Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – Attached to antibody or antibody fragment or immunoglobulin;...
Patent
1996-06-10
2000-07-04
Stucker, Jeffrey
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
Attached to antibody or antibody fragment or immunoglobulin;...
4353201, 4241791, 53038835, 5303913, 5303917, A61K 5100, A61K 39395, C12N 1500, C07K 1600
Patent
active
060834781
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Throughout this application, various publications are referenced by Arabic numerals. Full citations for these publications may be found at the end of the specification immediately preceding the claims. The disclosure of these publications is hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains.
The life cycle of animal viruses is characterized by a series of events that are required for the productive infection of the host cell. The initial step in the replicative cycle is the attachment of the virus to the cell surface which is mediated by the specific interaction of the viral attachment protein (VAP) to receptors on the surface of the target cell. The pattern of expression of these receptors is largely responsible for the host range and tropic properties of viruses. The interaction of the VAP with cellular receptors therefore plays a critical role in infection and pathogenesis of viral diseases and represents an important area to target the development of anti-viral therapeutics.
Cellular receptors may comprise of all of the components of membranes, including proteins, carbohydrates, and lipids. Identification of the molecules mediating the attachment of viruses to the target cell surface has been made in a few instances. The most extensively characterized viral receptor protein is CD4 (T4) (1). CD4 is a nonpolymorphic cell surface glycoprotein that is expressed primarily on the surface of helper T lymphocytes, cells of the monocyte/macrophage lineage and dendritic cells. CD4 associates with major histocompatibility complex (MHC) class II molecules on the surface of antigen-presenting cells to mediate efficient cellular immune response interactions. In humans, CD4 is also the target of interaction with the human immunodeficiency virus (HIV).
HIV primarily infects helper T lymphocytes, monocytes, macrophages and dendritic cells--cells that express surface CD4. HIV-infected helper T lymphocytes die, and the loss of these CD4+ T lymphocytes is one marker of the progress of HIV infection. The depletion of these cells is probably an important cause of the loss of immune function which results in the development of the human acquired immune deficiency syndrome (AIDS). In contrast to helper T lymphocytes, other CD4+ cells, notably dendritic cells, monocyte and macrophages, are chronically infected by HIV. They produce virus over a long period of time and appear to be major reservoirs of virus in vivo (2, 3).
The initial phase of the HIV replicative cycle involves the high affinity interaction between the HIV exterior envelope glycoprotein gp120 and surface CD4 (Kd approximately 4.times.10.sup.-9 M) (4). Several lines of evidence demonstrate the requirement of this interaction for viral infectivity. In vitro, the introduction of a functional cDNA encoding CD4 into human cells which do not express CD4 is sufficient to render otherwise resistant cells susceptible to HIV infection (5). In vivo, viral infection appears to be restricted to cells expressing CD4. Following the binding of HIV gp120 to cell surface CD4, viral and target cell membranes fuse, resulting in the introduction of the viral nucleocapsid into the target cell cytoplasm.
Characterization of the interaction between HIV gp120 and CD4 has been facilitated by the isolation of cDNA clones encoding both molecules (6, 7). CD4 is a nonpolymorphic, lineage-restricted cell surface glycoprotein that is a member of the immunoglobulin gene superfamily. High-level expression of both full-length CD4 and truncated, soluble versions of CD4 (sCD4) have been described in stable expression systems. The availability of large quantities of purified sCD4 has permitted a detailed understanding of the structure of this complex glycoprotein. Mature CD4 has a relative molecular mass (Mr) of 55 kilodaltons and consists of an amino-terminal 372 amino acid extracellular domain containing four tandem immunoglobulin-like regions denoted V1-V-4, followed by a 23 amino acid t
REFERENCES:
Fahey et al., Status of immune-based therapies in HIV infection and AIDS Clin. Exp. Immunol. (1992) 88, 1-5, Jan. 1992.
Fox, J.L., No winners against AIDS, Bio/Technology, (1994) vol. 12, p. 128, Feb. 1994.
Ashorn P., et al., Elimination Of Infectious Human Immunodeficiency Virus From Human T-Cell Cultures By Synergistic Action Of CD4-Pseudomonas Exotoxin and Reverse Transcriptase Inibitors, Proc. Nat'l. Acad. Sci. USA 87:8889-8893 (1990).
Aullo, P., et al., A Recombinant Diptheria Toxin Related Human CD4 Fusion Protein Specifically Kills HIV Infected Cells Which Express gp120 But Selects Fusion Toxin Resistant Cells Which Carry HIV, EMBO Journal 11, No. 11(2):575-583 (1992).
Byrn, R.A., et al., Biological Properties Of A CD4 Immunoadhesin, Nature 344:667-670 (1990).
Capon, D.J., et al., Designing CD4 Immunoadhesins For AIDS Therapy, Nature 337:525-531 (1989) (Exhibit B).
Chaudhary, V.K., et al., Selective Killing Of HIV-Infected Cells By Recombinant Human CD4-Pseudomonas Exotoxin Hybrid Protein, Nature 335:369-372 (1988).
Gartner, S., et al., The Role Of Mononuclear Phagocytes In HTLV-III/LAV Infection, Science 233: 215-219 (1986) (Exhibit C).
Houghton, A.N. and Scheinberg, D.A., Monoclonal Antibodies: Potential Applications To The Treatment Of Cancer, Seminars in Oncology, 13(2):165-179 (1986) (Exhibit D).
Jarman, M., A Radical Approach To Cancer, Nature 349:566-567 (1991).
Lasky, L.A., et al., Delineation Of A Region Of The Human Immunodeficiency Virus Type 1 gp120 Glycoprotein Critical For Interaction With The CD4 Receptor, Cell 50:975-985 (1987).
Moore, J.P., et al., Dissociation Of gp120 From HIV-1 Virions Induced By Soluble CD4, Science 250:1139-1142 (1990).
Morrison, S.L. et al., Chimeric Human Antibody Molecules: Mouse Antigen-Binding Domains With Human Constant Region Domains, Proc. Nat'l. Acad. Sci. USA 81:6851-6855 (1984).
Nicolaou, K.C., et al., Designed Enediynes: A New Class Of DNA-Cleaving Molecules With Potent And Selective Anticancer Activity Science 256:1172-1778 (1992).
Pound, J.D. and Walker M.R., Membrane Fc Receptors For IgG Subclasses In The Human IgG Subclasses: Molecular Analysis of Structure, Function and Regulation, Pergamon Press, Oxford, U.K. 111-133 (1990).
Schooley, R.T., et al., Recombinant Soluble CD4 Therapy In Patients With The Acquired Immunodeficiency Syndrome (AIDS) And AIDS-Related Complex, Ann. Internal Med. 112:247-253 (1990).
Till, M.A., et al., HIV-Infected Cells Are Killed By rCD4-Ricin A Chain, Science 242:1166-1168 (1988).
Traunecker, A., et al., Highly Efficient Neutralization Of HIV With Recombinant CD4-Immunoglobulin Molecules, Nature 339:68-70 (1989).
Magerstadt, M., et al., Antibody Conjugates and Malignant Disease, CRC Press, Boca Raton, Fl. (1991).
Allaway Graham P.
Maddon Paul J.
Park Hankyel T.
Progenics Pharmaceuticals Inc.
Stucker Jeffrey
White John P.
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