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WO1994017105A1 - Anticorps chimeres d'humain/de murin utilises contre le virus syncytial respiratoire - Google Patents

Anticorps chimeres d'humain/de murin utilises contre le virus syncytial respiratoire Download PDF

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Publication number
WO1994017105A1
WO1994017105A1 PCT/US1993/001168 US9301168W WO9417105A1 WO 1994017105 A1 WO1994017105 A1 WO 1994017105A1 US 9301168 W US9301168 W US 9301168W WO 9417105 A1 WO9417105 A1 WO 9417105A1
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WIPO (PCT)
Prior art keywords
antibody
human
murine
cdr
protein
Prior art date
Application number
PCT/US1993/001168
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English (en)
Inventor
Leslie Johnson
Original Assignee
Medimmune, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Medimmune, Inc. filed Critical Medimmune, Inc.
Priority to PCT/US1993/001168 priority Critical patent/WO1994017105A1/fr
Priority to AU36608/93A priority patent/AU3660893A/en
Publication of WO1994017105A1 publication Critical patent/WO1994017105A1/fr

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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide

Definitions

  • Respiratory syncytial virus is the major cause of acute respiratory illness in young children admitted to hospitals, and the community practice will treat perhaps five times the number of hospitalized children. It is therefore, the most common cause of lower respiratory tract infection in young children. While the majority of community-acquired infections resolve themselves in a week to ten days, many hospitalized children, especially under six months of age require assisted ventilation.
  • ribavirin has been licensed for therapy of RSV pneumonia and bronchiolitis (2,3); its value is contraversial (4).
  • ribavirin has shown efficacy (9), the drug has to be administered over an 18 hour period by aerosol inhalation.
  • the level of secondary infections following cessation of treatment is significantly higher than in untreated patients.
  • RSV immunoglobulin was effective both in prophylaxis and therapy for RSV infections in animal models (6, 7). Infected animals treated with RSV immune globulin, showed no evidence of pulmonary immune-complex disease (6, 7).
  • RSV hyperimmune globulin Even if RSV hyperimmune globulin is shown to reduce the incidence and severity of RSV lower respiratory tract infection in high risk children, several disadvantages may limit its use.
  • One drawback is the necessity for intravenous infusion in these children who have limited venous access because of prior intensive therapy.
  • a second disadvantage is the large volume of RSVIG required for protection, particularly since most these children have compromised cardiopulmonary function.
  • a third disadvantage is that intravenous infusion necessitates monthly hospital visits during the RSV season which places these children at risk of nosocomial RSV infection (1).
  • a final problem is that it may prove to be very difficult to select sufficient donors to produce a hyperimmune globulin for RSV to meet the demand for this product.
  • Currently only about 8% of normal donors have RSV neutralizing antibody titers high enough to qualify for the production of hyperimmune globulin.
  • Another approach may be the development of monoclonal antibodies with high specific neutralizing activity as an alternative to hyperimmune globulin. It is preferable, if not necessary, to use human monoclonal antibodies rather than murine or rat antibodies to minimize the development of human anti-rodent antibody responses which may compromise the therapeutic efficacy of the antibody or induce immune-complex pathology. However, the generation of human monoclonal antibodies with the desired specificity may be difficult and the level of production from human cell lines is often low, precluding their development.
  • CDR complementarity determining region
  • the murine monoclonal antibody is a neutralizing antibody. It is al ⁇ o preferable that said murine antibody is an antibody against RSV F antigen.
  • animal as used herein is used in its broadest sense includes mammals including humans.
  • Figure 1 shows the amino acid (AA) sequence design of CDR-Grafted anti-RSV F glycoprotein V render.
  • the figure depicts the AA sequence for the human HV3 V composition before grafting, CDR grafted V favor, and murine MAbl308F V render from which the CDR sequence was grafted.
  • the heavily underlined regions identify the CDR sequence which was grafted into the human HV3 V-, and each of the three regions is identified as CDR1, CDR2 and CDR3, respectively.
  • Figure 2 shows the amino acid (AA) sequence design of CDR-Grafted anti-RSV F Protein V.
  • the figure depicts the AA sequence for the human K102 V. before grafting, CDR grafted V-., and murine MAbl308F V. from which the CDR sequence was grafted.
  • the heavily underlined regions identify the CDR sequence which was grafted into the human K102 V- and each of the three regions is identified a ⁇ CDR1, CDR2 and CDR3, respectively.
  • Figure 3 depicts the oligonucleotides used to make Hul308V bin, the sequences which are underlined are the specific primer sequences.
  • Figure 4 depicts the oligonucleotides used to make Hul308V., the sequences which are underlined are the specific primer sequences.
  • Figure 5 depicts the plasmid construction of the expres ⁇ ion vectors for Humanized 1308.
  • Figure 6 depicts a graph of the Neutraliziation of RSV as percent neutralization versus ng MAb per reaction for neutralizing with Cos Hul308F and with Mul308F.
  • the murine antibody is a neutralizing antibody against RSV.
  • Another aspect of the present invention provides for the murine antibody to be an antibody against RSV F antigen.
  • the murine antibody is neutralizing antibody against RSV F antigen.
  • the sub ⁇ titution of the mouse CDR's into the human variable framework segments minimizes the potential for human anti-mouse antibody (HAMA) responses while retaining binding affinity and specificity for antigen, RSV F protein.
  • the human antibodies containing the murine antibody CDR' ⁇ are essentially indistinguishable from completely human antibodies, thereby, minimizing the human antibody response while retaining binding affinity and specificity for RSV F antigen.
  • murine antibodies of this type are: MAb 1436C, MAb 113, MAb 112, MAb 151, MAb 1200, MAb 1214, MAb 1237, MAb 1129, MAb 1121, MAb 1107, MAb 131-1, MAb 43-1, MAb 1112, MAb 1269, MAb 1243, MAb 1331H, MAb 1308F and MAb 1302A (see citation 21) .
  • An aspect of the present invention provides that the CDRs of the human antibody are comprised of three complementarity determining regions (CDRs) from each variable heavy and variable light chain of the murine antibody.
  • CDRs complementarity determining regions
  • the murine antibodies against RSV F antigen have been mapped by competitive binding and reactivity profiles of virus escape mutants to three broad antigenic sites (A, B, C) containing 16 distinct epitopes (20).
  • the epitopes within antigenic sites A and C have shown the least variability in natural isolates.
  • another aspect of this invention provides for a human antibody containing at least one CDR from each variable heavy and variable light chain of at least one murine antibody against RSV F antigen which is specific for antigenic site A or C.
  • this invention provides for the murine antibody against RSV F antigen specific for antigenic site C, where the murine antibody is MAb 1308F.
  • a preferred embodiment of this invention is a human antibody which contains CDR's of the variable heavy chain of murine antibody MAb 1308F against the RSV F antigen.
  • the CDR variable heavy chain of MAb 1308F comprises three CDRs having the following amino acid sequences: Nos. 31 to 35, 47 to 60 and 99 to 106.
  • this embodiment contains CDR's of a variable light chain of MAb 1308F of murine antibody against RSV F antigen.
  • the CDR variable light chain comprises three CDR's having the following amino acid sequences: Nos. 24 to 34, 50 to 56 and 89 to 97.
  • An additional aspect of applicants' invention is a process for preventing or treating RSV infection comprising administering to the animal an effective amount of a human antibody containing at least one CDR from each variable heavy and variable light chain, of at least one murine antibody against RSV F antigen.
  • compositions comprising administering an effective amount of the human antibody as described above in conjunction with an acceptable pharmaceutical carrier.
  • Acceptable pharmaceutical carriers include but are not limited to non-toxic buffers, fillers, isotonic solutions, etc.
  • composition of Applicant's invention may be administered topically or systemically.
  • topical administration are intranasal administration and inhalation of an aerosol containing the human antibody composition.
  • Systemic administration may be accomplished by intravenous or intramuscular injection of the human antibody composition.
  • a preferred aspect of Applicants' invention i ⁇ that the human antibody is administered as part of a plurality of human antibodies against RSV F antigen. These antibodies can be again ⁇ t the same or different epitopes of the RSV F antigen.
  • the human antibody of this invention can be used clinically for diagnosing respiratory syncytial virus in patients. Because of their affinity for RSV F antigen these human antibodies can be used in known diagnostic assay procedures for detecting the presence and concentration of RSV F antigen cells in samples, e..g., body
  • the human antibodies of the present invention can for example be attached or bound to a solid support, ⁇ uch a ⁇ latex beads, a column, etc., which are then contacted with a sample believed to contain RSV F antigen.
  • One such antibody was selected, which is specific for antigenic site C, to produce mouse-human chimeric antibodie ⁇ .
  • This antibody was chosen on -the basis that it: (i) reacted with a large number of virus strains tested (at least 13 out of 14 isolated); (ii) retained neutralizing activity again ⁇ t virus escape mutants selected with other anti-F antibodies and (iii) blocked RSV replication when administered at low doses to cotton rats by intranasal route prior to virus challenge.
  • the antibody showed significant reduction in pulmonary virus titer among antibodies in that respective region.
  • Murine antibody 1308F specific for the C region of RSV F protein, wa ⁇ chosen as the initial target for humanization.
  • the human antibodies were constructed as follows: the RNA wa ⁇ extracted from the murine antibody-producing cell line, the murine variable region ⁇ which are responsible for the binding of the antibody to RSV were cloned and sequenced, resulting in the identification of the murine antibody CDRs. Then a human variable heavy and light chain framework sequence having the highest homology with the variable heavy and light chain murine antibody, was selected. A human framework sequence such as described above is best able to accept the murine-derived CDRs. The murine 1308F variable heavy chain was compared to various human germline genes, the highest homology was to the human germline gene HV3. The two sequences were 62% homologous overall and 65% in the framework regions.
  • V- region A similar analysis of the V- region revealed high homology to the human germ line V-Kappa gene K 102. The alignment of these sequences is shown in Figure 2. In this case the homology is 62% overall and 73% in the framework regions. The murine-derived variable light CDRs were then sub ⁇ tituted into the human variable light chain of human germline gene K102.In each case a human J-region can be selected which is identical to the mouse sequence.
  • human antibodies are expressed and characterized relative to the parental murine antibodies to be certain that the genetic manipulation has not drastically altered the binding properties of the antibodies.
  • Examples 1 cDNA cloning and sequencing of anti-RSV F Protein antibody 1308F cDNA copies of the V render and V- of the target antibody were generated as follows.
  • the first strand CDNA reaction was carried out using AMV reverse trenscriptase and a phosphorylated oligonucleotide primer complementary to a ⁇ egment of the mRNA coding for the constant region of the particular heavy or light chain isotype.
  • the i ⁇ otype i ⁇ gammal, kappa and the specific oligonucleotides were 5'AGCGGATCCAGGGGCCAGTGGATAGAC complementary to codons 129-137 of the CHI region of the murine Gammal gene, and 5'TGGATGGTGGGAAGATG complementary to codons 116-122 of the murine C-kappa gene.
  • the primer anneals to a segment of the mRNA adjacent to the variable region.
  • Second strand cDNA synthesis was carried out using RNase H and E. coli DNA polymera ⁇ e I, as described by Gubler and Hoffman (Gene 25, ;263, 1983), followed by T4 DNA polymerase to assure that blunt ends are produced.
  • Oligonucleotide probes corresponding to C-region sequence lying between the first strand cDNA primer and the V-regi'on were used in colony hybridizations to identify transformant ⁇ carrying the desired cDNA segment.
  • the specific probe sequences were GGCCAGTGGATAGAC complementary to codons 121-125 of murine CHI regions and TACAGTTGGTGCAGCA complementary to codons 110-115 of c-Kappa, respectively.
  • Candidate plasmids isolated from colonies which were positive in the hybridization, were analyzed by digestion with restriction endonucleases Eco RI and Hind III to release the cDNA insert. Those with inserts of 400-500bp were subjected to DNA sequencing.
  • the cDNA inserts were inserted into M13 mpl8 and mpl9 for the determination of the DNA sequence on both strands.
  • the CDR regions of the V render and V. were identified by comparing the amino acid sequence to known sequences as described by Kabat (38). In order to select the human framework sequences best able to accept the mouse derived CDR sequences in a conformation which retains the structure of the antigen combining site, the following strategy was employed. First, the sequence of the murine V render and V-. regions will be compared to known human sequences from both the Genbank and NBRF protein databanks using the Wordsearch program in the Wisconsin package of sequence manipulation programs (Nucleic Acid Res. 12;387) . The best several human V-regions were then analyzed further on the basis of similarity in the framework regions, especially at the junctions of the framework and CDR regions (see Figures 1 and 2) .
  • the oligonucleotides were first allowed to anneal in pairwise combinations and extended with DNA polymerase to generate approximately 200bp ds DNA fragments with an overlapping region, the fragments were then mixed and subjected to PCR using primers at the 3'end of one fragment and the 5' end of the other fragment.
  • the only product which can be formed under these condition is the full length V H segment.
  • the specific primer sequences are underlined in Figure 3.
  • An endonuclease Sac I site was included at the 3' end of the V R sequence in order to join it to a human constant region gene segment.
  • the CDR-grafted V- region was synthesized in a similar way (see Figure 4).
  • the initial 200bp fragments were amplified separately and inserted into separate plasmeds.
  • the fragment coding for the amino terminus was cloned into a pUCl ⁇ derivative as an Ncol-Smal fragment while the fragment coding for the carboxyl-terminus was cloned as a Smal to Hind III fragment.
  • the fragments were subsequently combined via a Smal site at the junction.
  • the oligonucleotides are indicated in Figure 4.
  • a Hind III site was included near the 3' end of the gene segment in order to join it to a human C-kappa gene.
  • the NcoI-SacI fragment representing the humanized V thread was joined to a SacI -Notl fragment, representing a human c-Gamma I CDNA and inserted into pS 18 (which is pUC 1 8 with Ncol and Notl restriction sites incorporated into the polylinker region between the BamHI and Kpnl sites).
  • the humanized 1308F-gammal gene on a SacI-Notl fragment was then combined with a Pvul-NotI fragment from pSJ37 carrying a poly A addition site and a PvuI-SacI fragment from pSV2-dhfr-pCMV containing the SV40 origin of replication, a dhfr gene and the CMV immediate early promoter.
  • the resulting plasmid was designated pSJ60.
  • the Ncol-Hindlll fragment representing the humanized V r was joined to a HindiII-Notl fragment representing a human c-Kappa CDNA in pS18.
  • the humanized 1308F-Kappa gene on a SalI-Notl fragment was then combined with a Pvul-NotI fragment from pSJ37 carrying a poly A addition site and a Pvul-Sall fragment from pSV2-dhfr-pCMV, containing the SV40 origin of replication, a dhfr gene and the CMV immediate early promoter.
  • the resulting plasmid was designated pSJ61.
  • pSJ60 and pSJ61 were combined into a ⁇ ingle pla ⁇ mid containing both the light and heavy chains and expres ⁇ ion ⁇ ignals. This wa ⁇ accomplished by isolating a Pvul-Bam HI fragment from pSJ ⁇ l carrying the light chain with a Pvu I - Bgl II fragment from pSJ60 carrying the heavy chain to generate pSJ66. (See Figure 5).
  • COS 1 cells (ATCC CRL1650) were maintained in a humidified 5% C02 incubator in 75 cm tissue culture flasks in Dulbecco's Modified Eagle Medium (DMEM, GIBCO #320-1965) supplemented with 10% Fetal Bovine Serum (FBS, GIBCO #200-6140) and 2mM L-glutamine (BRL #320-5030) and passed at a split ratio of 1:20 when the cell ⁇ had reached confluence.
  • DMEM Dulbecco's Modified Eagle Medium
  • FBS Fetal Bovine Serum
  • BBL #320-5030 2mM L-glutamine
  • tissue culture dishes were seeded with 1.5 x 10 6 cells per dish in 12ml DMEM, 10% FBS, 2mM L-glutamine, 1% penicillin-streptomycin (P-S, GIBCO #600-5070).
  • the day of the transfection 120 ug each of the plasmid ⁇ pSJ60 and pSJ61 were combined, ethanol precipitated, and aseptically resuspended in 2.5ml Tris-Buffered-Saline.
  • the resuspended DNA wa ⁇ added dropwi ⁇ e, with mixing, to 10ml of DMLEM containing 1 mg/ml DEAE-dextran (Phamiacia #17-0350-01) and 250 uM chloroquine (Sigma #C6628).
  • DMLEM Dulbecco's phosphate buffered saline
  • DMEM Dulbecco's phosphate buffered saline
  • the medium was removed from the plate ⁇ , pooled, and stored at -20°C.
  • the cell ⁇ 2 were harvested, pooled, and seeded into 4 150cm tissue culture flasks two with 40ml DMEM/10% NuSerum and two with
  • the resuspended DNA was added dropwi ⁇ e, with mixing, to 4.0ml of DMEM containing lmg/ml DEAE-dextran (Pharmacia #17-0350-01) and 250uM chloroquine (Sigma #C6628) .
  • the medium was removed from the COS1 cells in the 100mm dishes and the cells were washed once with Dulbecco's phosphate buffered saline (D-PBS, GIBCO #310-4190), and 2.5ml DMEM supplemented with 10% NuSerum (Collaborative Research #55000) were added to each plate.
  • the concentration of humanized 1308F antibody secreted from the Cosl cell ⁇ into the medium was determined u ⁇ ing a capture ELISA.
  • Goat anti-human IgG Fc coated onto 96 well plate ⁇ wa ⁇ used to capture the humanized antibody.
  • Peroxidase conjugated goat anti-human whole IgG developed with a chromogenic substrate was then used to detect the bound antibody.
  • a purified human IgGl/Kappa preparation was used to calibrate the assay.
  • RSV was neutralized with either humanized 1308F from Cos cell supernatant or purified 1308F murine monoclonal antibody.
  • Thi ⁇ was done by incubating 50 plaque-forming units of RSV with serial 2-fold dilutions of antibody for 1.0 hour at 37°C.
  • Confluent monolayer ⁇ of Hep2 cell ⁇ in 24 well panel ⁇ were infected with lOO ⁇ l of antibody treated virus, untreated control virus, and mock infected controls. Incubated for 1.5 hours at 37°C, humidified , and 5% CO., and overlayed with 1.5mL EMEM, 1% FBS, and 1% methyl cellulose. Cells were fixed and stained with glutaldehyde and crystal violet on day 4.
  • Plaques were counted in triplicate wells and plotted a ⁇ percent neutralization.
  • the re ⁇ ults shown in Figure 6 indicate that both the purified murine 1308F monoclonal and the humanized 1308F monoclonal antibody at 5 to 10 ng per well yield similar 50% reductions in RSV plaques.

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Abstract

L'invention se rapporte à un anticorps humain qui contient au moins une région déterminant la complémentarité (région CDR) provenant de chaque chaîne lourde variable et de chaque chaîne légère variable d'au moins un anticorps monoclonal de murin (de préférence un anticorps neutralisant) dirigé contre le virus syncytial respiratoire (RSV). L'invention se rapporte également à l'anticorps de murin, lequel est un anticorps dirigé contre la protéine de RSV-F. Selon un mode de réalisation préféré, la région CDR contient trois régions déterminant la complémentarité provenant de la chaîne lourde variable et de la chaîne légère variable, d'au moins un anticorps de murin dirigé contre la protéine de RSV-F.
PCT/US1993/001168 1993-01-29 1993-01-29 Anticorps chimeres d'humain/de murin utilises contre le virus syncytial respiratoire WO1994017105A1 (fr)

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PCT/US1993/001168 WO1994017105A1 (fr) 1993-01-29 1993-01-29 Anticorps chimeres d'humain/de murin utilises contre le virus syncytial respiratoire
AU36608/93A AU3660893A (en) 1993-01-29 1993-01-29 Human-murine chimeric antibodies against respiratory syncytial virus

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996031186A3 (fr) * 1995-02-10 1996-11-14 Abbott Lab Produit et procede de prevention d'infection virale des voies respiratoires
WO1997010846A1 (fr) * 1995-09-18 1997-03-27 Intracel Corporation Anticorps monoclonaux neutralisants diriges contre le virus syncytial respiratoire
EP0783525A4 (fr) * 1994-08-15 2000-08-30 Medimmune Inc Anticorps chimeriques humains-murins opposes au virus respiratoire syncytial
US7485440B2 (en) 1995-09-27 2009-02-03 The United States Of America As Represented By The Department Of Health And Human Services Production of attenuated respiratory syncytial virus vaccines involving modification of M2 ORF2
US7829102B2 (en) 1999-07-09 2010-11-09 The United States Of America As Represented By The Department Of Health And Human Services Production of attenuated, human-bovine chimeric respiratory syncytial virus vaccines
WO2022057909A1 (fr) 2020-09-17 2022-03-24 上海霖羲致企业管理有限公司 Protéine recombinante bispécifique et son utilisation
WO2023016568A1 (fr) 2021-08-12 2023-02-16 上海才致药成生物科技有限公司 Protéine recombinante bispécifique et son utilisation

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9207479D0 (en) * 1992-04-06 1992-05-20 Scotgen Ltd Novel antibodies for treatment and prevention of respiratory syncytial virus infection in animals and man

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BIOTECHNOLOGY, Volume 9, Number 3, issued March 1991, P.R. TEMPEST et al., "Reshaping a Human Monoclonal Antibody to Inhibit Human Respiratory Syncytail Virus Infection In Vivo", pages 266 to 271. *
DEVELOPMENTAL AND BIOLOGICAL STANDARIZATION, Volume 57, issued 1984, E.J. STOTT et al., "The Characterization and Uses of Monoclonal Antibodies to Respiratory Syncytial Virus", pages 237 to 244. *
NATURE, Volume 321, issued 29 May 1986, P.T. JONES et al., "Replacing the Complementarity-Determining Regions in a Human Antibody with those from a Mouse", pages 522 to 525. *

Cited By (18)

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JP2009029817A (ja) * 1994-08-15 2009-02-12 Medimmune Llc ヒト−マウスキメラ抗呼吸シンシチアルウイルス抗体
JP2010241819A (ja) * 1994-08-15 2010-10-28 Medimmune Llc ヒト−マウスキメラ抗呼吸シンシチアルウイルス抗体
US8562994B2 (en) 1994-08-15 2013-10-22 Medimmune, Llc Human-murine chimeric antibodies against respiratory syncytial virus
JP2012207022A (ja) * 1994-08-15 2012-10-25 Medimmune Llc ヒト−マウスキメラ抗呼吸シンシチアルウイルス抗体
EP0783525A4 (fr) * 1994-08-15 2000-08-30 Medimmune Inc Anticorps chimeriques humains-murins opposes au virus respiratoire syncytial
EP1659133A3 (fr) * 1994-08-15 2009-01-21 MedImmune, Inc. Anticorps chimeriques humains-murins opposés au virus respiratoire syncytial
EP2371858A3 (fr) * 1994-08-15 2011-10-26 MedImmune, LLC Anticorps chimeriques humains-murins opposes au virus respiratoire syncytial
US7704505B2 (en) 1994-08-15 2010-04-27 Medimmune, Llc Human-murine chimeric antibodies against respiratory syncytial virus
WO1996031186A3 (fr) * 1995-02-10 1996-11-14 Abbott Lab Produit et procede de prevention d'infection virale des voies respiratoires
US5922344A (en) * 1995-02-10 1999-07-13 Abbott Laboratories Product for prevention of respiratory virus infection and method of use
WO1997010846A1 (fr) * 1995-09-18 1997-03-27 Intracel Corporation Anticorps monoclonaux neutralisants diriges contre le virus syncytial respiratoire
US7488477B2 (en) 1995-09-18 2009-02-10 Intracel Resources Llc Neutralizing monoclonal antibodies to respiratory syncytial virus
US8221759B2 (en) 1995-09-18 2012-07-17 Intracel Resources Llc Neutralizing monoclonal antibodies to respiratory syncytial virus
WO1997011177A1 (fr) * 1995-09-18 1997-03-27 Intracel Corporation Anticorps monoclonaux neutralisants diriges contre le virus respiratorie syncytial
US7485440B2 (en) 1995-09-27 2009-02-03 The United States Of America As Represented By The Department Of Health And Human Services Production of attenuated respiratory syncytial virus vaccines involving modification of M2 ORF2
US7829102B2 (en) 1999-07-09 2010-11-09 The United States Of America As Represented By The Department Of Health And Human Services Production of attenuated, human-bovine chimeric respiratory syncytial virus vaccines
WO2022057909A1 (fr) 2020-09-17 2022-03-24 上海霖羲致企业管理有限公司 Protéine recombinante bispécifique et son utilisation
WO2023016568A1 (fr) 2021-08-12 2023-02-16 上海才致药成生物科技有限公司 Protéine recombinante bispécifique et son utilisation

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