Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – Attached to antibody or antibody fragment or immunoglobulin;...
Reexamination Certificate
1998-05-21
2001-02-27
Dees, Jose′ G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
Attached to antibody or antibody fragment or immunoglobulin;...
C424S001110, C424S185100, C424S001570, C435S069300, C435S069100
Reexamination Certificate
active
06193948
ABSTRACT:
This invention was made in the course of work under Grant No. PD 359 from the American Cancer Society. The United States government has certain rights in this invention.
BACKGROUND OF THE INVENTION
Throughout this application various references are referred to within parentheses. Disclosures of these publications in their entirety are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains. Full bibliographic citations for these references maybe found at the end of this application, immediately preceding the claims.
Paraneoplastic sensory neuronopathy is a rare remote effect of cancer characterized clinically and pathologically by neuronal loss and inflammatory infiltrates. (1, 6, 7) A high percentage of such patients harbor a characteristic serum antibody which has been called anti-Hu. (4) These sera react with a group of proteins which have been found to be specifically expressed in tumor tissue (usually small cell lung cancer) and brain. (8) This observation suggested a model for the neurological dysfunction in which an immune response primarily directed against a tumor antigen is misdirected against similar antigens expressed in brain. (4,5) The synthesis of the anti-Hu antibody in the brain and the specific deposits of IgG and infiltrating lymphocytes provide circumstantial evidence for this model.
In addition to their neurological interest these cancer patients are unique in that they make a profound immunological response to their tumor. The mechanisms underlying this specific anti-tumor response are not well understood. It is not because these patients uniquely express the Hu-antigen in their small cell lung tumors. All small cell lung tumors (so far analyzed) express the Hu antigen. There are a number of possible mechanisms; (a) the Hu antigen may be mutated and perceived as foreign, (b) in the individuals the expression of a brain protein in extra-neural tissue provokes an extraordinary response, (c) there is an unknown secondary contributing factor e.g., viral infection.
Irrespective of the mechanism involved, the sera of these patients (which contains high-titre anti-Hu IgG) provides a reagent to isolate and characterize human small cell lung cancer tumor antigens.
SUMMARY OF THE INVENTION
An isolated nucleic acid sequence encoding Hu paraneoplastic antigenic polypeptide is provided by this invention. This invention also provides a purified Hu antigenic polypeptide and compositions containing the purified Hu antigenic polypeptide.
A method of detecting an antibody associated with paraneoplastic sensory neuronopathy (PSN) is provided by this invention. This method comprises contacting a suitable sample with the purified Hu antigenic polypeptide labelled with a detectable marker under conditions so as to form a complex between the purified Hu antigenic polypeptide and the antibody, detecting the presence of any complex so formed, thereby detecting an antibody associated with paraneoplastic sensory neuronopathy.
Also provided by this invention is a method of determining whether a patient exhibiting neurological symptoms harbors a tumor expressing Hu antigen, which comprises contacting a suitable tumor sample from the patient, with the monoclonal antibody directed against Hu antigen, the monoclonal antigen being labeled with a detectable marker, under suitable conditions so as to form a complex between the antibody and the tumor antigen, detecting the presence of any complex so formed, the presence of complex being a positive determination that the patient has a tumor which expresses Hu antigen.
A method of inhibiting the proliferation of neoplastic cells in a patient with small cell lung cancer also is provided by this invention. This method comprises administering to the patient an effective amount of a monoclonal antibody directed to the Hu paraneoplastic tumor antigen, the monoclonal antibody being labeled with a therapeutic agent, in an amount which is effective to inhibit the proliferation of the neoplastic cells, thereby inhibiting the proliferation of neoplastic cells in a patient exhibiting paraneoplastic sensory neuronopathy.
This invention further provides a method of imaging neoplastic cells in a patient, wherein the neoplastic cells are associated with paraneoplastic sensory neuronopathy, which comprises administering to the patient an effective amount of a monoclonal antibody directed to Hu paraneoplastic antigen, the monoclonal antibody being labelled with an imaging agent, under conditions to form a complex between the monoclonal antibody and the tumor antigen, imaging any complex so formed, thereby imaging neoplastic cells in a patient.
REFERENCES:
patent: 5603934 (1997-02-01), Posner et al.
patent: 5807705 (1998-09-01), Posner et al.
Brain, L. and Wilkinson, M. (1965) “Subacute cerebellar degeneration associated with neoplasms.”Brain88: 465-478.
Dalmau, J., et al. (1990) “Detection of the anti-Hu antibody in the serum of patients with small cell lung cancer-A quantitative Western blot analysis.”Ann. Neurol.27: 544-552.
Dalmau, J., et al. (1991) “Detection of the anti-Hu antibody in specific regions of the nervous system and tumor from patients with paraneoplastic encephalomyelitis/sensory neuronpathy.”Neurology41: 1757-1764.
Furneaux, H.M., et al. (1990) “Autoantibody synthesis in the central nervous system of patients with paraneoplastic syndromes.”Neurology40: 1085-1091.
Graus, F., et al. (1985) “Neuronal antinuclear antibody in sensory neuronopathy from lung cancer.”Neurology35: 538-543.
Graus, F., et al. (1987) “Neuronal antinuclear antibody (anti-Hu) in paraneoplastic encephalomyelitis stimulating acute polyneuritis.”Acta Neurol. Scand.75: 249-252.
Posner, J.B. and Furneaux, H.M. (1990) “Paraneoplastic Syndromes.”Immunologic Mechanisms in Neurologic and Psychiatric Disease(ed. B.H. Waksman, Raven Press, Ltd.) 187-219.
Szabo, A., et al. (1991) “HuD, a paraneoplastic encephalomeylitis antigen, contains RNA-binding domains and is homologous to Elav and Sex-Lethal.”Cell67: 325-333.
Furneaux Henry M.
Posner Jerome B.
Dees Jose′ G.
Hamilton Brook Smith & Reynolds P.C.
Jones Dameron
Sloan-Kettering Institute for Cancer Research
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