Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Animal cell – per se – expressing immunoglobulin – antibody – or...
Reexamination Certificate
1999-06-18
2002-07-02
Park, Hankyel T. (Department: 1648)
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Animal cell, per se, expressing immunoglobulin, antibody, or...
C435S005000, C435S007100, C530S388300, C424S147100, C424S159100, C424S192100, C424S211100
Reexamination Certificate
active
06413771
ABSTRACT:
BACKGROUND OF THE INVENTION
Respiratory syncytial virus (RSV) is a Parmixovirus of the Pneumovirus genus which commonly infects the upper and lower respiratory tract. It is so contagious that by age two, a large percentage of children have been infected by it. Moreover, by age four, virtually all humans have an immunity to RSV.
Typically, RSV infections are mild, remaining localized in the upper respiratory tract and causing symptoms similar to a common cold which require no extensive treatment. However, in some subjects, e.g., immunosuppressed individuals such as infants, elderly persons or patients with underlying cardiopulmonary diseases, the virus may penetrate to the lower respiratory tract requiring hospitalization and breathing support. In some of these cases, RSV infection may cause permanent lung damage or even be life threatening. In the United States alone, RSV results in about 90,000 hospitalizations each year, and results in about 4500 deaths.
RSV appears in two major strain subgroups, A and B, primarily based on serological differences associated with the attachment glycoprotein, G. The major surface glycoprotein, i.e., the 90 kD G protein, can differ up to 50% at the amino acid level between isolates Johnson et al,
Proc. Natl. Acad. Sci.
(1987), 84, 5625-5629. By contrast, a potential therapeutic target, the 70 kD fusion (F) protein, is highly conserved across different RSV strains, about i.e., 89% on the amino acid level Johnson et al.
J. Gen. Virol.
(1988), 69, 2623-2628, Johnson et al,
J. Virol.
(1987), 10, 3163-3166,
P. L. Collins, Plenum Press, NY (
1991), 103-162. Moreover, it is known that antibodies elicited against F-protein of a given type are cross-reactive with the other type.
The F-protein is a heterodimer, generated from a linear precursor, consisting of disulfide-linked fragments of 48 and 23 kD respectively Walsh et al,
J. Gen. Virol,
(1985), 66, 401-415. Inhibition of syncytia formation by polyclonal antibodies is associated with significant reaction to the 23 kD fragment.
As noted, while RSV infections are usually mild, in some individuals RSV infections may be life threatening. Currently, severe RSV infection is treated by administration of the antiviral agent Ribavarin. However, while Ribavarin exhibits some efficacy in controlling RSV infection, its use is disfavored for several reasons. For example, it is highly expensive and may be administered only in hospitals. Other known RSV treatments only treat the symptoms of RSV infection and include the use of aerosolized bronchodilators in patients with bronchiolitis and corticosteroid therapy in patients with bronchiolitis and RSV pneumonia.
To date, RSV vaccines intended to boost antiviral protective antibodies have been largely unsuccessful. For example, a vaccine based on formalin-inactivated RSV that was tested approximately 25 years ago, induced antibodies that were deficient in fusion inhibiting activity Murphy et al.
Clinical Microbiology
(1988), 26, 1595-1597, and sometimes even exacerbated the disease. This may potentially be explained to the inability of the formalin inactivated virus to induce protective antibodies. While high antibody titers were measured in vaccine recipients, specific protective titers were lower than in the control population. This may be because formalin inactivated RSV does not display the necessary conformational epitopes required to elicit protective antibodies.
While there is no known effective RSV vaccine to date, there exists some clinical evidence that antibody therapy may confer protection against RSV infection in susceptible individuals, and may even clear an existing RSV infection. For example, it has been reported that newborn infants show a low incidence of severe bronchiolitis, which is hypothesized to be attributable to the presence of protective maternal antibodies Ozilvie et al.
J. Med Virol
(1981), 7, 263-271. Also, children who are immune to reinfection exhibit statistically higher anti-F-protein titers than those who are reinfected. Moreover, intravenous immune globulin (IVIG) prepared from high titer RSV-immune donors reduces nasal RSV shedding and improves oxygenation Hemming et al.
Anti. Viral Agents and Chemotherapy
(1987), 31, 1882-1886. Also, recent studies have suggested that the virus can be fought and lung damage prevented by administering RSV-enriched immune globulin (RSVIG) Groothuis et al.
The New England J. Med.
(1993), 329, 1524-1530, K. McIntosh,
The New England J. Med.
(1993), 329, 1572-1573, J. R. Groothuis,
Antiviral Research,
(1994), 23, 1-10, Siber et al.
J. Infectious Diseases
(1994), 169, 1368-1373, Siber et al.
J. Infectious Diseases
(1992), 165:456-463.
Similarly, some animal studies suggest that antibody therapy with virus neutralizing antibodies may confer protection against RSV or even clear an existing RSV infection. For example, in vitro neutralizing mouse monoclonal antibodies have been reported to protect mice against infection and also to clear established RSV infections Taylor et al,
J.Immunology,
(1984), 52, 137-142, Stott et al., “
Immune Responses, Virus Infections and Disease,
I.R.L. Press, London (1989), 85-104. Also, monoclonal antibodies to the F-protein of RSV have shown high efficacy in both in vitro and in vivo RSV models Tempest et al,
Bio/Technology,
(1991), 9, 266-271, Crowe et al.
Proc. Natl. Acad. Sci.
(1994), 91, 1386-1390, Walsh et al.
Infection and Immunity,
(1984), 43, 756-758, Barbas III, et al,
Proc. Natl. Acad. Sci.
(1992), 89, 10164-10168, Walsh, et al,
J. Gen. Virol.
(1986), 67, 505-513. Antibody concentrations as low as 520-2000 &mgr;g/kg body weight have been reported to result in almost instant recovery in animal studies Crowe et al,
Proc. Natl. Acad. Sci.
(1994), 91, 1386-1390. Moreover, these monoclonal antibodies have been disclosed to neutralize both A and B strains, including laboratory strains and wildtype strains. These antibodies were administered either by injection Groothuis et al,
The New England J. Med.
(1993), 329, 1524-1530, Siber et al,
J. Infectious Diseases
(1994), 169, 1368-1373 or by aerosol Crowe et al,
Proc. Natl. Acad. Sci.
(1994), 91, 1386-1390.
Two different types of potentially therapeutic monoclonal antibodies to the RSV F-protein have been previously described in the literature, humanized murine antibodies Tempest et al,
Biol. Technology,
(1991) 9, 266-271, or true human antibodies (Fab fragments) Barbas III, et al,
Proc. Natl. Acad. Sci.
(1992), 89, 10164-10168. Humanized murine antibodies were generated by CDR grafting a cross-strain neutralizing murine anti-F-protein antibody onto a generic human Fc, as well as structural areas of the variable part. The human Fab fragments were produced by combinatorial library technology using human bone marrow cells obtained from an HIV positive donor (immunocompromised). The therapeutic in vivo titers of the humanized and human RSV antibodies were 5 and 2 mg/kg body weight, respectively. It is noted, however, that the humanized antibodies were tested in a syncytia inhibition assay, whereas the human anti-RSV Fab fragments were assayed to determine their virus neutralization activity. Therefore, the results reported with the humanized and human anti-RSV antibodies are not directly comparable.
The Fab fragment generated by the combinatorial library technology were disclosed to be efficient in aerosol. This is probably because of the relatively small size of the molecule. These results are highly encouraging because a major target population for an RSV vaccine is infants. Therefore, aerosol is a particularly desirable mode of administration.
However, notwithstanding the previous published reports of humanized and Fab fragments specific to RSV, there still exists a significant need for improved anti-RSV antibodies having improved therapeutic potential, in particular anti-RSV antibodies which possess high affinity and specificity for the RSV F-protein which effectively neutralize and prevent RSV infection.
Antibody therapy can be subdivided into two principally different acti
Brams Peter
Morrow Phillip R.
IDEC Pharmaceuticals Corporation
Park Hankyel T.
Teskin Robin L.
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