EP0530216A1 - Administration of monoclonal antibodies against respiratory viruses - Google Patents
Administration of monoclonal antibodies against respiratory virusesInfo
- Publication number
- EP0530216A1 EP0530216A1 EP91908428A EP91908428A EP0530216A1 EP 0530216 A1 EP0530216 A1 EP 0530216A1 EP 91908428 A EP91908428 A EP 91908428A EP 91908428 A EP91908428 A EP 91908428A EP 0530216 A1 EP0530216 A1 EP 0530216A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- mab
- monoclonal antibody
- administered
- virus
- respiratory
- 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.)
- Withdrawn
Links
- 241000700605 Viruses Species 0.000 title claims abstract description 75
- 230000000241 respiratory effect Effects 0.000 title claims abstract description 35
- 241000725643 Respiratory syncytial virus Species 0.000 claims abstract description 36
- 241001465754 Metazoa Species 0.000 claims abstract description 34
- 238000000034 method Methods 0.000 claims abstract description 30
- 238000011321 prophylaxis Methods 0.000 claims abstract description 13
- 238000011282 treatment Methods 0.000 claims abstract description 8
- 108020001507 fusion proteins Proteins 0.000 claims abstract description 6
- 102000037865 fusion proteins Human genes 0.000 claims abstract description 6
- 239000000203 mixture Substances 0.000 claims description 13
- 208000002606 Paramyxoviridae Infections Diseases 0.000 claims description 6
- 241000712431 Influenza A virus Species 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 241000713196 Influenza B virus Species 0.000 claims description 4
- 239000000443 aerosol Substances 0.000 claims description 4
- 230000029058 respiratory gaseous exchange Effects 0.000 claims description 4
- 210000002345 respiratory system Anatomy 0.000 claims description 4
- 241000701161 unidentified adenovirus Species 0.000 claims description 3
- 230000000699 topical effect Effects 0.000 claims 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 14
- 239000002953 phosphate buffered saline Substances 0.000 description 14
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 12
- 241000144282 Sigmodon Species 0.000 description 12
- RFKMCNOHBTXSMU-UHFFFAOYSA-N methoxyflurane Chemical compound COC(F)(F)C(Cl)Cl RFKMCNOHBTXSMU-UHFFFAOYSA-N 0.000 description 11
- 229960002455 methoxyflurane Drugs 0.000 description 11
- 241000700159 Rattus Species 0.000 description 10
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 9
- 229940098773 bovine serum albumin Drugs 0.000 description 9
- 230000003472 neutralizing effect Effects 0.000 description 9
- 210000004072 lung Anatomy 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- 206010003497 Asphyxia Diseases 0.000 description 6
- 229910002092 carbon dioxide Inorganic materials 0.000 description 6
- 239000001569 carbon dioxide Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 229930006000 Sucrose Natural products 0.000 description 5
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 5
- 230000002685 pulmonary effect Effects 0.000 description 5
- 239000005720 sucrose Substances 0.000 description 5
- 239000012981 Hank's balanced salt solution Substances 0.000 description 4
- 241001135569 Human adenovirus 5 Species 0.000 description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 239000013553 cell monolayer Substances 0.000 description 4
- 229930195712 glutamate Natural products 0.000 description 4
- 229920001184 polypeptide Polymers 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 230000010076 replication Effects 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 241000029792 Sigmodon fulviventer Species 0.000 description 3
- 241000144290 Sigmodon hispidus Species 0.000 description 3
- 230000003612 virological effect Effects 0.000 description 3
- 108010068327 4-hydroxyphenylpyruvate dioxygenase Proteins 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 102000003886 Glycoproteins Human genes 0.000 description 2
- 108090000288 Glycoproteins Proteins 0.000 description 2
- 101710154606 Hemagglutinin Proteins 0.000 description 2
- 101710133291 Hemagglutinin-neuraminidase Proteins 0.000 description 2
- 108060003951 Immunoglobulin Proteins 0.000 description 2
- 101710093908 Outer capsid protein VP4 Proteins 0.000 description 2
- 101710135467 Outer capsid protein sigma-1 Proteins 0.000 description 2
- 101710176177 Protein A56 Proteins 0.000 description 2
- 230000000890 antigenic effect Effects 0.000 description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 2
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 2
- 108010074605 gamma-Globulins Proteins 0.000 description 2
- 102000018358 immunoglobulin Human genes 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- CXURGFRDGROIKG-UHFFFAOYSA-N 3,3-bis(chloromethyl)oxetane Chemical compound ClCC1(CCl)COC1 CXURGFRDGROIKG-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 239000007836 KH2PO4 Substances 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 102000005348 Neuraminidase Human genes 0.000 description 1
- 108010006232 Neuraminidase Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000003022 colostrum Anatomy 0.000 description 1
- 235000021277 colostrum Nutrition 0.000 description 1
- 230000009137 competitive binding Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 210000001944 turbinate Anatomy 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
- C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
- C07K16/1027—Paramyxoviridae, e.g. respiratory syncytial virus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- This invention relates to the prophylaxis and/or treatment of respiratory viruses. More particularly, this invention relates to the prophylaxis and/or treatment of respiratory viruses through the administration of monoclonal antibodies against a respiratory virus .
- Walsh, et al. , Infect, and Immun. . Vol. 43, pgs. 756-758 discloses the intraperitoneal administration of monoclonal antibodies against glycoproteins of respiratory syncytial virus to cotton rats, followed by an intranasal challenge of respiratory syncytial virus three hours after administration of the monoclonal antibody.
- Such treatment with the monoclonal antibodies resulted in the reduction of viral titers or in the absence of virus in the lungs of the cotton rats which were given the monoclonal antibodies, while virus was detected in the lungs of all rats in the control group.
- the treated group of rats also showed a decrease in virus growth in nasal turbinates.
- USSR Patent No. 745,523 (1978) discloses the intranasal administration of secretory IgA antibodies, isolated from female colostrum, to a group of infants in a children's hospital, prior to an outbreak of respiratory syncytial virus. Those infants who were given the antibodies prior to the outbreak contracted less severe cases of respiratory syncytial virus and had developed fewer complications associated with the virus , than those infants who were not administered the antibodies.
- U. S . Patent No. 4,800,078, issued to Prince, et al. discloses a method of treating respiratory disease caused by respiratory syncytial virus (RSV) by topically administering RSV antibodies into the lower respiratory tract.
- RSV respiratory syncytial virus
- the antibodies are administered as a purified human gamma globulin, and may be administered in an amount of from about 0.025 to 0.05g/kg of body weight.
- the purified human gamma globulin preparation may contain RSV neutralizing antibodies at a titer greater than 1 :2 ,000.
- a process for the prophylaxis of at least one respiratory virus in an animal comprising topically administering to the animal at least one monoclonal antibody against the at least one respiratory virus.
- the at least one monoclonal antibody is administered to the respiratory tract.
- Such administration may be by intranasal administration or by breathing an aerosol containing said at least one monoclonal antibody.
- the animal is a human animal.
- the at least one monoclonal antibody is also a neutralizing antibody.
- Representative respiratory viruses include respiratory syncytial viruses, or RSV, parainfluenza viruses (types 1, 2, and 3) , influenza A viruses, influenza B viruses, and adenoviruses .
- the at least one respiratory virus is a respiratory syncytial virus, and the monoclonal antibody or antibodies administered are preferably against a fusion protein of RSV.
- monoclonal antibodies against a fusion protein of respiratory syncytial virus include MAb 1436C , MAb 1153 , MAb 1142 , MAb 151, MAb 1200, MAb 1214, MAb 1237, MAb 1129, MAb 1121 , MAb 1107, MAb 13-1 , MAb 43-1 , MAb 1112 , MAb 1269, MAb 1243 , MAb 1331H, MAb 1308F, MAb 1302 A.
- Such antibodies are neutralizing antibodies.
- Particularly preferred monoclonal antibodies are MAb 1121 , MAb 1129, MAb 1142 , MAb 1153 , MAb 1243, MAb 1302A, MAb 1308F, and MAb 1331H.
- monoclonal antibodies as hereinabove described may be employed in the prophylaxis of respiratory syncytial virus.
- These antibodies have been characterized with regard to their neutralizing potential, both to parental RSV strains used to immunize mice to generate these antibodies, as well as a number of different virus strains isolated from 1956 to 1985 from various geographical locations.
- These antibodies have also been mapped by competitive binding and reactivity profiles of virus escape mutants to three broad antigenic sites (A, B, and C) containing 16 distinct epitopes . Epitopes within antigenic sites A and C show the least variability in natural isolates.
- Such monoclonal antibodies are further described in Beeler, et al. , J. Virol. , Vol. 63, No. 7, pgs. 2941-2950 (July, 1989) .
- non-neutralizing monoclonal antibodies against a fusion protein of respiratory syncytial virus include MAb 1224-1, MAb 1175-40, MAb 1105-1, MAb 1219-22 , MAb 1228-28, and MAb 1113-44. These monoclonal antibodies do not neutralize virus infectivity in vitro; however, these antibodies prevent virus replication in cells in vivo . These antibodies may be obtained from Dr. Judy A. Beeler, of the Laboratory of Infectious Diseases, National Institutes of Allergy and Infectious Diseases, Bethesda, Maryland 20892.
- monoclonal antibodies against parainfluenza viruses include MAb 271/7, MAb 170/7, MAb 423/4, MAb 61/5, MAb 403/7 , MAb 77/5 , MAb 447/12 , MAb 101/1, MAb 128/9, MAb 454/11, MAb 149/3, MAb 429/5, MAb 66/4, MAb 68/2, MAb 451/4 and MAb 166/11.
- Such monoclonal antibodies recognize one of 10 epitopes of the hemagglutinin-neuraminidase (HN) protein of human parainfluenza Type 3 virus.
- HN hemagglutinin-neuraminidase
- monoclonal antibodies against influenza A viruses include MAb 22/1, MAb70/l, MAb 110/1, MAb 264/2, MAb W18/1, MAb 14/3, MAb 24/4, MAb 47/8, MAb 198/2 and MAb 215/2. These monoclonal antibodies are further described in Webster, et al. , Virology, Vol. 96 , pgs 258-264 (1979) . Further examples of monoclonal antibodies against influenza A virus include monoclonal antibodies H2/6A5, H3/4C4, H2/6C4, H2/4B3, H9/B20, H2/4B1, and PEG-1. These monoclonal antibodies are further described in Laver, et al. Proc. Nat. Acad. Sci. , Vol 76, No. 3 , pgs. 1425-1429 (March 1979) . The hereinabove described monoclonal antibodies react against the hemagglutinin protein or the neuraminidase protein of influenza A virus.
- monoclonal antibodies against influenza B viruses inlcude monoclonal antibodies 113/2 , 124/4, 128/2 , 134/1, 146/1 , 152/2 , 160/1 , 162/1, 195/3, 206/2 , 238/4, and 280/2.
- the monoclonal antibodies react against the hemagglutinin protein of influenza B virus.
- Such monoclonal antibodies are further described in Oxford, et al. , J ⁇ Gen. Virol. Vol. 64, pgs 2367-2377 (1983) .
- Monoclonal antibodies against adenoviruses include monoclonal antibodies 5Hx-l, 5Hx-2 , 5Hx-3, 5Hx-4, 5Hx-5, 5.100K-1 , 5PB-1, and 5Fb-l. Monoclonal antibodies 5Hx-l, 5Hx-2 , 5Hx-3 , 5Hx-4 , and 5Hx-5 were found to react against the hexon polypeptide of adenovirus type 5. Monoclonal antibody 5.100K-1 was found to react against the 100K polypeptide of adenovirus type 5.
- Monoclonal antibody 5PB-1 was found to react against the penton base polypeptide of adenovirus type 5, and monoclonal antibody 5Fb-l was found to react against the fibre polypeptide of adenovirus type 5.
- monoclonal antibodies are further described in Russell, et al. , J. Gen. Virol. . Vol. 56, pgs. 393-408 (1981) .
- a mixture of monoclonal antibodies may be administered against more than one type of respiratory virus .
- one may administer at least one monoclonal antibody against a respiratory syncytial virus and at least one monoclonal antibody against parainfluenza Type 3 virus for the prophylaxis of respiratory syncytial virus and parainfluenza Type 3 virus.
- other combinations of monoclonal antibodies may be administered as well, with such combinations depending upon the combination of respiratory viruses one wishes to prevent.
- the at least one monoclonal antibody when administered to the respiratory tract, either intranasally or by breathing an aerosol containing said at least one monoclonal antibody, is administered in an amount of from about lO ⁇ g to about 250mg, preferably of from about 5mg to about 125mg.
- a process for the prophylaxis of at least one respiratory virus in an animal which comprises intramuscularly administering to the animal at least one monoclonal antibody against the at least one respiratory virus.
- the at least one respiratory virus may be selected from those hereinabove described, and the monoclonal antibody or antibodies which may be administered, may be selected from those hereinabove described as well.
- the at least one monoclonal antibody when administered intramuscularly, is administered in an amount of from about lmg to about 250mg, preferably from about 5mg to about lOOmg.
- One monoclonal antibody, or a mixture of monoclonal antibodies against one or more respiratory viruses, may be administered.
- a process for the treatment of at least one respiratory virus in an animal which comprises administering to the animal at least one monoclonal antibody against the at least one respiratory virus.
- the at least one respiratory virus may be selected from those hereinabove described, and the monoclonal antibody or antibodies which may be administered, may be selected from those hereinabove described as well.
- One monoclonal antibody, or a mixture of monoclonal antibodies against one or more respiratory viruses may be administered.
- the at least one monoclonal antibody may be administered topically or systemically. Examples of topical administration include intranasal administration, or administration by breathing an aerosol containing the at least one monoclonal antibody. Examples of systemic administration include intramuscular administration and intravenous administration .
- the at least one monoclonal antibody when administered topically , is administered to the animal in an amount of from about lO ⁇ g to about 500mg preferably of from about 5mg to about 250mg.
- the at least one monoclonal antibody is administered in an amount of from about lmg to about 250mg, preferably from about 5mg to about lOOmg.
- the at least one monoclonal antibody whether administered topically or systemically, and whether administered for the prophylaxis or treatment of at least one respiratory virus, preferably is administered in conjunction with a suitable amount of a pharmaceutical carrier.
- suitable pharmaceutical carriers include isotonic solutions such as 5% dextrose or 0.9% saline. If a lyopholized preparation is desired , stabilizers such as 0.25M glycine, 10% maltose or 10% sucrose may be included.
- Example 1 Eight different monoclonal antibodies, each of which is specific for RSV fusion protein (F glycoprotein) , were tested for their ability to block RSV replication when administered to cotton rats by the intranasal route prior to the virus challenge. These antibodies represent seven different epitopes, reacted with at least 13 of 14 virus isolates tested, and retained the greatest neutralizing activity against virus escape mutants selected with the other antibodies. The features of each of the eight antibodies are summarized in Table I below.
- Cotton rats S. fulviventer
- Cotton rats in groups of three rats each, average weight 100 grams, were anesthetized with methoxyflurane and given 0.1ml of an antibody solution at a concentration of lOmg/ml or lmg/ml in phosphate buffered saline (PBS) by intranasal (i.n. ) instillation.
- PBS phosphate buffered saline
- the antibody was one of the eight monoclonal antibodies hereinabove described, or a pooled mixture of all eight monoclonal antibodies (lOmg/ml total, 1.25mg/ml each or lmg/ml total, 0.125mg/ml each) , or standard human immune globulin (Sandoglobulin, Sandoz, Inc . , East Hanover, N.J. ) .
- Control rats were given 0.1ml of a bovine serum albumin (BSA) suspension (lOmg/ml or lmg/ml) in PBS .
- BSA bovine serum albumin
- Each of the monoclonal antibodies showed a significant reduction in pulmonary virus titer, and were at least as effective and in most cases more effective than the standard immune globulin or the pool of the eight monoclonal antibodies. Five of the eight monoclonal antibodies appear to prevent infection at the high dose (lOmg/ml) and one (1331H) even at the low dose (lmg/ml) .
- Example 2 Cotton rats (S. fulviventer) in groups of three rats each, average weight 100 grams, were injected with 0.1ml in each flank (0.2ml total) of bovine serum albumin (BSA) , or 0.1ml in each flank (0.2ml total) of either MAb 1129 or MAb 1331H.
- the monoclonal antibodies are at a concentration of lOmg/ml.
- the rats were anesthetized with methoxyflurane and challenged by in tra- nasal instillation of 10 5 0 PFU of the Long Strain of RSV.
- Four days after the virus challenge the rats were sacrificed by carbon dioxide asphyxiation, the lungs were harvested, and the virus content was determined.
- FIG 2 there was a significant reduction in pulmonary virus titers in rats treated with either of the monoclonal antibodies as compared with the BSA treated rats.
- Example 3 Cotton rats (S. fulviventer) in groups of three rats each, average weight 100 grams, were anesthetized with methoxyflurane and challenged with 10 5 * 0 PFU of the Long strain of RSV. Three days later, the animals were anesthetized with methoxyflurane and given 0.1ml of a solution of
- Example 4 The eight monoclonal antibodies described above in Example 1 were further examined for their ability to block RSV replication when administered to cotton rats by the intranasal route prior to virus challenge.
- Cotton rats S . hispidus, 4 animals per group, average weight 100 grams
- PBS phosphate-buffered saline
- Control animals were given 0.1 ml of a bovine serum albumin suspension (1 mg/ml) in PBS .
- Virus titers were determined using a plaque assay on HEp-2 cell monolayers as disclosed by Prince, et al. , Am. J. Pathol. , Vol. 93, pgs. 771-792 (1978) and are expressed as PFU per gram of tissue.
- Figure 4 shows that each of the monoclonal antibodies, except MAb 1243, showed a significant reduction in pulmonary virus titer when given at the 0.1 mg or 1 mg doses.
- Example 5 Neutralizing monoclonal antibodies (MAbs) reactive with the F protein of RSV were examined for effectiveness in blocking RSV replication when combined and administered to cotton rats.
- MAbs 1121 and 1302 A were mixed in equal amounts.
- Cotton rats (S. hispidus. 4 animals per group, average weight 100 grams) were anesthetized with methoxyflurane and given 0.1 ml of antibody solution, either the mixture or the individual antibodies at 1 mg/ml, 0.1 mg/ml or 0.01 mg/ml in phosphate -buffered saline (PBS) by intranasal (i.n. ) instillation.
- Control animals were given 0.1 ml of a bovine serum albumin solution (1 mg/ml) in PBS .
- Figure 5 shows that MAbs 1121 and 1302A when combined together are more effective in reducing viral titers as compared to their individual effects even at a total concentration of 0.01 mg/ml.
- Example 6 Six non- neutralizing MAbs, reactive with the F protein of RSV were examined for their ability to block RSV replication when adminsitered to cotton rats by the intranasal route prior to challenge with virus.
- Cotton rats S . hispidus. 4 animals per group, average weight 100 grams
- PBS phosphate-buffered saline
- Control animals were given 0.1 ml of a bovine serum albumin solution (10 mg/ml) in PBS .
- animals were again anesthetized with methoxyflurane and challenged by i.n.
- plaque forming units 10 ' plaque forming units (PFU) of the Long strain of RSV.
- PFU plaque forming units
- Lungs were harvested and homogenized in 10 parts (wt/vol) of Hanks balanced salt solution supplemented with 0.218 M sucrose, 4.4 mM glutamate, 3.8 mM KH j PO. and 3.2 mM K j HPO, and the resulting suspension was stored at -70°C until assayed for virus content.
- Virus titers were determined using a plaque assay on HEp-2 cell monolayers as disclosed by Prince et al (1978) and are expressed as PFU per gram of tissue.
- these non-neutralizing antibodies were effective in significantly decreasing pulmonary viral titers in treated animals even though they do not neutralize virus infectivity in vitro .
Landscapes
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Virology (AREA)
- Biochemistry (AREA)
- Immunology (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pulmonology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
Procédé de prophylaxie et/ou de traitement de virus respiratoires consistant à administrer localement ou par voie générale, à un animal, au moins un anticorps monoclonal contre au moins un virus respiratoire. L'invention est applicable notamment à la prophylaxie du virus respiratoire syncytial, ou VRS, par administration d'au moins un anticorps monoclonal contre une protéine de fusion du virus respiratoire syncytial.Method for the prophylaxis and / or treatment of respiratory viruses comprising administering locally or generally, to an animal, at least one monoclonal antibody against at least one respiratory virus. The invention is applicable in particular to the prophylaxis of respiratory syncytial virus, or RSV, by administration of at least one monoclonal antibody against a fusion protein of respiratory syncytial virus.
Description
ADMINISTRATION OF MONOCLONAL ANTIBODIES AGAINST RESPIRATORY VIRUSES
This application is a continuation-in-part of Application Serial No . 522 ,922 , filed April 19, 1990.
This invention relates to the prophylaxis and/or treatment of respiratory viruses. More particularly, this invention relates to the prophylaxis and/or treatment of respiratory viruses through the administration of monoclonal antibodies against a respiratory virus .
Walsh, et al. , Infect, and Immun. . Vol. 43, pgs. 756-758 (Feb . 1984) , discloses the intraperitoneal administration of monoclonal antibodies against glycoproteins of respiratory syncytial virus to cotton rats, followed by an intranasal challenge of respiratory syncytial virus three hours after administration of the monoclonal antibody. Such treatment with the monoclonal antibodies resulted in the reduction of viral titers or in the absence of virus in the lungs of the cotton rats which were given the monoclonal antibodies, while virus was detected in the lungs of all rats in the control group. The treated group of rats also showed a decrease in virus growth in nasal turbinates.
USSR Patent No. 745,523 (1978) discloses the intranasal administration of secretory IgA antibodies, isolated from female colostrum, to a group of infants in a children's hospital, prior to an outbreak of respiratory syncytial virus. Those infants who were given the antibodies prior to the outbreak contracted less severe cases of respiratory syncytial virus and had developed fewer complications associated with the virus , than those infants who were not administered the antibodies.
U. S . Patent No. 4,800,078, issued to Prince, et al. discloses a method of treating respiratory disease caused by respiratory syncytial virus (RSV) by topically administering RSV antibodies into the lower respiratory tract. The antibodies are administered as a purified human gamma globulin, and may be administered in an amount of from about 0.025 to 0.05g/kg of body weight. The purified human gamma globulin preparation may contain RSV neutralizing antibodies at a titer greater than 1 :2 ,000.
In accordance with an aspect of the present invention, there is provided a process for the prophylaxis of at least one respiratory virus in an animal comprising topically administering to the animal at least one monoclonal antibody against the at least one respiratory virus.
Preferably, the at least one monoclonal antibody is administered to the respiratory tract. Such administration may be by intranasal administration or by breathing an aerosol containing said at least one monoclonal antibody. In another preferred embodiment, the animal is a human animal.
In one embodiment, the at least one monoclonal antibody is also a neutralizing antibody.
Representative respiratory viruses include respiratory syncytial viruses, or RSV, parainfluenza viruses (types 1, 2, and 3) , influenza A viruses, influenza B viruses, and adenoviruses . In one embodiment, the at least one respiratory virus is a respiratory syncytial virus, and the monoclonal antibody or antibodies administered are preferably against a fusion protein of RSV.
Representative examples of monoclonal antibodies against a fusion protein of respiratory syncytial virus include MAb 1436C , MAb 1153 , MAb 1142 , MAb 151, MAb 1200, MAb 1214, MAb 1237, MAb 1129, MAb 1121 , MAb 1107, MAb 13-1 , MAb 43-1 , MAb 1112 , MAb 1269, MAb 1243 , MAb 1331H, MAb 1308F, MAb 1302 A. Such antibodies are neutralizing antibodies. Particularly preferred monoclonal antibodies are MAb 1121 , MAb 1129, MAb 1142 , MAb 1153 , MAb 1243, MAb 1302A, MAb 1308F, and MAb 1331H. It is also contemplated that a mixture of such monoclonal antibodies as hereinabove described may be employed in the prophylaxis of respiratory syncytial virus. These antibodies have been characterized with regard to their neutralizing potential, both to parental RSV strains used to immunize mice to generate these antibodies, as well as a number of different virus strains isolated from 1956 to 1985 from various geographical locations. These antibodies have also been mapped by competitive binding and reactivity profiles of virus escape mutants to three broad antigenic sites (A, B, and C) containing 16 distinct epitopes . Epitopes within antigenic sites A and C show the least variability in natural isolates. Such monoclonal antibodies are further described in Beeler, et al. , J. Virol. , Vol. 63, No. 7, pgs. 2941-2950 (July, 1989) .
Representative examples of non-neutralizing monoclonal antibodies against a fusion protein of respiratory syncytial virus include MAb 1224-1, MAb 1175-40, MAb 1105-1, MAb 1219-22 , MAb 1228-28, and MAb 1113-44. These monoclonal antibodies do not neutralize virus infectivity in vitro; however, these antibodies prevent virus replication in cells in vivo . These antibodies may be obtained from Dr. Judy A. Beeler, of the
Laboratory of Infectious Diseases, National Institutes of Allergy and Infectious Diseases, Bethesda, Maryland 20892.
Representative monoclonal antibodies against parainfluenza viruses include MAb 271/7, MAb 170/7, MAb 423/4, MAb 61/5, MAb 403/7 , MAb 77/5 , MAb 447/12 , MAb 101/1, MAb 128/9, MAb 454/11, MAb 149/3, MAb 429/5, MAb 66/4, MAb 68/2, MAb 451/4 and MAb 166/11. Such monoclonal antibodies recognize one of 10 epitopes of the hemagglutinin-neuraminidase (HN) protein of human parainfluenza Type 3 virus. These monoclonal antibodies are further described in Coelingh, et al, Virology. Vol. 143 , pgs 569-582 (1985) .
Representative monoclonal antibodies against influenza A viruses include MAb 22/1, MAb70/l, MAb 110/1, MAb 264/2, MAb W18/1, MAb 14/3, MAb 24/4, MAb 47/8, MAb 198/2 and MAb 215/2. These monoclonal antibodies are further described in Webster, et al. , Virology, Vol. 96 , pgs 258-264 (1979) . Further examples of monoclonal antibodies against influenza A virus include monoclonal antibodies H2/6A5, H3/4C4, H2/6C4, H2/4B3, H9/B20, H2/4B1, and PEG-1. These monoclonal antibodies are further described in Laver, et al. Proc. Nat. Acad. Sci. , Vol 76, No. 3 , pgs. 1425-1429 (March 1979) . The hereinabove described monoclonal antibodies react against the hemagglutinin protein or the neuraminidase protein of influenza A virus.
Representative monoclonal antibodies against influenza B viruses inlcude monoclonal antibodies 113/2 , 124/4, 128/2 , 134/1, 146/1 , 152/2 , 160/1 , 162/1, 195/3, 206/2 , 238/4, and 280/2. The monoclonal antibodies react against the hemagglutinin protein of influenza B virus. Such
monoclonal antibodies are further described in Oxford, et al. , J^ Gen. Virol. Vol. 64, pgs 2367-2377 (1983) .
Representative monoclonal antibodies against adenoviruses include monoclonal antibodies 5Hx-l, 5Hx-2 , 5Hx-3, 5Hx-4, 5Hx-5, 5.100K-1 , 5PB-1, and 5Fb-l. Monoclonal antibodies 5Hx-l, 5Hx-2 , 5Hx-3 , 5Hx-4 , and 5Hx-5 were found to react against the hexon polypeptide of adenovirus type 5. Monoclonal antibody 5.100K-1 was found to react against the 100K polypeptide of adenovirus type 5. Monoclonal antibody 5PB-1 was found to react against the penton base polypeptide of adenovirus type 5, and monoclonal antibody 5Fb-l was found to react against the fibre polypeptide of adenovirus type 5. Such monoclonal antibodies are further described in Russell, et al. , J. Gen. Virol. . Vol. 56, pgs. 393-408 (1981) .
It is also contemplated, that within the scope of the present invention, a mixture of monoclonal antibodies may be administered against more than one type of respiratory virus . For example, one may administer at least one monoclonal antibody against a respiratory syncytial virus and at least one monoclonal antibody against parainfluenza Type 3 virus for the prophylaxis of respiratory syncytial virus and parainfluenza Type 3 virus. It is to be understood that other combinations of monoclonal antibodies may be administered as well, with such combinations depending upon the combination of respiratory viruses one wishes to prevent.
The at least one monoclonal antibody, when administered to the respiratory tract, either intranasally or by breathing an aerosol
containing said at least one monoclonal antibody, is administered in an amount of from about lOμg to about 250mg, preferably of from about 5mg to about 125mg.
In accordance with another aspect of the present invention, there is provided a process for the prophylaxis of at least one respiratory virus in an animal, preferably a human animal, which comprises intramuscularly administering to the animal at least one monoclonal antibody against the at least one respiratory virus. The at least one respiratory virus may be selected from those hereinabove described, and the monoclonal antibody or antibodies which may be administered, may be selected from those hereinabove described as well.
The at least one monoclonal antibody, when administered intramuscularly, is administered in an amount of from about lmg to about 250mg, preferably from about 5mg to about lOOmg. One monoclonal antibody, or a mixture of monoclonal antibodies against one or more respiratory viruses, may be administered.
In accordance with another aspect of the present invention, there is provided a process for the treatment of at least one respiratory virus in an animal, which comprises administering to the animal at least one monoclonal antibody against the at least one respiratory virus. The at least one respiratory virus may be selected from those hereinabove described, and the monoclonal antibody or antibodies which may be administered, may be selected from those hereinabove described as well. One monoclonal antibody, or a mixture of monoclonal antibodies against one or more respiratory viruses may be administered.
The at least one monoclonal antibody may be administered topically or systemically. Examples of topical administration include intranasal administration, or administration by breathing an aerosol containing the at least one monoclonal antibody. Examples of systemic administration include intramuscular administration and intravenous administration .
The at least one monoclonal antibody, when administered topically , is administered to the animal in an amount of from about lOμg to about 500mg preferably of from about 5mg to about 250mg. When administered systemically, the at least one monoclonal antibody is administered in an amount of from about lmg to about 250mg, preferably from about 5mg to about lOOmg.
The at least one monoclonal antibody, whether administered topically or systemically, and whether administered for the prophylaxis or treatment of at least one respiratory virus, preferably is administered in conjunction with a suitable amount of a pharmaceutical carrier. Examples of suitable pharmaceutical carriers include isotonic solutions such as 5% dextrose or 0.9% saline. If a lyopholized preparation is desired , stabilizers such as 0.25M glycine, 10% maltose or 10% sucrose may be included.
The invention will now be described with respect to the following examples; however, the scope of the present invention is not intended to be limited thereby.
Example 1
Eight different monoclonal antibodies, each of which is specific for RSV fusion protein (F glycoprotein) , were tested for their ability to block RSV replication when administered to cotton rats by the intranasal route prior to the virus challenge. These antibodies represent seven different epitopes, reacted with at least 13 of 14 virus isolates tested, and retained the greatest neutralizing activity against virus escape mutants selected with the other antibodies. The features of each of the eight antibodies are summarized in Table I below.
Table I
Cotton rats (S. fulviventer) , in groups of three rats each, average weight 100 grams, were anesthetized with methoxyflurane and given 0.1ml of an antibody solution at a concentration of lOmg/ml or lmg/ml in phosphate buffered saline (PBS) by intranasal (i.n. ) instillation. The antibody was one of the eight monoclonal antibodies hereinabove described, or a pooled mixture of all eight monoclonal antibodies (lOmg/ml total, 1.25mg/ml each or lmg/ml total, 0.125mg/ml each) , or standard human immune globulin (Sandoglobulin, Sandoz, Inc . , East Hanover,
N.J. ) . Control rats were given 0.1ml of a bovine serum albumin (BSA) suspension (lOmg/ml or lmg/ml) in PBS .
One day later, animals were again anesthetized with methoxyflurane and challenged by i.n . instillation of 10 5 0 plaque forming units (PFU) of the Long strain of RSV. Four days after virus challenge, all animals were sacrificed by carbon dioxide asphyxiation. Lungs were harvested and homogenized in 10 parts (wt/vol) of Hanks balanced salt solution supplemented with 0.218 M sucrose, 4.4 mM glutamate, 3.8 mM KH^PO . and 3.2 mM K-HPO. and the resulting suspension was stored at -70°C until assayed for virus content. Virus titers were determined using a plaque assay on HEp-2 cell monolayers as disclosed by Prince, et al. ,
Am. J. Pathol. . Vol. 93, pgs. 771-792 (1978) and are expressed as PFU per gram of tissue. The virus titers for each preparation administered are shown in Figure 1.
Each of the monoclonal antibodies showed a significant reduction in pulmonary virus titer, and were at least as effective and in most cases more effective than the standard immune globulin or the pool of the eight monoclonal antibodies. Five of the eight monoclonal antibodies appear to prevent infection at the high dose (lOmg/ml) and one (1331H) even at the low dose (lmg/ml) .
Example 2 Cotton rats (S. fulviventer) in groups of three rats each, average weight 100 grams, were injected with 0.1ml in each flank (0.2ml total) of bovine serum albumin (BSA) , or 0.1ml in each flank (0.2ml total) of
either MAb 1129 or MAb 1331H. The monoclonal antibodies are at a concentration of lOmg/ml. One day later, the rats were anesthetized with methoxyflurane and challenged by in tra- nasal instillation of 10 5 0 PFU of the Long Strain of RSV. Four days after the virus challenge, the rats were sacrificed by carbon dioxide asphyxiation, the lungs were harvested, and the virus content was determined. As shown in Figure 2 , there was a significant reduction in pulmonary virus titers in rats treated with either of the monoclonal antibodies as compared with the BSA treated rats.
Example 3 Cotton rats (S. fulviventer) in groups of three rats each, average weight 100 grams, were anesthetized with methoxyflurane and challenged with 10 5 * 0 PFU of the Long strain of RSV. Three days later, the animals were anesthetized with methoxyflurane and given 0.1ml of a solution of
MAb 1129 or MAb 1331H (lOmg/ml) in PBS , or of bovine serum albumin
(lOmg/ml) in PBS. Administration was by intranasal instillation. The animals were sacrificed the next day by carbon dioxide asphyxiation, the lungs were harvested, and the virus content was determined. As shown in Figure 3, a significant reduction in pulmonary virus titers of animals treated with either of the monoclonal antibodies as compared to the
BSA- treated animals was observed.
Example 4
The eight monoclonal antibodies described above in Example 1 were further examined for their ability to block RSV replication when administered to cotton rats by the intranasal route prior to virus challenge. Cotton rats (S . hispidus, 4 animals per group, average weight 100 grams) were anesthetized with methoxyflurane and given 0.1 ml of antibody solution (1 mg/ml, 0.1 mg/ml or 0.01 mg/ml in phosphate-buffered saline (PBS) ) by intranasal (i.n. ) instillation . Control animals were given 0.1 ml of a bovine serum albumin suspension (1 mg/ml) in PBS . One day later, animals were again anesthetized with methoxyflurane and challenged by intranasal instillation of 10 ' plaque forming units (PFU) of the Long strain of RSV. Four days after virus challenge, all animals were sacrificed by carbon dioxide asphyxiation. Lungs were harvested and homogenized in 10 parts (wt/vol) of Hanks balanced salt solution supplemented with 0.218 M sucrose, 4.4 mM glutamate, 3.8 mM KHjPO- and 3.2 mM K2HPO4 and the resulting suspension was stored at -70°C until assayed for virus content. Virus titers were determined using a plaque assay on HEp-2 cell monolayers as disclosed by Prince, et al. , Am. J. Pathol. , Vol. 93, pgs. 771-792 (1978) and are expressed as PFU per gram of tissue.
Figure 4 shows that each of the monoclonal antibodies, except MAb 1243, showed a significant reduction in pulmonary virus titer when given at the 0.1 mg or 1 mg doses.
Example 5
Neutralizing monoclonal antibodies (MAbs) reactive with the F protein of RSV were examined for effectiveness in blocking RSV replication when combined and administered to cotton rats. MAbs 1121 and 1302 A were mixed in equal amounts. Cotton rats (S. hispidus. 4 animals per group, average weight 100 grams) were anesthetized with methoxyflurane and given 0.1 ml of antibody solution, either the mixture or the individual antibodies at 1 mg/ml, 0.1 mg/ml or 0.01 mg/ml in phosphate -buffered saline (PBS) by intranasal (i.n. ) instillation. Control animals were given 0.1 ml of a bovine serum albumin solution (1 mg/ml) in PBS . One day later, animals were again anesthetized with methoxyflurane and challenged by i.n. instillation of 10 plaque forming units (PFU) of the Long strain of RSV. Four days after virus challenge, all animals were sacrificed by carbon dioxide asphyxiation. Lungs were harvested and homogenized in 10 parts (wt/vol) of Hanks balanced salt solution supplemented with 0.218 M sucrose, 4.4 mM glutamate, 3.8 mM KH2PO4 and 3.2 mM K2HPO4 and the resulting suspension was stored at -70°C until assayed for virus content. Virus titers were determined using a plaque assay on HEp-2 cell monolayers as disclosed by Prince et al (1978) and are expressed as PFU per gram of tissue.
Figure 5 shows that MAbs 1121 and 1302A when combined together are more effective in reducing viral titers as compared to their individual effects even at a total concentration of 0.01 mg/ml.
Example 6
Six non- neutralizing MAbs, reactive with the F protein of RSV were examined for their ability to block RSV replication when adminsitered to cotton rats by the intranasal route prior to challenge with virus. Cotton rats (S . hispidus. 4 animals per group, average weight 100 grams) were anesthetized with methoxyflurane and given 0.1 ml of antibody solution, at 10 mg/ml in phosphate-buffered saline (PBS) by intranasal (i. n . ) instillation. Control animals were given 0.1 ml of a bovine serum albumin solution (10 mg/ml) in PBS . One day later, animals were again anesthetized with methoxyflurane and challenged by i.n. instillation of 10 ' plaque forming units (PFU) of the Long strain of RSV. Four days after virus challenge, all animals were sacrificed by carbon dioxide asphyxiation. Lungs were harvested and homogenized in 10 parts (wt/vol) of Hanks balanced salt solution supplemented with 0.218 M sucrose, 4.4 mM glutamate, 3.8 mM KHjPO. and 3.2 mM KjHPO, and the resulting suspension was stored at -70°C until assayed for virus content. Virus titers were determined using a plaque assay on HEp-2 cell monolayers as disclosed by Prince et al (1978) and are expressed as PFU per gram of tissue.
As shown in Figure 6 , these non-neutralizing antibodies were effective in significantly decreasing pulmonary viral titers in treated animals even though they do not neutralize virus infectivity in vitro .
It is to be understood, however, that the scope of the present invention is not to be limited to the specific embodiments described above . The invention may be practiced other than as particularly described and still be within the scope of the accompanying claims.
Claims
1. A process for the prophylaxis of at least one respiratory virus in an animal, comprising: topically administering to said animal at least one monoclonal antibody against said at least one respiratory virus.
2. The process of Claim 1 wherein said at least one monoclonal antibody is administered to the respiratory tract.
3. The process of Claim 2 wherein said at least one monoclonal antibody is administered intranasally.
4. The process of Claim 2 wherein said at least one monoclonal antibody is administered through the breathing of an aerosol containing said at least one monoclonal antibody.
5. The process of Claim 1 wherein said at least one respiratory virus is selected from the group consisting of respiratory syncytial viruses, parainfluenza viruses, influenza A viruses, influenza B viruses, and adenoviruses .
6. The process of Claim 5 wherein said at least one respiratory virus is a respiratory syncytial virus.
7. The process of Claim 6 wherein said at least one monoclonal antibody is against a fusion protein of a respiratory syncytial virus.
8. The process of Claim 7 wherein said at least one monoclonal antibody is selected from the group consisting of MAb 1436C, MAb 1153 , MAb 1142 MAb 151, MAb 1200, MAb 1214, MAb 1237, MAb 1129, MAb 1121 , MAb 1107, MAb 13-1, MAb 43-1, MAb 1112, MAb 1269, MAb 1243 , MAb 1331H, MAb 1308F, and MAb 1302A.
9. The process of Claim 7 wherein said at least one monoclonal antibody is selected from the group consisting of MAb 1224-1, MAb 1175-40, MAb 1105-1, MAb 1219-22 , MAb 1228-28, and MAb 1113-44.
10. The process of Claim 8 wherein a mixture of at least two of said monoclonal antibodies are administered.
11. The process of Claim 2 wherein said at least one monoclonal antibody is administered in an amount of from about lOμg to about 250mg.
12. The process of Claim 11 wherein said at least one monoclonal antibody is administered in an amount of from about 5mg to about 125mg.
13. A process for the prophylaxis of at least one respiratory virus in an animal, comprising: intramuscularly administering to said animal at least one monoclonal antibody against said at least one respiratory virus.
14. The process of Claim 13 wherein said at least one monoclonal antibody is administered in an amount of from about lmg to about 250mg.
15. The process of Claim 14 wherein said at least one monoclonal antibody is administered in an amount of from about 5mg to about lOOmg.
16. A process for the treatment of at least one respiratory virus in an animal, comprising: administering to said animal at least one monoclonal antibody against said at least one respiratory virus.
17. The process of Claim 16 wherein said at least one monoclonal antibody is administered topically.
18. The process of Claim 17 wherein said at least one monoclonal antibody is administered in an amount of from about lOμg to about 500mg.
19. The process of Claim 18 wherein said at least one monoclonal antibody is administered in an amount of from about 5mg to about 250mg.
20. The process of Claim 16 wherein said at least one monoclonal antibody is administered systemically.
21. The process of Claim 20 wherein said at least one monoclonal antibody is administered in an amount of from about lmg to about 250mg.
22. The process of Claim 21 wherein said at least one monoclonal antibody is administered in an amount of from about 5mg to about lOOmg.
23. A topical composition for the prophylaxis of at least one respratory virus, comprising: at least one monoclonal antibody against said at least one respiratory virus; and a pharmaceutically acceptable carrier.
24. An intramuscularly administrable composition for the prophylaxis of at least one respiratory virus, comprising: at least one monoclonal antibody against said at least one respiratory virus; and a pharmaceutically acceptable carrier.
25. A composition for the treatment of at least one respiratory virus, comprising: at least one monoclonal antibody against said at least one respiratory virus; and a pharmaceutically acceptable carrier.
26. The process of Claim 1 wherein a mixture of at least two of said monoclonal antibodies are administered.
27. The process of Claim 13 wherein a mixture of at least two of said monoclonal antibodies are administered.
28. The process of Claim 16 wherein a mixture of at least two of said monoclonal antibodies are administered.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US52292290A | 1990-04-19 | 1990-04-19 | |
| US522922 | 1990-04-19 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0530216A1 true EP0530216A1 (en) | 1993-03-10 |
| EP0530216A4 EP0530216A4 (en) | 1993-06-30 |
Family
ID=24082929
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP19910908428 Withdrawn EP0530216A4 (en) | 1990-04-19 | 1991-04-18 | Administration of monoclonal antibodies against respiratory viruses |
Country Status (2)
| Country | Link |
|---|---|
| EP (1) | EP0530216A4 (en) |
| WO (1) | WO1991016074A1 (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU644210B2 (en) * | 1990-07-19 | 1993-12-02 | United States of America, as represented by the Secretary, U.S. Department of Commerce, The | Improved immunotherapeutic method of preventing or treating viral respiratory tract disease |
| US6685942B1 (en) | 1993-12-10 | 2004-02-03 | The Scripps Research Institute | Human neutralizing monoclonal antibodies to respiratory syncytial virus |
| DK0671927T3 (en) * | 1992-09-16 | 2003-04-22 | Us Gov Health & Human Serv | Neutralizing human monoclonal antibodies against respiratory syncytial virus |
| EP0724602A4 (en) * | 1993-07-30 | 1998-12-23 | Oravax Inc | MONOCLONAL IgA ANTIBODY AGAINST RESPIRATORY SYNCYTIAL VIRUS |
| AU2003256823B9 (en) * | 2002-07-25 | 2009-01-08 | Medimmune, Llc | Methods of treating and preventing RSV, hMPV, and PIV using anti-RSV, anti-hMPV, and anti-PIV antibodies |
| US20050271660A1 (en) * | 2002-09-06 | 2005-12-08 | Alexion Pharmaceuticals, Inc. | Nebulization of monoclonal antibodies for treating pulmonary diseases |
| WO2004061104A2 (en) | 2003-01-07 | 2004-07-22 | Symphogen A/S | Method for manufacturing recombinant polyclonal proteins |
| AU2006261920A1 (en) * | 2005-06-23 | 2007-01-04 | Medimmune, Llc | Antibody formulations having optimized aggregation and fragmentation profiles |
| AU2008255383B2 (en) | 2007-05-25 | 2012-11-01 | Symphogen A/S | Method for manufacturing a recombinant polyclonal protein |
| EP3105250B1 (en) | 2014-02-10 | 2020-08-05 | IGM Biosciences, Inc. | Iga multi-specific binding molecules |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992001473A1 (en) * | 1990-07-19 | 1992-02-06 | The United States Of America, As Represented By The Secretary, U.S. Department Of Commerce | Improved immunotherapeutic method of preventing or treating viral respiratory tract disease |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4625015A (en) * | 1982-08-23 | 1986-11-25 | Scripps Clinic & Research Foundation | Broad spectrum influenza antisera |
| US4719235A (en) * | 1984-10-16 | 1988-01-12 | Gerald N. Kern | Methods and compositions for treating viral infection |
| FR2590674B1 (en) * | 1985-11-25 | 1989-03-03 | Inst Nat Sante Rech Med | NEW DIAGNOSTIC REAGENTS |
| US4800078A (en) * | 1987-05-28 | 1989-01-24 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Immunotherapeutic method of treating respiratory disease by intranasal administration of Igb |
| US4891221A (en) * | 1988-11-23 | 1990-01-02 | Edward Shanborm | Whole blood antiviral process and composition |
-
1991
- 1991-04-18 EP EP19910908428 patent/EP0530216A4/en not_active Withdrawn
- 1991-04-18 WO PCT/US1991/002668 patent/WO1991016074A1/en not_active Application Discontinuation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992001473A1 (en) * | 1990-07-19 | 1992-02-06 | The United States Of America, As Represented By The Secretary, U.S. Department Of Commerce | Improved immunotherapeutic method of preventing or treating viral respiratory tract disease |
Non-Patent Citations (3)
| Title |
|---|
| JOURNAL OF VIROLOGY vol. 63, no. 7, July 1989, BALTIMORE pages 2941 - 2950 BEELER, J.A. ET AL 'Neutralization epitopes of the F glycoprotein of respiratory syncytial virus: Effect of mutation upon fusion function' * |
| See also references of WO9116074A1 * |
| VACCINES 91 vol. 91, 1991, NEW YORK pages 283 - 288 BANSAL, G.P. ET AL 'Efficacy of passively administered monoclonal antibodies against respiratory syncytial virus infection in cotton rats' Modern approaches to new vaccines including prevention of aids;eighth annual meeting, cold spring harbor, new york, USA, september 1990. * |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0530216A4 (en) | 1993-06-30 |
| WO1991016074A1 (en) | 1991-10-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Prince et al. | Effectiveness of topically administered neutralizing antibodies in experimental immunotherapy of respiratory syncytial virus infection in cotton rats | |
| Crowe Jr et al. | Recombinant human respiratory syncytial virus (RSV) monoclonal antibody Fab is effective therapeutically when introduced directly into the lungs of RSV-infected mice. | |
| EP0539522B1 (en) | Improved immunotherapeutic method of preventing or treating viral respiratory tract disease | |
| US4800078A (en) | Immunotherapeutic method of treating respiratory disease by intranasal administration of Igb | |
| Weltzin et al. | Intranasal monoclonal IgA antibody to respiratory syncytial virus protects rhesus monkeys against upper and lower respiratory tract infection | |
| EP0583356B1 (en) | A method for treating infectious respiratory diseases | |
| Prince et al. | Immunoprophylaxis and immunotherapy of respiratory syncytial virus infection in the cotton rat | |
| Murphy et al. | Passive transfer of respiratory syncytial virus (RSV) antiserum suppresses the immune response to the RSV fusion (F) and large (G) glycoproteins expressed by recombinant vaccinia viruses | |
| DE3853210T2 (en) | USE OF A VIRAL GLYCOPROTEIN VACCINE FOR INTRANASAL IMMUNIZATION AGAINST A VIRUS INFECTION. | |
| US20070224204A1 (en) | Combination therapy of respiratory diseases using antibodies and anti-inflammatory agents | |
| US20070092523A1 (en) | Combination Therapy Of Respiratory Diseases Using Antibodies | |
| EP0530216A1 (en) | Administration of monoclonal antibodies against respiratory viruses | |
| Prince et al. | Mechanism of antibody-mediated viral clearance in immunotherapy of respiratory syncytial virus infection of cotton rats | |
| Kanesaki et al. | Effectiveness of enteric immunization in the development of secretory immunoglobulin A response and the outcome of infection with respiratory syncytial virus | |
| Bastien et al. | Complete protection of mice from respiratory syncytial virus infection following mucosal delivery of synthetic peptide vaccines | |
| Corbeil et al. | Involvement of the complement system in the protection of mice from challenge with respiratory syncytial virus Long strain following passive immunization with monoclonal antibody 18A2B2 | |
| Wyde et al. | Protection of mice from lethal influenza virus infection with high dose-short duration ribavirin aerosol | |
| AU2001259379A1 (en) | Combination therapy of respiratory diseases using antibodies | |
| Sandritter et al. | Respiratory syncytial virus-immunoglobulin intravenous (RSV-IGIV) for respiratory syncytial viral infections: part I | |
| Crowe Jr et al. | Isolation of a second recombinant human respiratory syncytial virus monoclonal antibody fragment (Fab RSVF2-5) that exhibits therapeutic efficacy in vivo | |
| CA2040770A1 (en) | Administration of monoclonal antibodies against respiratory viruses | |
| Ottolini et al. | Topical immunoglobulin is an effective therapy for parainfluenza type 3 in a cotton rat model | |
| Cotte et al. | The effect of alcohol ingestion on the susceptibility of mice to viral infections | |
| Faverio et al. | Immunoprophylaxis of group B respiratory syncytial virus infection in cotton rats | |
| Mills | Management of respiratory syncytial virus infections |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
| 17P | Request for examination filed |
Effective date: 19921002 |
|
| AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE |
|
| A4 | Supplementary search report drawn up and despatched |
Effective date: 19930511 |
|
| AK | Designated contracting states |
Kind code of ref document: A4 Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE |
|
| 17Q | First examination report despatched |
Effective date: 19930930 |
|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
| 18D | Application deemed to be withdrawn |
Effective date: 20000126 |