US20180071389A1 - Monoclonal Antibodies for Ebola and Marburg Viruses - Google Patents
Monoclonal Antibodies for Ebola and Marburg Viruses Download PDFInfo
- Publication number
- US20180071389A1 US20180071389A1 US15/826,537 US201715826537A US2018071389A1 US 20180071389 A1 US20180071389 A1 US 20180071389A1 US 201715826537 A US201715826537 A US 201715826537A US 2018071389 A1 US2018071389 A1 US 2018071389A1
- Authority
- US
- United States
- Prior art keywords
- seq
- variable region
- amino acid
- chain variable
- heavy
- 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.)
- Abandoned
Links
- 201000011001 Ebola Hemorrhagic Fever Diseases 0.000 title claims abstract description 11
- 241001115402 Ebolavirus Species 0.000 title description 7
- 241001115401 Marburgvirus Species 0.000 title description 2
- 150000007523 nucleic acids Chemical class 0.000 claims description 19
- 108020004707 nucleic acids Proteins 0.000 claims description 16
- 102000039446 nucleic acids Human genes 0.000 claims description 16
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 15
- 125000000539 amino acid group Chemical group 0.000 claims description 14
- 239000000427 antigen Substances 0.000 claims description 13
- 102000036639 antigens Human genes 0.000 claims description 13
- 108091007433 antigens Proteins 0.000 claims description 13
- 230000027455 binding Effects 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 10
- 239000012634 fragment Substances 0.000 claims description 9
- 206010061192 Haemorrhagic fever Diseases 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims 5
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims 2
- 239000003937 drug carrier Substances 0.000 claims 2
- 241000700198 Cavia Species 0.000 description 13
- 241001465754 Metazoa Species 0.000 description 10
- 241000699670 Mus sp. Species 0.000 description 9
- 230000004083 survival effect Effects 0.000 description 6
- 241000282412 Homo Species 0.000 description 4
- 108091028043 Nucleic acid sequence Proteins 0.000 description 4
- 230000001681 protective effect Effects 0.000 description 4
- 238000002965 ELISA Methods 0.000 description 3
- 241000282887 Suidae Species 0.000 description 3
- 241000711975 Vesicular stomatitis virus Species 0.000 description 3
- 230000000890 antigenic effect Effects 0.000 description 3
- 239000013604 expression vector Substances 0.000 description 3
- 230000005847 immunogenicity Effects 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 230000003612 virological effect Effects 0.000 description 3
- 241000700199 Cavia porcellus Species 0.000 description 2
- SPEFJYZGXZENAF-UHFFFAOYSA-N N-cyclohexyl-1-(2,4-dichlorophenyl)-6-methyl-4H-indeno[1,2-c]pyrazole-3-carboxamide Chemical compound C=1C(C)=CC=C(C2=3)C=1CC=3C(C(=O)NC1CCCCC1)=NN2C1=CC=C(Cl)C=C1Cl SPEFJYZGXZENAF-UHFFFAOYSA-N 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 101100191768 Caenorhabditis elegans pbs-4 gene Proteins 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 101150117028 GP gene Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 108010067902 Peptide Library Proteins 0.000 description 1
- 239000012083 RIPA buffer Substances 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000001114 immunoprecipitation Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 238000002823 phage display Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Images
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
-
- 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
- A61K39/42—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum viral
-
- 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
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- 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
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
- A61K2039/507—Comprising a combination of two or more separate antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/46—Hybrid immunoglobulins
- C07K16/461—Igs containing Ig-regions, -domains or -residues form different species
- C07K16/462—Igs containing a variable region (Fv) from one specie and a constant region (Fc) from another
-
- 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
- C07K2317/50—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
-
- 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
Definitions
- Ebola and Marburg viruses are highly pathogenic and virulent viruses causing rapidly fatal hemorrhagic fever in humans.
- a monoclonal antibody comprising an amino acid sequence deduced from 1 H3-light (SEQ ID No. 2); 2G4-light (SEQ ID No. 4); 4G7-light (SEQ ID No. 6): 5D2-light (SEQ ID No. 8); 5E6-light (SEQ ID No. 10); 7C9-light (SEQ ID No. 12): 7G4-light (SEQ ID No. 14), 10C8-light(SEQ ID No. 16), 1H3-heavy (SEQ ID No. 1): 2G4-heavy (SEQ ID No. 3); 4G7-heavy (SEQ ID No. 5); 5D2-heavy (SEQ ID No. 7), 5E6-heavy (SEQ ID No. 9), 7C9-heavy (SEQ ID No. 11), 7G4 heavy (SEQ ID No. 13) and 10C8-heavy (SEQ ID No. 15).
- an expression vector comprising a nucleic acid molecule encoding a constant region domain of a human light chain or heavy chain genetically linked to a nucleic acid encoding a light chain variable region selected from the group consisting of 1H3-light (SEQ ID No. 2): 2G4-light (SEQ ID No. 4); 4G7-light (SEQ ID No. 6); 5D2-light (SEQ ID No. 8); 5E6-light (SEQ ID No. 10); 7C9-light (SEQ ID No. 12); 7G4-light (SEQ ID No. 14) and 10C8-light(SEQ ID No. 16) or a heavy chain variable region selected from the group consisting of 1H3-heavy (SEQ ID No.
- nucleotide sequence selected from the group consisting of 1H3-light (SEQ ID No. 2); 2G4-light (SEQ ID No. 4); 4G7-light (SEQ ID No. 6); 5D2-light (SEQ ID No. 8); 5E6-light (SEQ ID No. 10); 7C9-light (SEQ ID No. 12); 7G4-light (SEQ ID No. 14), 10C8-light(SEQ ID No. 16), 1H3-heavy (SEQ ID No. 1); 2G4-heavy (SEQ ID No. 3); 4G7-heavy (SEQ ID No. 5); 5D2-heavy (SEQ ID No. 7), 5E6-heavy (SEQ ID No. 9), 7C9-heavy (SEQ ID No. 11), 7G4-heavy (SEQ ID No. 3) and 10C8-heavy (SEQ ID No. 15);
- nucleic acid sequence such that at least one but fewer than about 30 of the amino acid residues encoded by said nucleic acid sequence has been changed or deleted without disrupting antigen binding of said peptide;
- FIG. 1 Kaplan-Meier survival curve of mice infected with MA-ZEBOV and treated with MAbs 1 day after infection. Survival curve of MS-Ebola virus-infected mice treated with 100 ⁇ g of MAbs. Mice were intraperitoneally treated with 100 ⁇ g of each MAb on day 1. Control mice were given equal volumes of PBS.
- FIG. 2 Weight changes of GPA-Ebola infected guinea pigs treated with MAbs. Weight changes of virus-infected guinea pigs treated with cocktail of MAbs. Guinea pigs were intraperitoneally treated with either 5D2, 5E6, 7C9, 7G4 or 10C8 (3 mg/treatment) on day 1 and 4G7+1H3+2G4[(2 mg+1 mg+1 mg)/treatment] on day 2. Control guinea pig were given equal volume of PBS. The results are shown as the means and standard deviations of 6 guinea pigs.
- FIG. 3 Weight changes of GPA-Ebola infected guinea pigs treated with MAbs. Weight changes of virus-infected guinea pigs treated with cocktail of MAbs. Guinea pigs were intraperitoneally treated with either 5D2, 5E6, 7C9, 7G4 or 10C8 (3 mg/treatment) on day 1 and 4G7+1H3+2G4 [(2 mg+1 mg+1 mg)/treatment] on day 2. Control guinea pig were given equal volume of PBS. The results are shown as the group weight of 6 guinea pigs.
- FIG. 4 Immunoprecipitation, 293T cells were transfected with pCAGGS-ZEbovGP1,2 by using Fugene 6, After 48 hrs, cells were collected and washed 2 ⁇ with cold PBS before being lysed with 2 ⁇ RIPA buffer. After clarifying the cell lysate, 100 ⁇ g protein was added to each MoNs (5 ⁇ g) coupled protein A+G beads. The IP samples were run 10% SDS-PAGE and transferred to Hybond-P membrane. The blot was probed with mouse ant-EBOV-GP1.
- neutralizing antibody refers to an antibody, for example, a monoclonal antibody, capable of disrupting a formed viral particle or inhibiting formation of a viral particle or prevention of binding to or infection of mammalian cells by a viral particle.
- diagnostic antibody or “detection antibody” or “detecting antibody” refers to an antibody, for example, a monoclonal antibody, capable of detecting the presence of an antigenic target within a sample.
- diagnostic antibodies preferably have high specificity for their antigenic target.
- humanized antibodies refer to antibodies with reduced immunogenicity in humans.
- chimeric antibodies refer to antibodies with reduced immunogenicity in humans built by genetically linking a non-human Variable region to human constant domains.
- VSV based vaccine delivery system was used to develop monoclonal antibodies in mice.
- 1H3 comprises 1H3-heavy chain (SEQ ID No. 1) and 1H3-light chain (SEQ ID No. 2);
- 2G4 comprises 2G4-heavy chain (SEQ ID No. 3) and 2G4-light chain (SEQ ID No. 4);
- 4G7 comprises 4G7-heavy chain (SEQ ID No. 5) and 4G7-light chain (SEQ ID No. 6);
- 5D2 comprises 5D2-heavy chain (SEQ ID No. 7) and 5D2-light chain (SEQ ID No.
- 5E6 comprises 5E6-heavy chain (SEQ ID No. 9) and 5E6-light chain (SEQ ID No. 10); 7C9 comprises 7C9-heavy chain (SEQ ID No. 11) and 7C9-light chain (SEQ ID No. 12); 7G4 comprises 7G4-heavy chain (SEQ ID No. 13) and 7G4-light chain (SEQ ID No. 14); and 10C8 comprises 10C8-light chain (SEQ ID No. 16) and 10C8-heavy chain (SEQ ID No. 15).
- mice infected with MA-ZEBOV and subsequently treated with the monoclonal antibodies described above showed increased survival compared to mice treated with PBS. Results are summarized in Tables 1 and 2.
- FIGS. 2 and 3 show weight changes in guinea pigs treated with the monoclonal antibodies or mixtures thereof post infection. As can be seen, guinea pigs treated with the monoclonal antibodies showed consistent weight while those treated with PBS showed significant weight loss. Results are summarized in Table 3.
- the amino acid sequences of these antibodies can easily be deduced from the nucleotide sequences. Accordingly, in some embodiments, the invention is directed to amino acid sequences deduced from 1H3-light (SEQ ID. No. 2); 2G4-light (SEQ ID No. 4); 4G7-light (SEQ ID No. 6); 5D2-light (SEQ ID No. 8); 5E6-light (SEQ ID No. 10); 7C9-light (SEQ ID No. 12); 7G4-light (SEQ ID No.
- mAb 1H3 heavy chain sequence 373 bp (SEQ ID No. 1) TGGGGCAGAGCTTGTGAAGCCAGGGGCCTCAGTCAAGTTGTCCTGCACAG CTTCTGGCTTCAACATTAAAGACACCTATATACATTGGGTGAAACAGGGC GCCTGAACAGGGCCTGGAGTGGATTGGAAGGATTGATCCTGCGAATGGTA ATACTAAATATGACCCGAAGTTCCAGGGCAAGGCCACTATCACAGCAGAC ACATCCTCCAATACAGCCTACCTGCAGCTCAGCGGCCTGACATCTGAGGA CACTGCCGTCTATTACTGTGCTAGGGAGTCGAGGATATCTACTATGCTTA CGACGGGGTACTTTGACTACTGGGGCCAAGGCACCACTCTCACAGTCTCC TCAGCCAAAACAACAGCCCCATCG mAb 1H3 light chain sequence: 303 bp (SEQ ID No.2) GCAATCATGTCTGCATCTCCAGGGGAGAAGGTCACCATGACCTGCAGTGC CAGCTCAAGT
- one or more of the nucleic acid sequences described above encoding the antibody are subjected to humanization techniques or converted into chimeric human molecules for generating a variant antibody which has reduced immunogenicity in humans.
- Humanization techniques are well known in the art—see for example U.S. Pat. No. 6,309,636 and U.S. Pat. No. 6,407,213 which arm incorporated herein by reference specifically for their disclosure on humanization techniques.
- Chimerics are also well known, see for example U.S. Pat. No. 6,461,824, U.S. Pat. No. 6,204,023, U.S. Pat. No. 6,020,153 and U.S. Pat. No. 6,120,767 which are similarly incorporated herein by reference.
- chimeric antibodies are prepared by preparing an expression vector which comprises a nucleic acid encoding a constant region domain of a human light or heavy chain genetically linked to a nucleic acid encoding a light chain variable region selected from the group consisting of 1H3-light (SEQ ID No. 2); 2G4-light (SEQ ID No. 4); 4G7-light (SEQ ID No. 6); 5D2-light (SEQ ID No. 8): 5E6-light (SEQ ID No. 10); 7C9-light (SEQ ID No. 12); 7G4-light (SEQ ID No. 14) and 10C8-light(SEQ ID No.
- recombinant antibodies comprising at least one modified variable region, said region selected from the group consisting of 1H3-light (SEQ ID No. 2); 2G4-light (SEQ ID No. 4); 4G7-light (SEQ ID No. 6); 5D2-light (SEQ ID No. 8); 5E6-light (SEQ ID No. 10); 7C9-light (SEQ ID No. 12); 7G4-light (SEQ ID No. 14), 10C8-light(SEQ ID No. 16), 1H3-heavy (SEQ ID No. 1); 2G4-heavy (SEQ ID No. 3); 4G7-heavy (SEQ ID No. 5); 5D2-heavy (SEQ ID No.
- immunoreactive fragments of any of the above-described monoclonal antibodies, chimeric antibodies or humanized antibodies are prepared using means known in the art, for example, by preparing nested deletions using enzymatic degradation or convenient restriction enzymes.
- immunoreactive fragment refers in this context to an antibody fragment reduced in length compared to the wild-type or parent antibody which retains an acceptable degree or percentage of binding activity to the target antigen. As will be appreciated by one of skill in the art, what is an acceptable degree will depend on the intended use.
- any of the above-described antibody or humanized variant thereof may be formulated into a pharmaceutical treatment for providing passive immunity for individuals suspected of or at risk of developing hemorrhagic fever comprising a therapeutically effective amount of said antibody.
- the pharmaceutical preparation may include a suitable excipient or carrier. See, for example, Remington: The Science and Practice of Pharmacy, 1995, Gennaro ed. As will be apparent to one knowledgeable in the art, the total dosage will vary according to the weight, health and circumstances of the individual as well as the efficacy of the antibody.
Abstract
Described herein are a number of Ebola and Marburg monoclonal antibodies.
Description
- The instant application is a continuation application of U.S. patent application Ser. No. 14/979,834 filed Dec. 28, 2015, itself a continuation application of U.S. patent application Ser. No. 13/940,712, filed Jul. 12, 2013, which was a divisional application of U.S. Ser. No. 12/864,584, filed Oct. 26, 2010, which was a 371 of PCT Application CA2009/000070, filed Jan. 27, 2009, which claims the benefit of US Provisional Patent Application 61/025,491, filed Feb. 1, 2008.
- Ebola and Marburg viruses are highly pathogenic and virulent viruses causing rapidly fatal hemorrhagic fever in humans.
- According to a first aspect of the invention, there is provided a monoclonal antibody comprising an amino acid sequence deduced from 1 H3-light (SEQ ID No. 2); 2G4-light (SEQ ID No. 4); 4G7-light (SEQ ID No. 6): 5D2-light (SEQ ID No. 8); 5E6-light (SEQ ID No. 10); 7C9-light (SEQ ID No. 12): 7G4-light (SEQ ID No. 14), 10C8-light(SEQ ID No. 16), 1H3-heavy (SEQ ID No. 1): 2G4-heavy (SEQ ID No. 3); 4G7-heavy (SEQ ID No. 5); 5D2-heavy (SEQ ID No. 7), 5E6-heavy (SEQ ID No. 9), 7C9-heavy (SEQ ID No. 11), 7G4 heavy (SEQ ID No. 13) and 10C8-heavy (SEQ ID No. 15).
- According to a second aspect of the invention, there is provided a method of preparing a chimeric antibody comprising;
- providing an expression vector comprising a nucleic acid molecule encoding a constant region domain of a human light chain or heavy chain genetically linked to a nucleic acid encoding a light chain variable region selected from the group consisting of 1H3-light (SEQ ID No. 2): 2G4-light (SEQ ID No. 4); 4G7-light (SEQ ID No. 6); 5D2-light (SEQ ID No. 8); 5E6-light (SEQ ID No. 10); 7C9-light (SEQ ID No. 12); 7G4-light (SEQ ID No. 14) and 10C8-light(SEQ ID No. 16) or a heavy chain variable region selected from the group consisting of 1H3-heavy (SEQ ID No. 1): 2G4-heavy (SEQ ID No. 3); 4G7-heavy (SEQ ID No. 5); 5D2-heavy (SEQ ID No. 7), 5E6-heavy (SEQ ID No. 9), 7C9-heavy (SEQ ID No. 11) 7G4-heavy (SEQ ID No. 13) and 10C8-heavy (SEQ ID No. 15):
- expressing the expression vector in a suitable host; and
- preparing a recombinant antibodies comprising:
- providing a nucleotide sequence selected from the group consisting of 1H3-light (SEQ ID No. 2); 2G4-light (SEQ ID No. 4); 4G7-light (SEQ ID No. 6); 5D2-light (SEQ ID No. 8); 5E6-light (SEQ ID No. 10); 7C9-light (SEQ ID No. 12); 7G4-light (SEQ ID No. 14), 10C8-light(SEQ ID No. 16), 1H3-heavy (SEQ ID No. 1); 2G4-heavy (SEQ ID No. 3); 4G7-heavy (SEQ ID No. 5); 5D2-heavy (SEQ ID No. 7), 5E6-heavy (SEQ ID No. 9), 7C9-heavy (SEQ ID No. 11), 7G4-heavy (SEQ ID No. 3) and 10C8-heavy (SEQ ID No. 15);
- modifying said nucleic acid sequence such that at least one but fewer than about 30 of the amino acid residues encoded by said nucleic acid sequence has been changed or deleted without disrupting antigen binding of said peptide; and
- expressing and recovering said modified nucleotide sequence.
-
FIG. 1 . Kaplan-Meier survival curve of mice infected with MA-ZEBOV and treated withMAbs 1 day after infection. Survival curve of MS-Ebola virus-infected mice treated with 100 μg of MAbs. Mice were intraperitoneally treated with 100 μg of each MAb onday 1. Control mice were given equal volumes of PBS. -
FIG. 2 . Weight changes of GPA-Ebola infected guinea pigs treated with MAbs. Weight changes of virus-infected guinea pigs treated with cocktail of MAbs. Guinea pigs were intraperitoneally treated with either 5D2, 5E6, 7C9, 7G4 or 10C8 (3 mg/treatment) onday 1 and 4G7+1H3+2G4[(2 mg+1 mg+1 mg)/treatment] onday 2. Control guinea pig were given equal volume of PBS. The results are shown as the means and standard deviations of 6 guinea pigs. -
FIG. 3 . Weight changes of GPA-Ebola infected guinea pigs treated with MAbs. Weight changes of virus-infected guinea pigs treated with cocktail of MAbs. Guinea pigs were intraperitoneally treated with either 5D2, 5E6, 7C9, 7G4 or 10C8 (3 mg/treatment) onday 1 and 4G7+1H3+2G4 [(2 mg+1 mg+1 mg)/treatment] onday 2. Control guinea pig were given equal volume of PBS. The results are shown as the group weight of 6 guinea pigs. -
FIG. 4 . Immunoprecipitation, 293T cells were transfected with pCAGGS-ZEbovGP1,2 by usingFugene 6, After 48 hrs, cells were collected and washed 2× with cold PBS before being lysed with 2× RIPA buffer. After clarifying the cell lysate, 100 μg protein was added to each MoNs (5 μg) coupled protein A+G beads. The IP samples were run 10% SDS-PAGE and transferred to Hybond-P membrane. The blot was probed with mouse ant-EBOV-GP1. - Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned hereunder are incorporated herein by reference.
- As used herein, “neutralizing antibody” refers to an antibody, for example, a monoclonal antibody, capable of disrupting a formed viral particle or inhibiting formation of a viral particle or prevention of binding to or infection of mammalian cells by a viral particle.
- As used herein, “diagnostic antibody” or “detection antibody” or “detecting antibody” refers to an antibody, for example, a monoclonal antibody, capable of detecting the presence of an antigenic target within a sample. As will be appreciated by one of skill in the art, such diagnostic antibodies preferably have high specificity for their antigenic target.
- As used herein, “humanized antibodies” refer to antibodies with reduced immunogenicity in humans.
- As used herein, “chimeric antibodies” refer to antibodies with reduced immunogenicity in humans built by genetically linking a non-human Variable region to human constant domains.
- Described herein are a number of Ebola and Marburg monoclonal antibodies. Specifically, antigens were developed using a live replicating vector vesicular stomatitis virus described in PCT Application PCT/CA03/001125.
- The VSV based vaccine delivery system was used to develop monoclonal antibodies in mice.
- Specifically, described herein are monoclonal antibodies 1H3, 2G4, 4G7, 5D2, 5E6, 7C9, 7G4 and 10C8. As discussed below, 1H3 comprises 1H3-heavy chain (SEQ ID No. 1) and 1H3-light chain (SEQ ID No. 2); 2G4 comprises 2G4-heavy chain (SEQ ID No. 3) and 2G4-light chain (SEQ ID No. 4); 4G7 comprises 4G7-heavy chain (SEQ ID No. 5) and 4G7-light chain (SEQ ID No. 6); 5D2 comprises 5D2-heavy chain (SEQ ID No. 7) and 5D2-light chain (SEQ ID No. 8); 5E6 comprises 5E6-heavy chain (SEQ ID No. 9) and 5E6-light chain (SEQ ID No. 10); 7C9 comprises 7C9-heavy chain (SEQ ID No. 11) and 7C9-light chain (SEQ ID No. 12); 7G4 comprises 7G4-heavy chain (SEQ ID No. 13) and 7G4-light chain (SEQ ID No. 14); and 10C8 comprises 10C8-light chain (SEQ ID No. 16) and 10C8-heavy chain (SEQ ID No. 15).
- These antibodies also appear to have high affinity and avidity to Ebola glycoproteins, which means that they could be used as highly sensitive diagnostic tools.
- For example, as shown in
FIG. 1 , mice infected with MA-ZEBOV and subsequently treated with the monoclonal antibodies described above showed increased survival compared to mice treated with PBS. Results are summarized in Tables 1 and 2. -
FIGS. 2 and 3 show weight changes in guinea pigs treated with the monoclonal antibodies or mixtures thereof post infection. As can be seen, guinea pigs treated with the monoclonal antibodies showed consistent weight while those treated with PBS showed significant weight loss. Results are summarized in Table 3. - The nucleotide sequences of the heavy and light chains of 1H3, 2G4, 4G7, 5D2, 5E6, 7C9, 7G4 and 10C8 follow. As will be appreciated by one of skill in the art, the amino acid sequences of these antibodies can easily be deduced from the nucleotide sequences. Accordingly, in some embodiments, the invention is directed to amino acid sequences deduced from 1H3-light (SEQ ID. No. 2); 2G4-light (SEQ ID No. 4); 4G7-light (SEQ ID No. 6); 5D2-light (SEQ ID No. 8); 5E6-light (SEQ ID No. 10); 7C9-light (SEQ ID No. 12); 7G4-light (SEQ ID No. 14), 10C8-light(SEQ ID No. 16), 1H3-heavy (SEQ ID No. 1); 2G4-heavy (SEQ ID No. 4G7-heavy (SEQ ID No. 5); 5D2-heavy (SEQ ID No. 7), 5E6-heavy (SEQ ID No. 9), 7C9-heavy (SEQ ID No. 11), 7G4-heavy (SEQ ID No. 13) and 10C8-heavy (SEQ ID No. 15).
-
mAb 1H3 heavy chain sequence: 373 bp (SEQ ID No. 1) TGGGGCAGAGCTTGTGAAGCCAGGGGCCTCAGTCAAGTTGTCCTGCACAG CTTCTGGCTTCAACATTAAAGACACCTATATACATTGGGTGAAACAGGGC GCCTGAACAGGGCCTGGAGTGGATTGGAAGGATTGATCCTGCGAATGGTA ATACTAAATATGACCCGAAGTTCCAGGGCAAGGCCACTATCACAGCAGAC ACATCCTCCAATACAGCCTACCTGCAGCTCAGCGGCCTGACATCTGAGGA CACTGCCGTCTATTACTGTGCTAGGGAGTCGAGGATATCTACTATGCTTA CGACGGGGTACTTTGACTACTGGGGCCAAGGCACCACTCTCACAGTCTCC TCAGCCAAAACAACAGCCCCATCG mAb 1H3 light chain sequence: 303 bp (SEQ ID No.2) GCAATCATGTCTGCATCTCCAGGGGAGAAGGTCACCATGACCTGCAGTGC CAGCTCAAGTGTAAGTTACATGTACTGGTACCAGCAGAAGCCAGGATCCT CCCCCAGACTCCTGATTTATGACACATCCAACCTGGCTTCTGGAGTCCCT GTTCGCTTCAGTGGCAGTGGGTCTGGGACCTCTTACTCTCTCACAATCAG CCGAATGGAGGCTGAAGATGCTGCCACTTATTACTGCCAGCAGTGGAGTA GTTACCCGTACACGTTCGGAGGGGGGACCAAGCTGGAAATAAAACGGGCT GAT mAb 2G4 heavy chain sequence: 364 bp (SEQ ID No. 3) TGGAGGAGGCTTGATGCAACCTGGAGGATCCATGAAACTCTCCTGTGTTG CCTCAGGATTCACTTTCAGTAACTACTGGATGAACTGGGTCCGCCAGTCT CCAGAGAAGGGGCTTGAGTGGGTTGCTGAAATTAGATTGAAATCTAATAA TTATGCAACACATTATGCGGAGTCTGTGAAAGGGAGGTTCACCATTTCAA GAGATGATTCCAAAAGGAGTGTCTACCTGCAAATGAATACCTTAAGAGCT GAAGACACTGGCATTTATTACTGTACCCGGGGGAATGGTAACTACAGGGC TATGGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCAGCCAAAA CAACACCCCCATCA mAb 2G4 light chain sequence: 306 bp (SEQ ID No. 4) GCCTCCCTATCTGTATCTGTGGGAGAAACTGTCTCCATCACATGTCGAGC AAGTGAGAATATTTACAGTAGTTTAGCATGGTATCAGCAGAAACAGGGAA AATCTCCTCAGCTCCTGGTCTATTCTGCAACAATCTTAGCAGATGGTGTG CCATCAAGGTTCAGTGGCAGTGGATCAGGCACTCAGTATTCCCTCAAGAT CAACAGCCTGCAGTCTGAAGATTTTGGOACTTATTACTGTCAACATTTTT GGGGTACTCCGTACACGTTCGGAGGGGGGACCAAGCTGGAAATAAAACGG GCTGAT mAb 4G7 heavy chain sequence: 358 bp (SEQ ID No. 5) TGGACCTGAGCTGGAGATGCCTGGCGCTTCAGTGAAGATATCCTGCAAGG CTTCTGGTTCCTCATTCACTGGCTTCAGTATGAACTGGGTGAAGCAGAGC AATGGAAAGAGCCTTGAGTGGATTGGAAATATTGATACTTATTATGGTGG TACTACCTACAACCAGAAATTCAAGGGCAAGGCCACATTGACTGTGGACA AATCCTCCAGCACAGCCTACATGCAGCTCAAGAGCCTGACATCTGAGGAC TCTGCAGTCTATTACTGTGCAAGATCGGCCTACTACGGTAGTACTTTTGC TTACTGGGGCCAAGGGACTCTGGTCACTSTCTCTGCAGCCAAAACAACAG CCCCATCG mAb 4G7 light chain sequence: 306 bp (SEQ ID No. 6) GCCTCCCTATCTGCATCTGTGGGAGAAACTGTCACCATCACATGTCGAGC AAGTGAGAATATTTACAGTTATTTAGCATGGTATCAGCAGAAACAGGGAA AATCTCCTCAGCTCCTGGTCTATAATGCCAAAACCTTAATAGAGGGTGTG CCATCAAGGTTCAGTGGCAGTGGATCAGGCACACAGTTTTCTCTGAAGAT CAACAGCCTGCAGCCTGAAGATTTTGGGAGTTATTTCTGTCAACATCATT TTGGTACTCCATTCACATTCGGCTCGGGGACAGAGTTGGAAATAAAACGG GCTGAT mAb 5D2 heavy chain sequence: 340 bp (SEQ ID No. 7) GGGACCTGGCCTGGTGAGACCTTCTCAGTCTCTGTCCCTCACCTGCACTG TCACTGGCTACTCAATCACCAGTGATTATGCCTGGAACTGGATCCGGCAG TTTCCAGGAAACAAACTGGAGTGGCTGGGCTATATAACCAACACTGGTAG CACTGGCTTCAACCCATCTCTCAAAAGTCGAATCTCTATCACTCGAGACA CATCCAAGAACCAGTTCTTCCTGCAGTTGATTTCTGTGACTACTGAGGAC ACAGCCACATATCACTGTGCAAGGGGCCTTGCYTACTGGGGCCAAGGGAC TCTGGTCACTGTCTCTGCAGCCAAAACAACAGCCCCATCG mAb 5D2 light chain sequence: 321 bp (SEQ ID No. 8) CTCACTTTGTCGGTTACCATTGGACAACCAGCCTCCATCTCTTGCAAGTC AAGTCAGAGCCTCTTAGATAGTGATGGAAAGACATATCTGAATTGGTTGT TACAGAGGCCAGGCCAGTCTCCAAAGCGCCTAATCTATCTGGTGTCTAAA CTGGACTCTGGAGTCACTGACAGGTTCACTGGCAGTGGATCAGGGACAGA TTTCACACTGAAAATCAGCAGAGTGGAGGCTGAGGATTIGGGAGTTTATT ATTGTTGGCAAGGTACACACTCTCCATTCACGTTCGGCTCGGGGACAAAG TTGGAAATAAAACGGGCTGAT mAb 5E6 heavy chain sequence: 370 bp (SEQ ID No. 9) TGGGGGAGGCTTAGTGAAGCCTGGAGGGTCCCTGAAACTCTCCTGTGCAG CCTCTGGATCCGCTTTCAGTAGATATGACATGTCTTGGGTTCGCCAGACT CCGGAGAAGAGGCTGGAGTGGGTCGCATACATTAGTCGTGGTGGTGGTTT CATCTACTATCCAGACACTGTGAAGGGCCGATTCACCATCTCCAGAGACA ATGCCAAGAACACCCTGTACCTGCAAATGAGCAGTCTGAAGTCTGACGAC ACAGCCATGTATTACTGTGCAAGACACGTTTACTACGGTAGTAGCCCGCT CTATGCTATGGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCAG CCAAAACAACAGCCCCATCG mAb 5E6 light chain sequence: 324 bp (SEQ ID No. 10) TCAGCCTCTTTGTCCCTGGGAGCCTCAGCAAAACTCACGTGCACCTTGAG TAGTCAGCACAGTACGTTCACCATTGAATGGTATCAGCAACAGCCACTCA AGCCTCCTAAGTATGTGATGGAGCTTAAGAAAGATGGAAGCCACAGTACA GGTGATGGGATTCCTGATCGCTTCTCTGGATCCAGCTGGTGCTGATCGCT ACCTTAGCATTTCCAACATCCAGCCTGAAGATGAAGCAATATACATCTGT GGTGTGGGTGATACAATTAATGAACAATTTGTGTATGTTTTCGGCGGTGG AACCAAGGTCACTGTCCTAGGT mAb 7C9 heavy chain sequence: 358 bp (SEQ ID No. 11) TGGGGCAGAGCTTGTGAAGCCAGGGGCCTCAGTCAAGTTGTCCTGCACAG CTTCTGGCTTCAACATTAAAGACACCTATATGCACTGGGTGAAGGAGAGG CCTGACAAGGGCCTGGAGTGGATTGGAAGGATTGATCCAGCGAATGGTAA TACTAAATGTGACTCGAGGTTTCAGGGCAAGGCCACTATAACAGCAGACA CATCCTCCAACACAGCCTACCTGCAGCTCAGCAGCCTGACATCTGAGGAC ACTGCCGTCTATTACTGTGCTAGAAGGATCTACTTTGGTAAGGGCTTTGA CTTTTGGGGCCAAGGCACCACTCTCACAGTCTCCTCAGCCAAAACAACAG CCCCATCG mAb 7C9 light chain sequence: 324 bp (SEQ ID No. 12) TCCTCCCTGAGTGTGTCAGCAGGAGAGAAGGTCACTATGAGCTGCAAGTC CAGTCAGAGTCTGTTTAACAGTGGAGATCAAAAGAACTACTTGGCCTGGT ACCAGCAGAAACCAGGGCAGCCTCCTAAACTGTTGATCTACGGGGCATCC ACTAGGGAATCTGGGGTCCCTGATCGCTTCACAGGCAGTGGATCTGGAAC CGATTTCACTCTTACCATCAGCAGTGTGCAGGCTGAAGACCTGGCAGTTT ATTACTGTCAGAATGATCAATTTTATCCTCCCACGTTCGGTGATGGGACC AAGCTGGACCTGAAACGGGCTGAT mAb 7G4 heavy chain sequence: 367 bp (SEQ ID No. 13) TGGAGGGGGCTTGGTACAGCCTGGGGGTTCTCTGAGACTCTCCTGTGCAA CTTCTGGCTTCACCTTTACTGATCACTACATGGGCTGGGTCCGCCAGCCT CCAGGAAAGGCACTTGAGTGGTTGGCTTTTGTTAGATACAAAGCTAAGGG TTACACAACAGAGTACACTGCATCTGTGAAGGGTCGGTTCACCATCTCCA GAGATAATTCCCAAAGCATCCTCTATCTTCAAATGAACACCCTGAGAACT GAGGACAGTGCCACTTATTACTGTGCAAGAGATAGAGGGGGTTACGTGGG AGCTATGGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCAGCCA AAACGACACCCCCATCT mAb 7G4 light chain sequence 321 bp (SEQ ID No. 14) CTCTCCCTGCCTGTCAGTCTTGGAGATCAAGCCTCCATCTCTTGCAGATC TAGTCAGAGCCTTGTACACAGGAATGGAAACACCTATTTCCATTGGTACC TGCAGAAGCCAGGCCAGTCTCGACTCCTGATCTACAAAGTTTCCAACCGA TTTTCTGGGGTCCCAGACAGGTTCAGTGGCAGTGGATCAGGGACAGATTT CACACTCAAGATCAGCAGAGTGGAGGCTGAGGATCTGGGAGTTTATTTCT GCTCTCAAAGTACACATGTTCCGTACACTTTCGGAGGGGGGACCAAGCTG GAAATAAAACGGGCTGAT mAb 10C8 heavy chain sequence: 352 bp (SEQ ID No. 15) TGGGGCAGAGCTTGTGAGGTCAGGGGCCTCAGTCAAGTTGTCCTGCACAT CTTCTGGCTTCAACATTAAAGACTACTTTCTACACTGGGTGAAACAGAGG CCTGAACAGGGCCTGGAGTGGATTGGATGGATTGATCCTGAGAATGGTGA TACTGAATATGCCCCGAAGTTCCAGGACAAGGCCACTATGACTGCAGACA CATCCTCCAACACAGCCTACCTGCACCTCAGCAGCCTGACATCTGAGGAC ACTGGCGTCTATTACTGTAATGCAGATGGTAACTACGGGAAGAACTACTG GGGCCAAGGCACCACTCTCACCGTCTCCTCAGCCAAAACAACAGCCCCAT CG mAb 10C8 light chain sequence: 324 bp (SEQ ID No. 16) CTCTCCCTGCCTGTCAGTCTTGGAGATCAAGCCTCCATCTCTTGCAGATC TAGTCAGAGCCTTGTACACAGTAATGGAAACACCTTTTTACATTGGTACC TGCAGAAGCCAGGCCAGTCTCCAAAGCTCCTGATCTACAGAGTTTCCAAC CGATTTTCTGGGGTCCCAGACAGGTTCAGTGGCAGTGGATCAGGGACAGA TTTCACACTCAAGATCAGCAGAGTGGAGGCTGAGGATCTGGGAGTTTATT TCTGCTCTCAAAGTACACATGTTCCTCCGTACACGTTCGGAGGGGGGACC AAGCTGGAAATAAAACGGGCTGAT - In another embodiment of the invention, one or more of the nucleic acid sequences described above encoding the antibody are subjected to humanization techniques or converted into chimeric human molecules for generating a variant antibody which has reduced immunogenicity in humans. Humanization techniques are well known in the art—see for example U.S. Pat. No. 6,309,636 and U.S. Pat. No. 6,407,213 which arm incorporated herein by reference specifically for their disclosure on humanization techniques. Chimerics are also well known, see for example U.S. Pat. No. 6,461,824, U.S. Pat. No. 6,204,023, U.S. Pat. No. 6,020,153 and U.S. Pat. No. 6,120,767 which are similarly incorporated herein by reference.
- In one embodiment of the invention, chimeric antibodies are prepared by preparing an expression vector which comprises a nucleic acid encoding a constant region domain of a human light or heavy chain genetically linked to a nucleic acid encoding a light chain variable region selected from the group consisting of 1H3-light (SEQ ID No. 2); 2G4-light (SEQ ID No. 4); 4G7-light (SEQ ID No. 6); 5D2-light (SEQ ID No. 8): 5E6-light (SEQ ID No. 10); 7C9-light (SEQ ID No. 12); 7G4-light (SEQ ID No. 14) and 10C8-light(SEQ ID No. 16) or a heavy chain variable region selected from the group consisting of 1H3-heavy (SEQ ID No. 1); 2G4-heavy (SEQ ID No. 3); 4G7-heavy (SEQ ID No. 5); 5D2-heavy (SEQ ID No. 7). 5E6-heavy (SEQ ID No. 9), 7C9-heavy (SEQ ID No. 11), 7G4-heavy (SEQ ID No. 13) and 10G8-heavy (SEQ ID No. 15). It is of note that all of these sequences are described above.
- In another embodiment of the invention, there are provided recombinant antibodies comprising at least one modified variable region, said region selected from the group consisting of 1H3-light (SEQ ID No. 2); 2G4-light (SEQ ID No. 4); 4G7-light (SEQ ID No. 6); 5D2-light (SEQ ID No. 8); 5E6-light (SEQ ID No. 10); 7C9-light (SEQ ID No. 12); 7G4-light (SEQ ID No. 14), 10C8-light(SEQ ID No. 16), 1H3-heavy (SEQ ID No. 1); 2G4-heavy (SEQ ID No. 3); 4G7-heavy (SEQ ID No. 5); 5D2-heavy (SEQ ID No. 7), 5E6-heavy (SEQ ID No. 9), 7C9-heavy (SEQ ID No. 11), 7G4-heavy (SEQ ID No. 13) and 10C8-heavy (SEQ ID No. 1), in which at least one but fewer than about 30 of the amino acid residues of said variable region has been changed or deleted without disrupting antigen binding. It is of note that all of these sequences are described above.
- In yet other embodiments, immunoreactive fragments of any of the above-described monoclonal antibodies, chimeric antibodies or humanized antibodies are prepared using means known in the art, for example, by preparing nested deletions using enzymatic degradation or convenient restriction enzymes.
- It is of note that in all embodiments describing preparation of humanized antibodies, chimeric antibodies or immunoreactive fragments of monoclonal antibodies, these antibodies are screened to ensure that antigen binding has not been disrupted. This may be accomplished by any of a variety of means known in the art, but one convenient method would involve use of a phage display library. As will be appreciated by one of skill in the art, as used herein, ‘immunoreactive fragment’ refers in this context to an antibody fragment reduced in length compared to the wild-type or parent antibody which retains an acceptable degree or percentage of binding activity to the target antigen. As will be appreciated by one of skill in the art, what is an acceptable degree will depend on the intended use.
- It is of note hat as discussed herein, any of the above-described antibody or humanized variant thereof may be formulated into a pharmaceutical treatment for providing passive immunity for individuals suspected of or at risk of developing hemorrhagic fever comprising a therapeutically effective amount of said antibody. The pharmaceutical preparation may include a suitable excipient or carrier. See, for example, Remington: The Science and Practice of Pharmacy, 1995, Gennaro ed. As will be apparent to one knowledgeable in the art, the total dosage will vary according to the weight, health and circumstances of the individual as well as the efficacy of the antibody.
- While the preferred embodiments of the invention have been described above, it will be recognized and understood that various modifications may be made therein, and the appended claims are intended to cover all such modifications which may fall within the spirit and scope of the invention.
-
TABLE 1 Dose-dependent protective efficacy of McAbs in mice Dose Meantime to Treatmenta (μg/treatment) deathb No. of survivors/total McAb 4G7 100 7.00 (n = 1) 5/6 50 7.00 (n = 1) 5/6 25 6.00 (n = 3) 3/6 12.5 6.80 (n = 5) 1/6 6.25 8.20 (n = 5) 2/6 McAb 5D2 100 N/Ac 6/6 50 N/Ac 6/6 25 N/Ac 6/6 12.5 N/Ac 6/6 6.25 7.50 (n = 2) 4/6 McAb 5E6 100 N/Ac 6/6 50 N/Ac 6/6 25 N/Ac 6/6 12.5 6.50 (n = 2) 4/6 6.25 6.67 (n = 3) 3/6 McAb 7C9 100 N/Ac 6/6 50 N/Ac 6/6 25 7.00 (n = 1) 5/6 12.5 7.00 (n = 1) 5/6 6.25 6.50 (n = 4) 2/6 McAb 7G4 100 N/Ac 6/6 50 7.50 (n = 1) 4/6 25 7.00 (n = 1) 5/6 12.5 7.60 (n = 5) 1/6 6.25 6.60 (n = 5) 1/6 McAb 10C8 100 7.00 (n = 1) 5/6 50 7.00 (n = 1) 5/6 25 7.50 (n = 4) 2/6 12.5 7.00 (n = 5) 1/6 6.25 6.40 (n = 5) 1/6 PBS 5.80 (n = 5) 0/5 aMice were intraperitoneally treated with antibodies 1 day after challenge with 1000 LD50 of the mouse-adapted Ebola virus. bData for animals that died (numbers of animals are shown in parentheses). cN/A: not applicable. -
TABLE 2 Time dependency of the protective efficacy of MAbs in mice MAbs Day of treatmenta Mean time to deathb No. of survivors/total 1H3 −4 6.70 ± 0.61 (n = 10) 0/10 100 μg −1 6.60 ± 0.61 (n = 10) 0/15 +1 8.10 ± 0.74 (n = 9) 6/15 +2 6.60 ± 0.80 (n = 5) 5/10 +3 6.40 ± 0.97 (n = 10) 0/10 2G4 −4 7.40 ± 0.63 (n = 10) 0/10 100 μg −1 7.86 ± 0.74 (n = 14) 1/15 +1 8.00 (n = 6) 9/15 +2 7.30 ± 0.47 (n = 3) 7/10 +3 5.70 ± 1.13 (n = 10) 0/10 4G7 −4 7.42 ± 0.46 (n = 7) 3/10 100 μg −1 7.08 ± 0.74 (n = 14) 1/15 +1 8.25 ± 0.43 (n = 4) 11/15 +2 n/ac 10/10 +3 5.67 ± 1.34 (n = 9) 1/10 5D2 −4 7.00 (n = 1) 9/10 100 μg −1 8.00 ± 1.00 (n = 2) 13/15 +1 n/a 15/15 +2 7.00 (n = 4) 6/10 +3 6.30 ± 1.05 (n = 10) 0/10 5E6 −4 7.00 (n = 2) 8/10 100 μg −1 8.25 ± 0.43 (n = 4) 11/15 +1 7.00 (n = 1) 14/15 +2 6.00 (n = 1) 9/10 +3 5.80 ± 1.03 (n = 10) 0/10 7C9 −4 7.00 (n = 1) 9/10 100 μg −1 7.75 ± 0.43 (n = 4) 11/15 +1 8.00 ± 0.82 (n = 3) 12/15 +2 7.00 (n = 1) 9/10 +3 6.10 ± 0.67 (n = 10) 0/10 7G4 −4 8.20 ± 0.71 (n = 10) 0/10 100 μg −1 8.07 ± 0.59 (n = 14) 1/15 +1 n/a 15/15 +2 7.10 ± 0.57 (n = 9) 1/10 +3 6.70 ± 0.44 (n = 10) 0/10 10C8 −4 7.83 ± 0.64 (n = 6) 4/10 100 μg −1 7.64 ± 1.17 (n = 14) 1/15 +1 8.50 ± 0.50 (n = 2) 13/15 +2 6.83 ± 0.37 (n = 6) 4/10 +3 6.30 ± 1.13 (n = 10) 0/10 17F8d −4 6.00 ± 1.10 (n = 9) 1/10 100 μg −1 6.13 ± 0.88 (n = 15) 0/15 +1 7.21 ± 0.86 (n = 14) 1/15 +2 6.10 ± 0.83 (n = 10) 0/10 +3 6.00 ± 1.13 (n = 10) 0/10 PBS −4 5.40 ± 1.43 (n = 10) 0/10 −1 6.60 ± 0.80 (n = 5) 0/5 +3 5.00 ± 0.60 (n = 10) 0/10 aMice were intraperitoneally treated with each MAb at indicated time before or after challenge with 1000 LD50 of the mouse-adapted Ebola virus. bData for animals that died (numbers of animals are shown in parentheses). cN/A: not applicable. dControl Mab: anti-MAR GP. -
TABLE 3 Protective efficacy of MAbs in guinea pigs Day of Meantime No. Treatment treatmenta to deathb of survival/Tatalc Cocktail of 5D2(3 mg) + 1 N/ A d6/6 4G7(2 mg) + 1H3(1 mg) + 2 2GA(1 mg) Cocktail of 5E6(3 mg) + 1 N/ A 6/6 4G7(2 mg) + 1H3(1 mg) + 2 2G4(1 mg) Cocktail of 7C9(3 mg) + 1 N/ A 6/6 4G7(2 mg) + 1H3(1 mg) + 2 2G4(1 mg) Cocktail of 7G4(3 mg) + 1 N/ A 6/6 4G7(2 mg) + 1H3(1 mg) + 2 2G4(1 mg) Cocktail of 10C8(3 mg) + 1 9.00 (n = 1) 5/6 4G7(2 mg) + 1H3(1 mg) + 2 2G4(1 mg) Cocktail of PBS + 1 7.00 (n = 6) 0/6 PBS 2 aGuinea pigs were intraperiotoneally treated with the MAbs as showed dose in the table on the indicated days after challenge with 1000 LD50 of the guinea pig-adapted Ebola virus. bData for all animals that died(numbers of animals are shown in parentheses). cSurvival rate on day 28 after challenge. dN/A: not applicable. -
TABLE 4 Summary of ELISA Result of Anti-Ebola-GP McAbs Antigen Rf-GP1 Mucin eGP1,2 sGP sub-f-D domain GP1 McAb Isotype eVLPs ΔTm 1-295aa 157-369aa 333-458aa 1-501aa 1H3 IgG2a, κ + + + − − + 2G4 IgG2b, κ + + − − − − 4G7 IgG2a, κ + + − − − + 5D2 IgG2a, κ + + − + + + 5E6 IgG2a, λ + + − − + + 7C9 IgG2a, κ + + − +/− + + 7G4 IgG1, κ + + − − +/− + 10C8 IgG2a, κ + + − − +/− + Antigens (0.3 μg/well) were coated in 96 well microtitre plate then blocking with 2% skim milk. Serial dilutions of each MAb were applied to the plate followed by HRP-conjugated goat anti-mouse IgG. After incubabing with substrate, the asorbance awas read at OD405. Cut off was 2X background. -
TABLE 5 Prolonged survival seen in McAb-treated Guinea pigs Treatmenta Mean time to deathb Student's t-test MAb 1H3 11.7 ± 2.18 (n = 5) p = 0.0181 MAb 2G4 11.5 ± 1.50 (n = 2) N/Ac MAb 4G7 10.5 ± 1.50 (n = 2) N/Ac MAb 5D2 9.4 ± 1.02 (n = 5) p = 0.0244 MAb 5E6 10.8 ± 1.47 (n = 5) p = 0.0092 MAb 7C9 9.6 ± 0.80 (n = 5) p = 0.0056 MAb 7G4 9.6 ± 0.80 (n = 5) p = 0.0056 MAb 10C8 9.4 ± 1.20 (n = 5) p = 0.0428 PBS 7.67 ± 0.75 (n = 6) N/Ac aGuinea pigs were intraperiotoneally treated with 5 mg of the MAb as showed in the table on day 1 after challenge with 1000 LD50 of the guinea pig-adapted Ebola virus.bData for all animals that died (numbers of animals are shown in parentheses). cN/A: not applicable. -
TABLE 6 Protective efficacy of MAbs in guinea pigs No. Day of of survival/ Treatment treatmenta Meantime to deathb Tatalc Cocktail of 4G7(2 mg) + −1 11.17 ± 3.09 (n = 3) 3/6 1H3(1.5 mg) + 2G4(1.5 mg) Cocktail of 4G7(2 mg) + +1 7.92 ± 0.42 (n = 3) 3/6 1H3(1.5 mg) + 2G4(1.5 mg) Cocktail of 4G7(2 mg) + +2 N/ A d6/6 1H3(1.5 mg) + 2G4(1.5 mg) Cocktail of 4G7(2 mg) + +3 11.17 ± 3.09 (n = 3) 4/6 1H3(1.5 mg) + 2G4(1.5 mg) PBS +2 6.58 ± 0.59 (n = 6) 3/6 aGuinea pigs were intraperiotoneally treated with the MAbs as showed dose in the table on the indicated days before or after challenge with 1000 LD50 of the guinea pig-adapted Ebola virus. bData for all animals that died(numbers of animals are shown in parentheses). cSurvival rate on day 28 after challenge. dN/A: not applicable. -
TABLE 7 Epitopes bound by ZEbov GP MoAbs Ebota GPs epitope epitope mAb name with epitope sequence position IH3(IgG2a/κ): sGPa SNTTGKLIWKVNPEI 267-280 aa 2G4(IgG2b/κ): GP2a REAIVNAQPKCNPNL 502-516 aa 4G7(IgG2a/κ): GP2a REAIVNAQPKCNPNL 502-516 aa 5D2(IgG2a/κ): GP1b,c,d DPGTNTTTEDHKIMA 329-343 aa 5E6(IgG2a/κ): GP1b,c,d ATQVEQHHRRTDNDS 401-415 aa 7C9(IgG2a/λ): GP1b,c unknown unknown 7G4(IgG1, κ): GP1b,c unknown unknown 10C8(IgG2a, κ): GP1b,c unknown unknown adetermined by using recombinant vesicular stamatitis virus(VSV) containing ZEbov GP gene to identify the amino acid changes in antigenic variants that escape antibody neutralization; bdetermined by Western blot reactivity with Ebola Zaire 1976 or VLPs, cdetermined by ELISA using recombinant GP1 protein; ddetermined by ELISA using peptide library.
Claims (5)
1-4. (canceled)
5. A pharmaceutical composition for the treatment of Ebola, the pharmaceutical composition comprising at least a first monoclonal antibody and a second monoclonal antibody, wherein the first monoclonal antibody is selected from a group consisting of:
(a) a monoclonal antibody or antigen binding fragment thereof comprising a light chain variable region comprising the amino acid sequence deduced from the nucleic acid molecule as set forth in SEQ ID NO: 2, or variants thereof whereby at least one but fewer than 30 of the amino acid residues of said light chain variable region have been changed or deleted; and a heavy chain variable region comprising the amino acid sequence deduced from the nucleic acid molecule as set forth in SEQ ID No: 1, or variants thereof whereby at least one but fewer than 30 of the amino acid residues of said heavy chain variable region have been changed or deleted;
(b) a monoclonal antibody or antigen binding fragment thereof comprising a light chain variable region comprising the amino acid sequence deduced from the nucleic acid molecule as set forth in SEQ ID NO: 4, or variants thereof whereby at least one but fewer than 30 of the amino acid residues of said light chain variable region have been changed or deleted; and a heavy chain variable region comprising the amino acid sequence deduced from the nucleic acid molecule as set forth in SEQ ID No: 3, or variants thereof whereby at least one but fewer than 30 of the amino acid residues of said heavy chain variable region have been changed or delete& and
(c) a monoclonal antibody or antigen binding fragment thereof comprising a light chain variable region comprising the amino acid sequence deduced from the nucleic acid molecule as set forth in SEQ ID NO:6, or variants thereof whereby at least one but fewer than 30 of the amino acid residues of said light chain variable region have been changed or deleted; and a heavy chain variable region comprising the amino acid sequence deduced from the nucleic acid molecule as set forth in SEQ ID No: 5, or variants thereof whereby at least one but fewer than 30 of the amino acid residues of said heavy chain variable region have been changed or deleted.
6. The pharmaceutical composition of claim 5 , further comprising a pharmaceutically acceptable excipient or carrier.
7. A method of treating a patient suspected of having hemorrhagic fever or at risk of developing hemorrhagic fever, the method comprising:
i) identifying such a patient
ii) administering a therapeutically effective amount of a pharmaceutical composition comprising at least a first monoclonal antibody and a second monoclonal antibody, wherein the first monoclonal antibody is selected from a group consisting of:
(a) a monoclonal antibody or antigen binding fragment thereof comprising a light chain variable region comprising the amino acid sequence deduced from the nucleic acid molecule as set forth in SEQ ID NO: 2, or variants thereof whereby at least one but fewer than 30 of the amino acid residues of said light chain variable region have been changed or deleted and a heavy chain variable region comprising the amino acid sequence deduced from the nucleic acid molecule as set forth in SEQ ID No: 1, or variants thereof whereby at least one but fewer than 30 of the amino acid residues of said heavy chain variable region have been changed or deleted;
(b) a monoclonal antibody or antigen binding fragment thereof comprising a light chain variable region comprising the amino acid sequence deduced from the nucleic acid molecule as set forth in SEQ ID NO: 4, or variants thereof whereby at least one but fewer than 30 of the amino acid residues of said light chain variable region have been changed or deleted and a heavy chain variable region comprising the amino acid sequence deduced from the nucleic acid molecule as set forth in SEQ ID No: 3, or variants thereof whereby at least one but fewer than 30 of the amino acid residues of said heavy chain variable region have been changed or deleted; and
(c) a monoclonal antibody or antigen binding fragment thereof comprising a light chain variable region comprising the amino acid sequence deduced from the nucleic acid molecule as set forth in SEQ ID NO: 6, or variants thereof whereby at least one but fewer than 30 of the amino acid residues of said light chain variable region have been changed or deleted and a heavy chain variable region comprising the amino acid sequence deduced from the nucleic acid molecule as set forth in SEQ ID No: 5, or variants thereof whereby at least one but fewer than 30 of the amino acid residues of said heavy chain variable region have been changed or deleted.
8. The method of claim 7 , wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipient or carrier.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US15/826,537 US20180071389A1 (en) | 2008-02-01 | 2017-11-29 | Monoclonal Antibodies for Ebola and Marburg Viruses |
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US2549108P | 2008-02-01 | 2008-02-01 | |
PCT/CA2009/000070 WO2009094755A1 (en) | 2008-02-01 | 2009-01-27 | Monoclonal antibodies for ebola and marburg viruses |
CAPCT/CA2009/000070 | 2009-01-27 | ||
US86458410A | 2010-10-26 | 2010-10-26 | |
US13/940,712 US9249214B2 (en) | 2008-02-01 | 2013-07-12 | Monoclonal antibodies for Ebola and Marburg viruses |
US14/979,834 US9861696B2 (en) | 2008-02-01 | 2015-12-28 | Monoclonal antibodies for Ebola and Marburg viruses |
US15/826,537 US20180071389A1 (en) | 2008-02-01 | 2017-11-29 | Monoclonal Antibodies for Ebola and Marburg Viruses |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/979,834 Continuation US9861696B2 (en) | 2008-02-01 | 2015-12-28 | Monoclonal antibodies for Ebola and Marburg viruses |
Publications (1)
Publication Number | Publication Date |
---|---|
US20180071389A1 true US20180071389A1 (en) | 2018-03-15 |
Family
ID=40912198
Family Applications (5)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/864,584 Active 2029-09-29 US8513391B2 (en) | 2008-02-01 | 2009-01-27 | Monoclonal antibodies for Ebola and Marburg viruses |
US13/940,688 Active US9145454B2 (en) | 2008-02-01 | 2013-07-12 | Monoclonal antibodies for Ebola and Marburg viruses |
US13/940,712 Active US9249214B2 (en) | 2008-02-01 | 2013-07-12 | Monoclonal antibodies for Ebola and Marburg viruses |
US14/979,834 Active US9861696B2 (en) | 2008-02-01 | 2015-12-28 | Monoclonal antibodies for Ebola and Marburg viruses |
US15/826,537 Abandoned US20180071389A1 (en) | 2008-02-01 | 2017-11-29 | Monoclonal Antibodies for Ebola and Marburg Viruses |
Family Applications Before (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/864,584 Active 2029-09-29 US8513391B2 (en) | 2008-02-01 | 2009-01-27 | Monoclonal antibodies for Ebola and Marburg viruses |
US13/940,688 Active US9145454B2 (en) | 2008-02-01 | 2013-07-12 | Monoclonal antibodies for Ebola and Marburg viruses |
US13/940,712 Active US9249214B2 (en) | 2008-02-01 | 2013-07-12 | Monoclonal antibodies for Ebola and Marburg viruses |
US14/979,834 Active US9861696B2 (en) | 2008-02-01 | 2015-12-28 | Monoclonal antibodies for Ebola and Marburg viruses |
Country Status (5)
Country | Link |
---|---|
US (5) | US8513391B2 (en) |
EP (3) | EP2262832A4 (en) |
CA (3) | CA2952055C (en) |
ES (1) | ES2728095T3 (en) |
WO (1) | WO2009094755A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110655572A (en) * | 2019-10-11 | 2020-01-07 | 中国科学院广州生物医药与健康研究院 | Monoclonal antibody for resisting filovirus GP protein and application thereof |
US11437023B2 (en) | 2019-07-19 | 2022-09-06 | Samsung Electronics Co., Ltd. | Apparatus and method with speech recognition and learning |
Families Citing this family (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2262832A4 (en) * | 2008-02-01 | 2011-03-09 | Ca Minister Health & Welfare | Monoclonal antibodies for ebola and marburg viruses |
US20170183396A1 (en) * | 2014-02-19 | 2017-06-29 | Jody Berry | Ebola monoclonal antibodies |
EP2944321A1 (en) * | 2014-05-12 | 2015-11-18 | Institut De Recherche Pour Le Développement (IRD) | Immunogenic peptides of EBOLA and applications thereof |
AU2015327819B2 (en) * | 2014-10-03 | 2021-07-01 | Massachusetts Institute Of Technology | Antibodies that bind ebola glycoprotein and uses thereof |
EP3875481A1 (en) | 2014-11-14 | 2021-09-08 | The U.S.A. as represented by the Secretary, Department of Health and Human Services | Neutralizing antibodies to ebola virus glycoprotein and their use |
TWI710573B (en) | 2015-01-26 | 2020-11-21 | 美商再生元醫藥公司 | Human antibodies to ebola virus glycoprotein |
EP3271388A1 (en) | 2015-02-09 | 2018-01-24 | INSERM - Institut National de la Santé et de la Recherche Médicale | Antibodies specific to glycoprotein (gp) of ebola virus and uses for the treatment and diagnosis of ebola virus infection |
GB201502209D0 (en) | 2015-02-10 | 2015-03-25 | Sec Dep For Health The And Chancellor Masters And Scholars Of The University Of Oxford The And Micro | Filovirus therapy |
WO2016131128A1 (en) * | 2015-02-19 | 2016-08-25 | Cangene Corporation | Humanized ebola antibodies and uses thereof |
US20160324965A1 (en) * | 2015-05-07 | 2016-11-10 | Andrew Hiatt | Monoclonal antibody cocktails for treatment of ebola infections |
US20160326234A1 (en) * | 2015-05-07 | 2016-11-10 | Andrew Hiatt | Monoclonal antibody cocktails for treatment of ebola infections |
EP3302563A1 (en) * | 2015-05-29 | 2018-04-11 | H. Hoffnabb-La Roche Ag | Humanized anti-ebola virus glycoprotein antibodies and methods of use |
JP6761821B2 (en) | 2015-07-15 | 2020-09-30 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | Etinyl derivative as a metabolic glutamate receptor modulator |
CN105542002B (en) * | 2016-02-01 | 2019-01-04 | 清华大学 | A kind of monoclonal antibody Q206 and application |
CN105601737B (en) * | 2016-02-01 | 2019-01-04 | 清华大学 | A kind of monoclonal antibody Q411 and application |
CN105622750B (en) * | 2016-02-01 | 2019-01-04 | 清华大学 | A kind of monoclonal antibody Q314 and application |
WO2018017964A2 (en) | 2016-07-21 | 2018-01-25 | Emory University | Ebola virus antibodies and binding agents derived therefrom |
WO2018152452A1 (en) | 2017-02-17 | 2018-08-23 | Mapp Biopharmaceutical, Inc. | Monoclonal antibodies and cocktails for treatment of ebola infections |
CN115243718A (en) | 2020-01-24 | 2022-10-25 | 瑞泽恩制药公司 | Stable antibody formulations |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8513391B2 (en) * | 2008-02-01 | 2013-08-20 | Steven Jones | Monoclonal antibodies for Ebola and Marburg viruses |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2549108A (en) | 1943-12-29 | 1951-04-17 | United Aircraft Corp | Propeller pitch control |
US5618920A (en) | 1985-11-01 | 1997-04-08 | Xoma Corporation | Modular assembly of antibody genes, antibodies prepared thereby and use |
IL85035A0 (en) * | 1987-01-08 | 1988-06-30 | Int Genetic Eng | Polynucleotide molecule,a chimeric antibody with specificity for human b cell surface antigen,a process for the preparation and methods utilizing the same |
GB8800077D0 (en) | 1988-01-05 | 1988-02-10 | Ciba Geigy Ag | Novel chimeric antibodies |
WO1990002569A1 (en) | 1988-09-06 | 1990-03-22 | International Genetic Engineering, Inc. | Production of chimeric mouse-human antibodies with specificity to human tumor antigens |
LU91067I2 (en) | 1991-06-14 | 2004-04-02 | Genentech Inc | Trastuzumab and its variants and immunochemical derivatives including immotoxins |
US6309636B1 (en) | 1995-09-14 | 2001-10-30 | Cancer Research Institute Of Contra Costa | Recombinant peptides derived from the Mc3 anti-BA46 antibody, methods of use thereof, and methods of humanizing antibody peptides |
US6875433B2 (en) * | 2002-08-23 | 2005-04-05 | The United States Of America As Represented By The Secretary Of The Army | Monoclonal antibodies and complementarity-determining regions binding to Ebola glycoprotein |
-
2009
- 2009-01-27 EP EP09705944A patent/EP2262832A4/en not_active Withdrawn
- 2009-01-27 WO PCT/CA2009/000070 patent/WO2009094755A1/en active Application Filing
- 2009-01-27 CA CA2952055A patent/CA2952055C/en active Active
- 2009-01-27 US US12/864,584 patent/US8513391B2/en active Active
- 2009-01-27 ES ES15196615T patent/ES2728095T3/en active Active
- 2009-01-27 EP EP19163540.8A patent/EP3572125A3/en not_active Withdrawn
- 2009-01-27 EP EP15196615.7A patent/EP3048115B1/en active Active
- 2009-01-27 CA CA2712605A patent/CA2712605C/en active Active
- 2009-01-27 CA CA3081694A patent/CA3081694C/en active Active
-
2013
- 2013-07-12 US US13/940,688 patent/US9145454B2/en active Active
- 2013-07-12 US US13/940,712 patent/US9249214B2/en active Active
-
2015
- 2015-12-28 US US14/979,834 patent/US9861696B2/en active Active
-
2017
- 2017-11-29 US US15/826,537 patent/US20180071389A1/en not_active Abandoned
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8513391B2 (en) * | 2008-02-01 | 2013-08-20 | Steven Jones | Monoclonal antibodies for Ebola and Marburg viruses |
US9145454B2 (en) * | 2008-02-01 | 2015-09-29 | Her Majesty the Queen in the Right of Canada as represented by the Minister of Health | Monoclonal antibodies for Ebola and Marburg viruses |
US9249214B2 (en) * | 2008-02-01 | 2016-02-02 | Her Majesty the Queen in the Right of Canada as represented by the Minister of Health | Monoclonal antibodies for Ebola and Marburg viruses |
US9861696B2 (en) * | 2008-02-01 | 2018-01-09 | Her Majesty The Queen In Right Of Canada As Represented By The Minister Of Health | Monoclonal antibodies for Ebola and Marburg viruses |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11437023B2 (en) | 2019-07-19 | 2022-09-06 | Samsung Electronics Co., Ltd. | Apparatus and method with speech recognition and learning |
CN110655572A (en) * | 2019-10-11 | 2020-01-07 | 中国科学院广州生物医药与健康研究院 | Monoclonal antibody for resisting filovirus GP protein and application thereof |
Also Published As
Publication number | Publication date |
---|---|
CA2952055C (en) | 2020-07-21 |
EP3048115A9 (en) | 2016-10-26 |
CA2712605C (en) | 2017-02-07 |
EP3572125A3 (en) | 2019-12-18 |
CA3081694A1 (en) | 2009-08-06 |
US9861696B2 (en) | 2018-01-09 |
EP3048115A3 (en) | 2016-09-28 |
CA3081694C (en) | 2022-07-26 |
EP2262832A4 (en) | 2011-03-09 |
US8513391B2 (en) | 2013-08-20 |
US20150344546A1 (en) | 2015-12-03 |
US20160151492A1 (en) | 2016-06-02 |
EP3572125A2 (en) | 2019-11-27 |
CA2952055A1 (en) | 2009-08-06 |
US9249214B2 (en) | 2016-02-02 |
EP3048115A2 (en) | 2016-07-27 |
ES2728095T3 (en) | 2019-10-22 |
EP2262832A1 (en) | 2010-12-22 |
US9145454B2 (en) | 2015-09-29 |
US20120283414A1 (en) | 2012-11-08 |
US20150232538A1 (en) | 2015-08-20 |
WO2009094755A1 (en) | 2009-08-06 |
CA2712605A1 (en) | 2009-08-06 |
EP3048115B1 (en) | 2019-05-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20180071389A1 (en) | Monoclonal Antibodies for Ebola and Marburg Viruses | |
US10294293B2 (en) | Human monoclonal antibody with specificity for dengue virus serotype 1 E protein and uses thereof | |
US20170183396A1 (en) | Ebola monoclonal antibodies | |
JP2012518425A5 (en) | ||
SA96170384B1 (en) | Methods of preparation and therapeutic uses (RSV) Human neutralizing monoclonal antibodies with high affinity for the F-protein of respiratory syncytial virus | |
CN115996954A (en) | Methods of treating infections | |
Esmaeilzadeh et al. | Recent advances in antibody‐based immunotherapy strategies for COVID‐19 | |
CN111344302A (en) | Multispecific antibodies that specifically bind to epitopes of Zika virus and uses thereof | |
WO2022127793A1 (en) | Respiratory syncytial virus-specific binding molecule | |
WO2014043215A1 (en) | Bi-specifc diabodies for masking and targeting vaccines | |
WO2022216223A1 (en) | Vaccine and/or antibody for viral infection | |
US20230242623A1 (en) | Compositions and methods for the diagnosis and treatment of sars-cov-2 virus infection | |
US20230218735A1 (en) | Immunogenic compositions against clostridioides (clostridium) difficile and methods thereof | |
US20220160859A1 (en) | Compositions and methods for eliciting an immune response against clostridium difficile | |
Cao et al. | Unbiased approach to identify and assess efficacy of human SARS-CoV-2 neutralizing antibodies | |
CN114773461B (en) | Japanese encephalitis virus antibody 1D11 and application thereof | |
US20220289827A1 (en) | Neutralizing antibodies to sars-cov-2 and its variants | |
US20030103977A1 (en) | Antibodies to polysaccharide of C. neoformans | |
CN112574297A (en) | Monoclonal antibody against neuraminidase and application thereof | |
JPWO2019129214A5 (en) |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STPP | Information on status: patent application and granting procedure in general |
Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |