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WO1993006843A1 - Peptide correspondant a des determinants antigeniques du virus du syndrome immunodeficitaire acquis htlv - Google Patents

Peptide correspondant a des determinants antigeniques du virus du syndrome immunodeficitaire acquis htlv Download PDF

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Publication number
WO1993006843A1
WO1993006843A1 PCT/US1992/008405 US9208405W WO9306843A1 WO 1993006843 A1 WO1993006843 A1 WO 1993006843A1 US 9208405 W US9208405 W US 9208405W WO 9306843 A1 WO9306843 A1 WO 9306843A1
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Prior art keywords
htlv
peptide
amino acid
acid sequence
envelope
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Application number
PCT/US1992/008405
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English (en)
Inventor
Thomas J. Palker
Barton F. Haynes
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Duke University
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Priority to EP92922125A priority Critical patent/EP0618804A4/fr
Priority to JP5507082A priority patent/JPH07502493A/ja
Publication of WO1993006843A1 publication Critical patent/WO1993006843A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • 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
    • A61P31/12—Antivirals
    • 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
    • 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
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/14011—Deltaretrovirus, e.g. bovine leukeamia virus
    • C12N2740/14022—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Definitions

  • the present invention relates, in general, to immunogenic preparations and, in particular, to synthetic peptides having amino acid sequences corresponding to antigenic determinants of the envelope proteins of human T-cell leukemia virus (HTLV) types I or II, and immunogenic compositions comprising same.
  • HTLV human T-cell leukemia virus
  • HTLV-1 and -II are exogenous, naturally occurring human retroviruses that preferentially infect thymus-derived (T) lymphocytes.
  • HTLV-1 and -II are causative agents of adult T-cell leukemias and lymphomas (ATLL) (Poiesz et al. Proc. Natl.
  • HTLV-1 infection in man can be associated with a "smoldering" pre-leukemic condition that can progress to an overt aggressive ATLL or can remain unchanged for years (Yamaguchi et al. Blood 62:758, 1983).
  • the apparent long latency period prior to onset of ATLL presents a major epidemiological problem in containing the spread of infection by healthy, HTLV-I+ carriers and in identifying those exposed to the virus.
  • HTLV-I can be transmitted by sexual intercourse, shared
  • HTLV-I infection has also been associated with tropical spastic
  • HTLV-II has been associated with a rare form of chronic leukemia called T-cell variant of Hairy Cell Leukemia
  • the envelope gene of HTLV-I encodes a 63-67 kilodalton (kd) glycoprotein precursor that is proteolytically processed to give rise to a mature gp46 external envelope glycoprotein and a 21kd transmembrane protein (Lee et al. Proc. Natl. Acad. Sci. USA 81:3856, 1984).
  • Kiyokawa et al (Proc. Natl. Acad. Sci. USA 81:6202, 1984) have expressed in E. coli the entire gp63 envelope precursor molecule of HTLV-I as two fragments, an N-terminal portion containing all but 12 amino acids of the external gp46 envelope
  • polymerized to form molecular aggregates are capable of inducing in mammals the production of high titers of neutralizing antibodies against HTLV-I or HTLV-II.
  • the invention relates to immunogenic preparations and vaccines made therefrom.
  • Synthetic peptides having amino acid sequences corresponding to antigenic determinants of the envelope proteins of either HTLV-I or HTLV-II are covalently coupled, either directly or through spacer molecules, to suitable carrier molecules to form immunogenic conjugates.
  • Vaccines comprising one or more such conjugates are disclosed.
  • the present invention comprises a synthetic peptide having an amino acid sequence corresponding to an antigenic determinant of the envelope glycoprotein of HTLV-I (or HTLV- II), which peptide is capable, either alone or when covalently linked to a carrier molecule, of inducing in a mammal high titers of protective antibodies against HTLV-I ( or HTLV-II).
  • the peptide of the instant invention corresponds to an antigenic determinant present in a hydrophilic region (Kyte and Doolittle J. Mol. Biol. 157:105, 1982) of an HTLV-I (Seiki et al. Proc. Natl. Acad. Sci. USA
  • the present invention comprises an immunogenic conjugate capable of inducing in a mammal high titers of protective antibodies against HTLV-I (or HTLV-II), said
  • conjugate comprising: (i) a carrier molecule
  • the present invention comprises a method of producing immunity to HTLV-I (or HTLV-II) comprising administering the above-described HTLV-I (or HTLV-II) specific
  • invention comprises a method of detecting the presence of anti-HTLV-I (or HTLV-II) antibodies in a biological test sample comprising contacting a peptide of the instant invention with the sample, allowing antibodies in the sample to complex with the peptide, and measuring the formation of the complex.
  • FIGURE 1 Reactivity of antibodies from
  • FIGURE 2 Reactivity of anti-synthetic peptide antisera to gp46 and gp63 envelope glycoproteins of
  • FIGURE 3 Specific inhibition of antipeptide antibody reactivity to HTLV-I gp46 in an immunoblot assay.
  • FIGURE 4A and 4B Mapping of an epitope of HTLV-I gp46 that is
  • TSP restricted cytotoxic T cell line P-10 from patient A with HTLV-I associated tropical spastic paraparesis
  • FIGURE 5 Absorption of neutralizing
  • FIGURE 6 Peptide absorption of
  • FIGURE 7 HTLV-I T-Cell/B-Cell Peptide. DETAILED DESCRIPTION OF INVENTION
  • the present invention relates to peptides corresponding to immunogenic epitopes of HTLV-1 and to peptides corresponding to immunogenic epitopes of HTLV-II, and to synthetic vaccines against HTLV-I and HTLV-II, respectively, made therefrom.
  • novel immunogenic agents are prepared by chemically synthesizing peptides sharing antigenic determinants with the gp46 envelope protein of HTLV-I or HTLV- II.
  • the peptides are linked to carrier molecules, thus, forming immunogenic conjugates (and/or are polymerized), rendering them suitable as vaccines.
  • These vaccines are useful for immunization against HTLV-I- or HTLV-II-related diseases when
  • peptides that should be studied for immunogenic potential included those corresponding to hydrophilic, charged regions of the HTLV-I and HTLV-II gp46 envelope
  • glycoproteins It was further determined that, of such peptides, those with predicted beta turns would likely be of particular importance. It was
  • disulfide bonds would be useful in establishing native configurational determinants. Also, it was recognized that formation of interchain disulfide bonds would be useful in polymerizing peptide molecules so as to form larger, more immunogenic peptide aggregates.
  • the peptides of the instant invention include peptides that correspond to, or are
  • peptides are about 25 amino acids (units) or less in length, are hydrophilic, and when conjugated to an appropriate carrier molecule, evoke the production in a mammal of high titers (1:1000) of anti-peptide antibodies that can react with the native gp46 envelope glycoprotein of HTLV-I.
  • Other peptides of the instant invention correspond to, or are
  • the synthetic peptides of the present invention can have an amino acid sequence as shown in Table 1, or a sequence which is similar enough to one of the sequences shown in Table l so as to be treated in the same manner by an antibody which bonds with the epitope represented by the specific sequence given in the table (that is, an
  • Each amino acid is represented by its single - letter code, which is the first letter of its name, except for arginine
  • R aspartic acid
  • D asparagine
  • N glutamine
  • Q glutamic acid
  • E glutamic acid
  • K lysine
  • F phenylalanine
  • W tryptophan
  • Y tyrosine
  • other synthetic peptides of the instant invention can have an amino acid sequence as shown in Table 2, or a sequence similar enough to one of the sequence shown in Table 2 so as to be treated in the same manner by an antibody which bonds with the epitope represented by the specific sequence given in the table (that is, an
  • Such synthetic peptides are hereinafter designated "HTLV-II-specific peptides.”
  • Cys can be either at N- or C-terminus.
  • Carrier molecules to which peptides of the invention are covalently linked (conjugated) are advantageously non-toxic, pharmaceutically
  • HTLV-I-specific and HTLV-II-specific peptides are suitable, and of a size sufficient to produce an immune response in a mammal.
  • suitable carrier molecules include tetanus toxoid, and keyhole limpet hemocyanin (KLH).
  • KLH keyhole limpet hemocyanin
  • Other carrier molecules to which HTLV-I-specific and HTLV-II-specific peptides can be linked include peptides comprising sequences corresponding to T-cell
  • LASGKSL amino acids to the N-terminus of I-T1 result in a peptide identified by murine T-helper cells.
  • HTLV-I and HTLV-II-specific peptides can also be administered with a pharmaceutically acceptable adjuvant, for example, alum, or
  • Linkage of a carrier molecule to HTLV-I or HTLV-II-specific peptides of the invention can be direct or through a spacer molecule.
  • Two glycine residues added to the amino terminal end of an HTLV-I or HTLV-II-specific peptide can provide a suitable spacer molecule for linking the peptide to a carrier molecule;
  • HTLV-I- or HTLV-II-specific peptides can, for example, be synthesized directly adjacent to, for example, another immunogenic HTLV-I or HTLV- II envelope sequence, for example, such as those sequences (or portions thereof) shown in Table 3. Cysteines can be added either at the N- or C- terminus of the HTLV-I or HTLV-II-specific peptides for conjugation to the carrier molecule, or to both ends to facilitate interchain polymerization via disulfide bond formation to form larger molecular aggregates.
  • HTLV-I- or HTLV-II-specific peptide is accomplished using a coupling agent.
  • M-maleimidobenzoyl-N-hydroxysuccinimide ester M-maleimidobenzoyl-N-hydroxysuccinimide ester
  • sulfo-MBS water soluble compound m-maleimido-benzoylsulfosuccinimide este
  • Vaccines of the instant invention which, when administered to a mammal, induce a protective immunogenic response against HTLV-I, comprise one or more immunogenic conjugate(s), each conjugate comprising an HTLV-I-specific peptide, wherein each HTLV-I-specific peptide corresponds to a different portion of the HTLV-I gp46 envelope protein.
  • one or more of the HTLV-I-specific peptides listed in Table 1 is conjugated to, or synthesized with, a predicted T-cell epitope of HTLV-I envelope or gag proteins, for example, those shown in Table 3.
  • a "chimera” is LPPTAPPLLPHSNLDHILEPSIPWKSKWTKKPNRNGGG (amino acid numbers 183-209/88-98 of HTLV-I envelope; designated DP-91).
  • immunogenic response against HTLV-II comprise one or more immunogenic conjugate(s), each conjugate comprising an HTLV-II-specific peptide, wherein each peptide corresponds to a different portion of the HTLV-II gp46 envelope protein.
  • one or more of the HTLV-II-specific peptides listed in Table 2 is conjugated to, or synthesized with, a predicted T-cell epitope, for example, those shown in Table 3.
  • a bivalent vaccine can be constructed whereby immunogenic conjugates as described above, comprising synthetic peptides from envelope proteins of HTLV-I and HTLV-II, are mixed to form a single inoculum such that protective antibodies will be simultaneously raised in a mammal to HTLV-I and HTLV-II.
  • helper T cells recognized by helper T cells, is that no other carrier molecule, such as tetanus toxoid, is required, and the B and T cell response to HTLV-I, or HTLV-II, is specific.
  • HTLV-I and HTLV-II- specific peptides alone or synthesized with a corresponding T cell epitope, can be treated with oxidizing agents to induce disulfide bond formation between peptide chain cysteines, to effect
  • HTLV-II-specific peptides as a vaccine, or as a component of a vaccine, these peptides can also be used for diagnostic purposes.
  • the presence and titers of antibodies to HTLV-I or HTLV-II envelope proteins in biological samples can be detected using HTLV-I- and HTLV-II-specific peptides in a solid phase radioimmunoassay (RIA) (Palker et al J.
  • RIA radioimmunoassay
  • HTVL-I- and HTLV-II-specific peptides of the instant invention can also be used in standard enzyme-linked immunosorbent assays (ELISA) to detect the presence of antibodies to HTLV-I or HTLV-II envelope
  • glycoproteins in biological samples are glycoproteins in biological samples.
  • synthetic peptides from HTLV-I gp46 envelope and HTLV-I p19 gag proteins are used, advantageously peptide 4A of Table 1 and a peptide containing the following carboxy-terminal sequence of HTLV-I pl9: Pro-Tyr-Val-Glu-Pro-Thr-Ala-Pro-Gln-Val-Leu.
  • these two peptides are recognized by antibodies in 95% of sera from HTLV-I+ subjects having antibodies to pl9 or gp46 (Palker et al. J. Immunol. 136:2393, 1986, and Figure 1).
  • combination of these two peptides can be used in an ELISA or a RIA to detect antibodies in sera from HTLV-I+ patients.
  • HTLV-I and HTLV-II specific test kits can be constructed for detecting antibodies to HTLV-I and HTLV-II in biological samples using techniques for detection that include ELISA, RIA, indirect immunofluorescence and Western blot analysis.
  • HTLV-II-specific peptides of the instant invention can be used in an antigen diagnostic assay using standard techniques.
  • Peptides were conjugated to the carrier molecule tetanus toxoid (TT) with MBS, as described by Green et al. (Cell, 28:447, 1982; Palker et al. Proc. Natl. Acad. Sci. USA 84:2479, 1987).
  • TT carrier molecule
  • MBS carrier molecule
  • Tetanus toxoid treated with MBS was then subjected to sieving chromatpgraphy on a PD-10 (Pharmacia) column to remove unreacted MBS from TT-MBS, and fractions containing TT-MBS were recovered in the void volume of the column as determined by spectrophotometric assay at an optical density of 280 nm.
  • TT-MBS was then incubated with rocking at 23°C for 3 hr. with 6-9 mg of synthetic peptide (molar ratio 30:1, peptide carrier protein) in PBS containing reduced cysteine at either the carboxyl or amino terminus.
  • TT-peptide conjugates were dialyzed overnight at 4°C against PBS or again desalted on a PD-10 column and were used as an immunogen.
  • Synthetic Peptides Synthetic peptides derived from hydrophilic regions of HTLV-1 gp46 (HTLV-I-synthetic peptides) were dissolved or suspended in 0.1M NaHCO buffer, pH 9.6 and 50 ⁇ g/well were incubated in
  • Immulon 2 microtiter wells (Dynatech) overnight at 4°C. Wells were emptied, and 200 ⁇ l of 5% nonfat dry milk (Carnation) in phosphate buffered saline (PBS) and 0.1% sodium azide were added to wells and incubated for 2 hr. Wells were emptied, washed once with PBS containing 5% nonfat dry milk and 0.05% Tween 20 (wash buffer) and incubated further with 1:50 dilutions of sera from either HTLV-I+ patients or normal subjects in wash buffer for 1 hr.
  • PBS phosphate buffered saline
  • Tween 20 wash buffer
  • HTLV-I encoded synthetic peptides SP-71 (Pro-Tyr-Val-Glu-Pro-Thr-Ala-Pro-Gln-Val-Leu) from the C-terminus of pl9 or portions thereof and synthetic peptide SP-4A of Table 1 from gh46 can be mixed, added to microtiter wells (10-50 ⁇ g of each peptide per microtiter well) in the RIA described above and used to detect antibodies to HTLV-I.
  • Pro-Tyr-Val-Glu-Pro-Thr-Thr-Thr-Gln-Cys-Phe or portions thereof containing an amino acid sequence from the C-terminus of HTLV-II pl9 can be added to microtiter wells (10-50 ⁇ g/well) as described above and used to detect antibodies to HTLV-II.
  • HTLV-I-specific peptides were covalently linked to tetanus toxoid (TT) as previously described, and used to immunize rabbits. After 1 immunization with 5mg of peptide-TT conjugate in Freunds complete adjuvant followed by 2 additional weekly boosts with conjugate in Freunds incomplete adjuvant, sera were collected and tested for reactivity to the
  • Antisera to HTLV-I synthetic peptides 1-6 reacted with a high degree of specificity to the immunizing peptide with minimum titers of 1:2000 in RIA.
  • antisera to peptides 1, 3, 4, 4A and 6 reacted with HTLV-I gp46 and/or gp63 (lanes 2, 4, 6, 8, 10, respectively), while pre-immune sera (lanes 1, 3, 5, 8, 9) did not react; anti-HTLV-I envelope monoclonal antibody 1C11, used as a positive control, also reacted with gp46 and gp63 (line 12) whereas negative control ascites fluid (P3X63) did not react (lane 11).
  • antiserum to gp46 in immunoblot assay could be specifically inhibited by pre-incubating antiserum with the corresponding peptide ( Figure 3).
  • Figure 3 To evaluate the specificity of anti-peptide antibody binding to gp46, antiserum to HTLV-I gp46 peptide SP-6 was pre-incubated with 200 ⁇ g of either SP-6 (lane 1) or SP-5 (lane 2) and then reacted with gp46 in immunoblot assay.
  • HTLV-I-specific peptides when coupled to carrier molecules can be used to raise antibodies to HTLV-I gp46.
  • FIG. 4A EBV-transformed B cells from patient A were incubated with HTLV-I env-encoded synthetic peptides 1-11 (Table 1), labelled with 51 Cr and used as targets to assess peptide-specific killing by autologous, cloned, cytotoxic T cell line P-10.
  • B cells coated with peptide SP-4A (A-A) and autologous T cells infected with HTLV-I (•-•) were both killed by the cytotoxic T cell line P-10 from patient A.
  • Untreated autologous B cells (o-o) or B cells coated with any of the remaining 11 peptides ( ⁇ - ⁇ ) were not killed.
  • FIG. 5B Two heterologous B cell lines (•-•, ⁇ - ⁇ ) matched with the cytotoxic T cell line P-10 at HLA-DR2 and one B cell line mismatched at HLA-DR2 (o-o) coated with peptide SP-4A and used as targets in cytotoxicity assays as described above. B cells coated with peptide 4A and matched at HLA-DR2 were killed by T cell line P-10 while
  • HTLV-I gp46 defined by peptide SP-4A (amino acids 198-209) contains an epitope identified by an HLA-DR2
  • VSV Virus
  • Pseudotype particles containing the VSV genome and HTLV-I envelope glycoproteins were titered to give 150-200 plaques per assay.
  • the assay was performed by Dr. Paul Clapham according to the procedure of Clapham et al. Proc. Natl. Acad. Sci. USA 81:2886, 1984, the entire contents of which document is hereby incorporated by reference.
  • Truncated peptides containing partial amino acid sequences of HTLV-I peptide SP-2 were synthesized and used in absorption experiments as described above. Only peptides containing HTLV-I envelope amino acids 86-98, 88-98 and 90-98 could absorb neutralizing antibodies in goat antisera #20 and 21. Studies mapped the neutralizing site to HTLV-I envelope amino acids 90-98. (See Table 6.)
  • 11 peptides (2L1.1 to 2L1.11) were synthesized in which sequential amino acids were each replaced by the amino acid alanine. These 11 mutated peptides, as well as peptide 2L-1 bearing the native HTLV-I sequence, were used to absorb neutralizing antibodies in three goat anti-SP-2 antisera (#20, 21 and 128), as described in Example 6.B. As shown in Table 7, peptides with alanine substitutions of asparagines in positions 91 and 93 (peptides 1.6 and 1.8) were not able to absorb neutralizing antibodies to HTLV-I in all 3 sera.
  • peptide 1.3 with an alanine substitution in position 90 was unable to absorb antibodies in sera #21 and 128, while peptide 1.5 (alanine in position 92) was unable to absorb neutralizing antibodies in serum #20.
  • Results identified HTLV-I envelope amino acids #90 (K), #92 (P), #93 (N), and #95 (N) as being important for HTLV-I neutralization.
  • Figure 6 Depicted in Figure 6 are the results of the same experiments summarized in Table 7 except that Figure 6 shows numbers of HTLV-I induced syncytia obtained for each peptide absorption of antisera #20, 21 and 128. Results are
  • Antisera were raised in 2 goats to a peptide with an amino acid sequence (amino acids 82-97) of HTLV-II envelope that was homologous to the neutralizing region of HTLV-I envelope defined above.
  • This HTLV-II peptide designated DP-90, was coupled to tetanus toxoid, and conjugates were used to immunize goats #120 and 135. (See Table 8.) Sera from both of these goats (but not pre-immune sera), neutralized HTLV-II as determined in
  • syncytium assays performed as described in Example 6.B., except that HTLV-II infected Mo-T cells were substituted for HTLV-I infected C91PL cells.
  • Antisera to the HTLV-II peptide DP-90 did not neutralize HTLV-I, indicating that HTLV-II envelope amino acids 82-97 contained an HTLV-II type-specific neutralizing site.
  • chimeric HTLV-I peptide containing HTLV-I envelope amino acids 183-209 synthesized amino-terminally to the HTLV-I envelope amino acids 183-209 contain a site recognized by murine T-helper cells (amino acids 190-209, Kurata et al, J. Immunol. 143:2024-2030, 1989), sites recognized by neutralizing monoclonal antibody 0.5 alpha (amino acids 186-195, Ralston et al, J. Biol. Chem. 264:16343-16346, 1989) and a neutralizing murine monoclonal antibody (amino acids 190-199, Tanaka et al, J. Immunol. 147:354-360), as well as a site (amino acids 196-209) recognized by CD4+, human cytotoxic T-cells
  • a vaccine for HTLV-I can further comprise at least one synthetic peptide
  • YAAQNRRGLDLLFWEQGGFLC amino acids 374-388 of gp21
  • CRFPNITNSHVPILQE amino acids 399-415

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Abstract

L'invention concerne des préparations immunogènes de peptides comprenant des séquences d'acides aminés correspondant à des déterminants antigéniques de la glycoprotéine d'enveloppe de HTLV-I ou HTLV-II couplés de manière covalente, directement ou par l'intermédiaire d'une molécule d'espacement, à des molécules porteuses permettant la vaccination de mammifères. L'invention concerne également l'utilisation desdits peptides dans des méthodes de diagnostic.
PCT/US1992/008405 1991-10-08 1992-10-08 Peptide correspondant a des determinants antigeniques du virus du syndrome immunodeficitaire acquis htlv WO1993006843A1 (fr)

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EP92922125A EP0618804A4 (fr) 1991-10-08 1992-10-08 Peptide correspondant a des determinants antigeniques du virus du syndrome immunodeficitaire acquis htlv.
JP5507082A JPH07502493A (ja) 1991-10-08 1992-10-08 Ｈｔｌｖの抗原決定基に対応するペプチド

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US771,553 1991-10-08

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US6110662A (en) * 1992-02-24 2000-08-29 Genelabs Technologies, Inc. HTLV-I/HTLV-II assay and method
EA009056B1 (ru) * 2002-12-20 2007-10-26 Амген, Инк. Связывающие агенты, ингибирующие миостатин

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US4663436A (en) * 1984-04-24 1987-05-05 Scripps Clinic And Research Foundation Leukemia-associated virus immunogen, vaccine and assay
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6110662A (en) * 1992-02-24 2000-08-29 Genelabs Technologies, Inc. HTLV-I/HTLV-II assay and method
EA009056B1 (ru) * 2002-12-20 2007-10-26 Амген, Инк. Связывающие агенты, ингибирующие миостатин
US7511012B2 (en) 2002-12-20 2009-03-31 Amgen Inc. Myostatin binding agents
AU2003301195B2 (en) * 2002-12-20 2010-01-07 Amgen Inc. Binding agents which inhibit myostatin
US7803923B2 (en) 2002-12-20 2010-09-28 Amgen Inc. Polynucleotides encoding myostatin binding agents
US7928075B2 (en) 2002-12-20 2011-04-19 Amgen Inc. Binding agents which inhibit myostatin
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AU2879292A (en) 1993-05-03
EP0618804A1 (fr) 1994-10-12
JPH07502493A (ja) 1995-03-16
EP0618804A4 (fr) 1995-06-07

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