Drug – bio-affecting and body treating compositions – Enzyme or coenzyme containing – Hydrolases
Reexamination Certificate
2000-11-28
2003-01-28
Witz, Jean C. (Department: 1651)
Drug, bio-affecting and body treating compositions
Enzyme or coenzyme containing
Hydrolases
Reexamination Certificate
active
06511662
ABSTRACT:
TECHNICAL FIELD
This invention relates to the use of aminopeptidases (AP), preferably human aminopeptidase N (APN), for the prevention and treatment of human cytomegalovirus (CMV).
BACKGROUND OF THE INVENTION
Human cytomegalovirus is responsible for significant morbidity and mortality in the immunocompromised groups, i.e., neonates, organ transplant recipients, AIDS patients (1-3).* Treatment is limited because the early events of CMV infection, involving cell binding and penetration, are largely unknown (4). At least four different cell surface proteins, a 30-34 K protein(s) (5-7), a 92.5 K protein (8), a heparin-binding protein (9), and class I human leukocyte antigen (10), have been suggested as important in virus binding.
* A bibliography precedes the claims.
It has recently been reported that CD13 (human aminopeptidase N, APN) is expressed on blood cells susceptible in vitro to HCMV infection (11, 12, 13).
APN is a metalloprotease present on apical surfaces of epithelial cells (14-17). It has been reported to be a binding protein for certain coronaviruses (18, 19).
CD4 is a T-cell receptor for the HIV virion surface glycoprotein gp 120 which also migrates to the surface of HIV infected cells. Soluble forms of CD4 have been developed for circulation in the blood to bind both HIV and infected T-cells and thus prevent the virus from infecting new T-cells. See, e.g.,
Research News
, 1559-1560 (1989).
SUMMARY OF THE INVENTION
It has been discovered that AP, including aminopeptidase N and fragments thereof, are important in CMV infection. It is surprisingly present both on CMV virions and on the cell surface and mediates critical event(s) of infection. Another aspect of the invention includes neutralization or mediation of CMV infection by the use of an AP antibody to remove CMV from blood products and from bone marrow by binding to the virions. Bone marrow transplant (BMT) recipients may receive marrow or blood products which have been purged by treatment with free or immobilized antibody to AP or water soluble AP (SAP) linked to a solid support to remove both CMV virions and cells which are susceptible to and thus may harbor and transmit CMV infection. Such cells form a relatively small sub-population and may eventually be replaced by differentiation of healthy stem cells.
An important aspect of the invention is the discovery that sAP inhibits or neutralizes CMV infection. sAP thus functions as an antiviral agent. Pursuant to this aspect of the invention, sAPN or truncated forms thereof which contain the domain which mediates infection after CMV is bound to the cell are administered exogenously to a patient or expressed as a polypeptide in the cells of a CMV patient. In like manner, APN or truncated forms thereof may be administered prophylactically prior to infection. For example, AP preemptive therapy is provided for management of patient populations such as AIDS patients, bone marrow transplant or organ transplant recipients at risk for CMV disease. The procedure is similar to that previously used for ganciclovir (20).
The invention also includes the administration of antibodies to aminopeptidases and the administration of enzyme inhibitors of aminopeptidase. Further, combinations of an aminopeptidase and an antibody thereto or an enzyme inhibitor thereof are contemplated.
REFERENCES:
Sörberg et al., “In Situ Hybridization and Immunofluorescence Methods for Identification of CMV Encoded RNA and Antigens . . . ,” 17thInternational Herpes Virus Workshop, Edinburgh, Scotland, Aug. 1-7, 1992, p. 222.
Bowden et al., “A Comparison of Filtered leukocyte-Reduced and Cytomegalovirus (CMV) Seronegative Blood Products . . . ,”Blood,86(9):3598-3603, 1995 (Abstract).
Dumont et al., “The Effect of leukoycyte-Reduction Method on the Amount of Human Cytomegalovirus in Blood Products . . . ,”Blood, 97(11):3640-3647, 2001 (Abstract).
Soderberg, C. et al., “Identification of Blood Mononuclear Cells Permissive of Cytomegalovirus Infection in Vitro,”Transpl. Proc., 25(1):1416-1418, 1993.
Soderberg, C. et al., “Definition of a Subset of Human Peripheral Blood Mononuclear Cells that are Permissive in Human Cytomegalovirus Infection,”J. Virol.67(6):3166-3175, 1993.
Look, A. T. et al., “Human Myeloid Plasma Membrane Glycoprotein CD13 (gp150) is Identical to Aminopeptidase N,”J. Clin. Invest., 83:1299-1307, 1989.
Noren, O. et al., “Molecular and Cellular Basis of Digestion,”Elsevier Biomedical Press, Amsterdam, p. 324-325, 1986, ix-xix.
Vallee, B. L. et al., “Zinc Coordination, Function, and Structure of Zinc Enzymes and Other Proteins,”Biochemistry, 29(24):5647-5659, 1990.
Robert H. Rubin, M.D., “Preemptive Therapy in Immunocompromised Hosts,”N. Engl. J. Med., 324(15):1057-1059, 1991.
Ashmun, R. A. et al., “Deletion of the Zinc-Binding Motif of CD13/Aminopeptidase N Molecules Results in Loss of Epitopes that Mediate Binding of Inhibitory Antibodies,”Blood, 79(12):3344-3349, 1992.
Spaete, R. R. et al., “Insertion and Deletion Mutagenesis of the Human Cytomegalovirus Genome,”Proc. Natl. Acad. Sci. USA, 84:7213-7217, 1987.
The Merck Manual of Diagnosis and Therapy, Merck Research Laboratories, Rahway, NJ 1992; pp. 204-205.
Giugni Terrence D.
Moller Erna
Söderberg Cecilia
Zaia John A.
Möller Erna
Rothwell Figg Ernst & Manbeck
Witz Jean C.
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