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Neutralizing monoclonal antibodies to respiratory syncytial virus

a monoclonal antibody and respiratory syncytial virus technology, applied in the field of immunology, to achieve the effect of reducing the amount of antibody required, facilitating immunotherapy, and facilitating therapy

Inactive Publication Date: 2009-04-30
PILKINGTON GLENN R +4
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The monoclonal antibodies significantly reduce the amount of antibody required for therapy, offer improved safety by minimizing immune responses, and enable effective prophylaxis and treatment with reduced inconvenience and risk of iatrogenic infections, particularly when administered directly to the lungs as Fab fragments.

Problems solved by technology

This problem is commonly encountered when the prior art monoclonal antibodies of xenogeneic or chimeric derivation are utilized.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Isolation of RSVF2-5 Monoclonal Antibody Fab Fragment

[0084]PCR amplification of Fab and library construction. Peripheral blood lymphocytes were purified from 50 ml of whole heparinized blood of an HIV-1-infected donor, by single step density gradient using Histopaque-1077 (Sigma Chemical Co., St. Louis, Mo.) and washed once in Dulbecco's phosphate-buffered saline (PBS). Total RNA (30 mg) was purified from peripheral blood lymphocytes using a rapid single step guanidiniun isothiocyanate / phenol chloroform-based RNA isolation technique (Stratagene, La Jolla, Calif.), and cDNA was generated by reverse transcriptase (RT) using Superscript RNlase H (Gibco-BRL, Grand Island, N.Y.). PCR amplification of the IgG1 Fd heavy chain fragments and light chains was performed for 35 cycles of 94° C.×1 min, 54° C.×1 min, 72° C.×3 min. This was followed by a single incubation at 72° C. for 10 min. 5′ primers for the individual H and light chain V region gene families, and 3′ constant region primers fo...

example 2

The therapeutic efficacy of human monoclonal Fab RSVF2-5 in treating RSV Infected Mice

[0093]Clearance of RSV from the lungs of infected mice by purified RSVF2-5 Fab. Groups of six mice were infected intranasally (i.n.) with 107 pfu of RSV strain A2, in 100 μl of sterile PBS, under light methoxyflurane anesthesia, on day 0. Four days post infection, representing the height of the infection, different groups were treated with the indicated dose (Table 3) of affinity purified Fab in 100 μl of sterile PBS, instilled intranasally under the same conditions of anesthesia as for inoculation with virus. The ELISA titer of this purified Fab preparation, at a concentration of 3.6 mg / ml, was 1 / 60,000, the neutralization titer was 1 / 803,471 (Example I) and the purity was greater than 99%. Control mice were treated with PBS or with a human monoclonal Fab (HBVc41) isolated from the same combinatorial Fab library, which binds to hepatitis B virus (HBV) core antigen (Table 3). Lung tissue homogenate...

example 3

Identification of the RSVF2-5 Binding Epitope

[0095]The following example demonstrates that the human Fab RSVF2-5, which neutralizes RSV in vitro and cures mice of lung infection with RSV, identifies an epitope (linear or conformational) which includes the F glycoprotein amino acid (aa) residue number 429 or which is contormationally affected by this residue.

[0096]Neutralization of escape mutants of the RSV strain A2. Monoclonal antibody RSV escape mutants (MARM) were tested for in vitro neutralization by human monoclonal Fab RSVF2-5, using the plaque reduction assay described in Example I (Coates, et al., J. Epid. 83:299, 1966), on Vero cell monolayers. The titer of neutralizing antibody was expressed as the highest dilution of affinity purified Fab which reduced the plaque number by 60%. Results of neutralization testing of the purified RSVF2-5 Fab, against these RSV are expressed in Table 4. Affinity purified anti-RSV Fab RSVF2-5 does not neutralize the RSV MARM v324 of Dr. G. Tay...

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Abstract

The present invention relates to the identification and cloning of a novel neutralizing human monoclonal antibody to the Respiratory Syncytial Virus. The invention provides such antibodies, fragments of such antibodies retaining RSV-binding ability, chimeric antibodies retaining RSV-binding ability, and pharmaceutical compositions including such antibodies. The invention further provides for isolated nucleic acids encoding the antibodies of the invention and host cells transformed therewith. Finally, the invention provides for diagnostic and therapeutic methods employing the antibodies and nucleic acids of the invention.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a divisional application of U.S. application Ser. No. 10 / 425,855, filed Apr. 30, 2003, granted on Jan. 24, 2008, which is a continuation application (and claims the benefit of priority under 35 U.S.C. § 120) of U.S. application Ser. No. 09 / 043,530, filed Oct. 29, 1998. now abandoned, which is a national stage application (under 35 U.S.C. § 371) of and claims priority to PCT Application No. PCT / US96 / 14937, Sep. 18, 1996, which claims priority from U.S. provisional application Ser. No. 60 / 003,9312, Sep. 18, 1995. The disclosures of the prior applications are considered part of (and are incorporated by reference in) the disclosure of this application.FIELD OF THE INVENTION[0002]This invention relates generally to the field of immunology and specifically to monoclonal antibodies which bind to and neutralize respiratory syncytial virus (RSV).BACKGROUND OF THE INVENTION[0003]RSV represents a major health problem, worldwide. ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395A61K31/7088A61P31/12A61K38/00A61K39/00A61K48/00A61K51/10C07K16/10C12N1/21C12N15/13G01N33/569
CPCA61K38/00A61K39/00A61K48/00A61K51/1006G01N33/56983C07K16/1027C07K2317/21C07K2317/55C07K2317/565A61K2039/505A61P31/12
Inventor PILKINGTON, GLENN R.GILMOUR, PAGE S.CHANOCK, ROBERT M.CROWE, JR., JAMES E.MURPHY, BRIAN R.
Owner PILKINGTON GLENN R
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