 (hr) 2021-01-22
JP2016521283A (ja) 2016-07-21
EP3816625B1 (en) 2025-09-17
IL319092A (en) 2025-04-01
ES3053907T3 (en) 2026-01-27
SG10201913751RA (en) 2020-03-30
US20170210798A1 (en) 2017-07-27
US9758577B2 (en) 2017-09-12
ES2837042T3 (es) 2021-06-29
AU2017203611B2 (en) 2019-03-07
PL2981822T3 (pl) 2021-07-12
US12577296B2 (en) 2026-03-17
US20170190767A1 (en) 2017-07-06
PT2981822T (pt) 2020-12-07
RS61778B1 (sr) 2021-06-30
PL3816625T3 (pl) 2026-01-26
US20240368261A1 (en) 2024-11-07
IL301607B1 (en) 2025-04-01
SG10201800800YA (en) 2018-03-28
US12454570B2 (en) 2025-10-28
JP2021050201A (ja) 2021-04-01
DK2981822T3 (da) 2020-12-07
US20150361421A1 (en) 2015-12-17
US20160031980A1 (en) 2016-02-04
WO2014182676A3 (en) 2015-02-05
HUE052232T2 (hu) 2021-04-28
AU2021204415B2 (en) 2024-11-21
LT2981822T (lt) 2020-12-28
US11827698B2 (en) 2023-11-28
IL281549B1 (en) 2023-04-01
IL281549B2 (en) 2023-08-01
AU2019203834A1 (en) 2019-06-20
CY1123907T1 (el) 2022-03-24
JP2025179097A (ja) 2025-12-09
EP2981822B1 (en) 2020-09-02
IL281549A (en) 2021-05-31
EP3816625A1 (en) 2021-05-05
PL2981822T4 (pl) 2021-07-12
JP2017200915A (ja) 2017-11-09
EP2981822A2 (en) 2016-02-10
US9573995B2 (en) 2017-02-21
AU2017203611C1 (en) 2021-12-23
IL242193B (en) 2021-04-29
US20260109757A1 (en) 2026-04-23
SG11201508681QA (en) 2015-11-27
US20180022798A1 (en) 2018-01-25
AU2017203611A1 (en) 2017-06-15
EP4674866A3 (en) 2026-03-11
US20180016332A1 (en) 2018-01-18
CA2911514A1 (en) 2014-11-13
EP4674866A2 (en) 2026-01-07
HRP20251426T1 (hr) 2026-01-02
US10597443B2 (en) 2020-03-24
JP2020062007A (ja) 2020-04-23
JP2023156328A (ja) 2023-10-24
US20160289318A1 (en) 2016-10-06
US9399676B2 (en) 2016-07-26
SI2981822T1 (sl) 2021-08-31
US9758576B2 (en) 2017-09-12
US9580500B2 (en) 2017-02-28
AU2014262843A1 (en) 2015-11-19
AU2014262843B2 (en) 2017-06-22
US20150361175A1 (en) 2015-12-17
AU2021204415A1 (en) 2021-07-29
US20190085067A1 (en) 2019-03-21
EP2981822A4 (en) 2017-02-15
JP7819158B2 (ja) 2026-02-24
US20210284722A1 (en) 2021-09-16

Similar Documents

Publication Publication Date Title
US12454570B2 (en) Compositions and methods for growth factor modulation
US20170073406A1 (en) Compositions and methods for growth factor modulation
HK40048816A (en) Compositions and methods for growth factor modulation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14795041

Country of ref document: EP

Kind code of ref document: A2

WWE Wipo information: entry into national phase

Ref document number: 242193

Country of ref document: IL

ENP Entry into the national phase

Ref document number: 2911514

Country of ref document: CA

Ref document number: 2016513010

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2014795041

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2014262843

Country of ref document: AU

Date of ref document: 20140506

Kind code of ref document: A

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14795041

Country of ref document: EP

Kind code of ref document: A2

WWD Wipo information: divisional of initial pct application

Ref document number: 319092

Country of ref document: IL