Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Amino acid sequence disclosed in whole or in part; or...
Reexamination Certificate
2001-10-22
2003-04-08
Mosher, Mary E. (Department: 1648)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Amino acid sequence disclosed in whole or in part; or...
C424S230100, C424S093700, C530S327000, C514S015800, C435S005000, C435S235100, C435S320100
Reexamination Certificate
active
06544521
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Technical Field
This invention relates to human cytomegalovirus (HCMV), and in particular to peptide fragments from a protein that produces T-cell epitopes of HCMV in human beings. The peptide fragment epitopes are capable of directing human cytotoxic T lymphocytes (CTL) to recognize and lyse human cells infected with HCMV.
2. Description of the Background Art
The HCMV genome is relatively large (about 235,000 base pairs) and can encode more than two hundred proteins. HCMV comprises a nuclear complex of double-stranded DNA surrounded by capsid proteins having structural or enzymatic functions, and an external glycopeptide- and glycolipid-containing membrane envelope.
HCMV infection is relatively common and is usually self-limiting in the healthy, immunocompetent child or adult (L. Rasmussen,
Curr. Top. Microbiol. Immunol.
154:221-254 (1990)). However, the virus can cause severe disease in the fetus or infant. For example, HCMV is a common cause of congenital mental retardation in children who acquire the infection in utero from mothers carrying an active infection. Other newborn infants can carry cytomegalovirus for some time before they show symptoms of the disease. Approximately 10% of all newborn infants carry HCMV.
Patients with an active HCMV infection often suffer impairment of at least some of their vital organs, including salivary glands, brain, kidney, liver and lungs. Furthermore, HCMV is associated with a wide spectrum of classical syndromes including mononucleosis and interstitial pneumonia. HCMV also has an oncogenic potential and a possible association with certain types of malignancies, including Kaposi's sarcoma.
Persistent and apparently asymptomatic HCMV infection in an otherwise healthy adult also may pose health risks in certain individuals. For example, individuals who have undergone coronary angioplasty sometimes subsequently develop restenosis as a result of arterial remodeling. In one study, about one third of such patients with restenosis had detectable HCMV DNA in their arterial lesions (E. Speir et al.,
Science
265:391-394 (1994)), whereas in another study HCMV seropositive patients were five times more likely to develop restenosis than their seronegative counterparts (Y. F. Zhou et al.,
New England J. Med.
335:624-630 (1996)). These studies suggest that decreasing the number of HCMV infected host cells can benefit certain individuals.
HCMV also has been associated with morbidity and mortality in immunocompromised patients. HCMV is an important consideration in the treatment of patients suffering from Acquired Immunodeficiency Syndrome (AIDS). The defining complication of HCMV is viral retinitis, which, if left untreated, can lead to blindness. Other disease manifestations of HCMV viremia include encephalitis, enteritis and pneumonia. At autopsy there is multi-organ involvement of HCMV disease in the majority of AIDS patients who had severe HCMV retinitis. Historically, HCMV disease has been one of the more devastating of the opportunistic infections that beset HIV-infected individuals whose CD4
+
T cell level diminishes below 100/mm
3
.
HCMV can cause opportunistic infections in, for example, immunosuppressed organ transplant patients. Prior to the use of antiviral chemotherapy, HCMV infection had been responsible for a substantial proportion of post-bone marrow transplantation complications (J. Meyers et al.,
J. Infect Dis.
153:478-488 (1986)). The use of drugs such as gancyclovir with substantial anti-HCMV activity have reduced complications associated with post-bone marrow transplant HCMV infections (G. Schmidt et al.
New England J. Med.
324:1005-1011 (1991); J. M. Goodrich et al.,
New England J. Med.
325:1601-1607 (1991)). However, prophylactic administration of gancyclovir has several negative consequences, including neutropenia and increased numbers of fatal bacterial and fungal diseases. Equally importantly, gancyclovir also delays reconstitution of cellular immunity as well as specific cellular responses to CMV. This results in a complication referred to as “late CMV disease,” which arises about 90 days post-transplant. Late CMV disease can result in morbidity or mortality and is most common in patients who have received either prophylactic or therapeutic gancyclovir treatment soon after transplant.
A CD8
+
CTL response is believed to be important in a mammalian host response to acute viral infections such as HCMV. The observations that HCMV infection is widespread and persistent, and may be reactivated and become clinically evident in the immunosuppressed patient, suggest that virus-specific T-cells play an important role in the control of persistent infection and the recovery from HCMV disease.
In humans, protection from the development of HCMV disease in immunosuppressed bone marrow transplant recipients correlates with the recovery of measurable CD8
+
HCMV-specific class I MHC-restricted T cell responses (Quinnan et al.,
N. Eng. J. Med.
307:7-13 (1982); Reusser et al.,
Blood
78:1373-1380 (1991)). The transfer of donor-derived HCMV-specific CD8
+
CTL clones to allergenic bone marrow transplant recipients results in detectable CTL-based HCMV immunity, and statistically significant diminution of HCMV disease after bone marrow transplant (Walter et al.,
N. Eng. J. Med.
333:1038-1044 (1995)). Although successful in application, this approach has the disadvantage that it requires a sophisticated laboratory setup, which is also highly labor-intensive and costly, to derive the HCMV-specific CTL in vitro.
Because human cytomegalovirus is relatively common, yet is associated with some extremely serious health conditions, a vaccine which can reduce disease incidence and severity in a bone marrow transplant recipient, a solid organ transplant, a heart patient, an AIDS patient or a woman of child-bearing years would be highly desirable. Several HCMV vaccines are in development, including live attenuated CMV, CMV proteins carried in attenuated pox-viruses and soluble analogs of CMV membrane proteins. Unfortunately, the FDA has not approved any of these vaccines as safe and effective, despite the great efforts made in their development.
Vaccine development using CTL epitopes has become a widely adapted strategy to immunize individuals against infectious diseases and cancer. The specificity of CTL epitopes, and the fact that intracellular protein processing is not required, makes them an attractive alternative to the use of whole proteins as immunogens. To develop such a vaccine, the viral proteins which cause the host to recognize HCMV must be identified.
A variety of antigens, including tumor antigens, viral antigens and self-proteins are processed into peptides which are delivered to MHC Class I for presentation on the surface of antigen presenting cells (Reddehase et al.,
Nature
337:651-653 (1989); Rosenberg et al.,
Nat. Med.
4:321-327 (1998); Visseren et al.,
J. Immunol.
154:3991-3998 (1995)). Since the discovery that 8-12 amino acid fragments of cellular or viral proteins are embedded in the peptide binding groove of MHC Class I, there has been considerable interest in identifying the amino acid sequence of these fragments (Joyce and Nathenson 1994; Rammensee et al. 1993). Some of these peptides have been identified, formulated into vaccines, and evaluated for efficacy against certain viral diseases and cancer (Vitiello et al. 1995; Wang et al. 1990).
The viral life cycle provides insight as to the most effective time frame for targeting a vaccine to maximally disrupt virus production and spread. Following HCMV entry into the host cell and uncoating, the viral genome is expressed sequentially via immediate early (0-2 hour), early (2-24 hour) and late (>24 hour) viral proteins. However, certain viral structural proteins such as pp65 and pp150 are chaperoned into the cell because of their existence in large quantity in the viral particle.
The viral structural protein, pp150, has been identified as a target antigen for HCMV-specific class I MHC restricted CTL deri
City of Hope
Mosher Mary E.
Rothwell Figg Ernst & Manbeck
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