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
1994-08-31
2001-03-27
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, C530S324000, C530S326000, C530S327000, C530S328000, C435S325000, C435S372300, C435S377000
Reexamination Certificate
active
06207161
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to human cytomegalovirus (HCMV) vaccines in which the immunogen is an HCMV matrix protein or a fragment of such a protein. This invention also relates to immunologic cytomegalovirus proteins or peptides that induce cytolytic T-lymphocytes effective to lyse cytomegalovirus infected cells, to the production of such proteins or peptides and to vaccines and skin tests in which such proteins or peptides are utilized.
ABBREVIATIONS
CMV
Cytomegalovirus
HCMV
Human Cytomegalovirus
CTL
Cytotoxic T-lymphocytes
MHC
Major Histocompatibility Complex
IE
Immediate Early
gB
Glycoprotein B
CNBr
Cyanogen Bromide
HF
Human Foreskin Fibroblasts
FCS
Fetal Calf Serum
PBL
Peripheral Blood Lymphocytes
APC
Antigen Presenting Cell
ActD
Actinomycin D
pp65
An HCMV Matrix Protein--corresponds to
”gp64” of Ser. No. 07/307,526
TFA
Trifluoroacetic acid
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BACKGROUND OF THE INVENTION
Cytomegalovirus (CMV) infection is a frequent pathogen in humans. It is usually associated with asymptomatic primary infection, followed by a state of viral persistence or latency (1, 2). In patients with congenital or acquired immune deficiencies and those undergoing solid organ or bone marrow transplantation, primary CMV infection and reactivation of persistent CMV have frequently been associated with life-threatening invasive visceral disease (3, 5).
Application Ser. No. 07/307,526 reports T-lymphocyte reactivity to the matrix protein of HCMV following natural infection of an individual. As that application explains, peripheral blood mononuclear leukocytes were separated using Ficoll-hypaque, washed, suspended in RPMI-1640 medium with ten percent (10%) AB+, Rh+ human serum and were then cultured at 37° C. in microtiter plates (10
5
cells/well). Different samples of the peripheral blood mononuclear leukocytes were then stimulated with optimal dilutions of either (a) the matrix protein of human cytomegalovirus (HCMVgp64) such as HCMVgp64, (b) HCMV-infected cell lysate or (c) control cell lysate, and cultures were analyzed for cell proliferation and for lymphokine production.
The matrix protein of human cytomegalovirus (4 &mgr;g/ml) stimulated H
3
-thymidine in HCMV seropositive donor peripheral blood mononuclear leukocytes but not in seronegative donor peripheral blood mononuclear leukocytes. The peripheral blood mononuclear leukocytes produced the same stimulation with HCMV-infected cell lysate as when the matrix protein of human cytomegalovirus (HCMVgp64) was used. The matrix protein of human cytomegalovirus (HCMVgp64) induced interleukin-2 (IL-2) production, IL-2 receptor expression and interferon production. The addition of antibody to the IL-2 receptor blocked the reactivity of the peripheral blood mononuclear leukocytes to HCMVgp64.
The development of cell-mediated immunity, particularly that involving CD8+ class I MHC-restricted CMV-specific CTL, represents an essential host factor in the control of persistent infection and the recovery from CMV disease (6, 9). The importance of CD8+ CTL responses in providing protective immunity in CMV seropositive individuals has fostered studies to elucidate the specificity of this response for selected CMV antigens with the objective of developing methods to augment CTL responses in immunocompromised hosts. Studies using vaccinia recombinant viruses to express the non-structural 72 KD CMV immediate early protein (IE) and the major envelope glycoprotein, gB, have demonstrated that in two CMV seropositive individuals, a subset of CTL recognized IE and a minor subset recognized gB (10). However, the majority of CMV-specific CTL in these individuals recognized other undefined viral antigens (10).
It is now established that CD8+ CTL recognize peptide fragments of antigens, derived as a result of intracellular processing of cytoplasmic protein and subsequent association with class I MHC molecules in the endoplasmic reticulum prior to cell surface presentation (12, 13, 14, 15). Consequently, small protein fragments or synthetic viral peptides can sensitize uninfected target cells by direct association with MHC molecules at the cell surface (16, 17, 18). Thus, an alternative approach to using recombinant expression vectors for examining the specificity of CTL recognition is to directly sensitize target cells by incubation with synthetic peptides or peptides derived from native protein by proteolytic digestion (19, 20).
REFERENCES:
patent: 88 07077 (1988-09-01), None
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European Search Report dated Feb. 29, 1996 for related patent application EP 92915562.0.
Pande Hema
Zaia John A.
City of Hope
Mosher Mary E.
Rothwell Figg Ernst & Manbeck
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