Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Conjugate or complex
Reexamination Certificate
1999-11-15
2002-05-07
Bansal, Geetha P. (Department: 1642)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Conjugate or complex
C424S093700, C424S093710, C424S196110, C424S197110, C424S204100, C424S234100, C424S274100, C424S265100, C530S403000, C530S417000, C514S002600, C436S543000
Reexamination Certificate
active
06383491
ABSTRACT:
TABLE OF CONTENTS
1. Introduction
2. Background of the Invention
2.1. Tumor-specific Immunogenicities of Heat Shock/Stress Proteins hsp70, hsp90 and gp96
2.2. Pathobiology of Cancer
2.3. Immunotherapy
2.3.1. Adoptive Cellular Immunotherapy
2.3.2. Interleukins (IL-2, IL-4 and IL-6)
2.3.3. Tumor Necrosis Factor
2.3.4. Interferons
2.4. Pharmacokinetic Models for Anticancer Chemotherapeutic and Immunotherapeutic Drugs: Extrapolation and Scaling of Animal Data to Humans
3. Summary of the Invention
4. Brief Description of Figures
5. Detailed Description of the Invention
5.1. Dosage Regimens
5.2. Therapeutic Compositions Comprising Purified Hsp-Peptide Complexes, for Eliciting Immune Responses to Cancer or Infectious Disease, and for In Vitro Sensitization of APC
5.2.1. Preparation and Purification of Hsp70-peptide Complexes
5.2.2. Preparation and Purification of Hsp90-peptide Complexes
5.2.3. Preparation and Purification of gp96-peptide Complexes
5.2.4. Isolation of Antigenic/Immunogenic Components
5.2.4.1. Peptides From Stress Protein-Peptide Complexes
5.2.4.2. Peptides from MHC-peptide Complexes
5.2.5. Exogenous Antigenic Molecules
5.2.6. In Vitro Production of Stress Protein-Antigenic Molecule Complexes
5.2.7. Determination of Immunogenicity of Stress Protein-Peptide Complexes
5.3. Combination With Adoptive Immunotherapy
5.3.1. Obtaining Macrophages and Antigen-Presenting Cells
5.3.2. Sensitization of Macrophages and Antigen Presenting Cells With Hsp-Peptide Complexes
5.3.3. Reinfusion of Sensitized APC
5.4. Formulation, Administration & Kits
5.5. Target Infectious Diseases
5.6. Target Cancers
5.6.1. Colorectal Cancer Metastatic to the Liver
5.6.2. Hepatocellular Carcinoma
5.6.3. Breast Cancer
5.7. Autologous Embodiment
5.8. Prevention and Treatment of Primary and Metastatic Neoplastic Diseases
5.9. Monitoring of Effects During Cancer Prevention and Immunotherapy with Hsp-peptide Complexes
5.9.1. Delayed Hypersensitivity Skin Test
5.9.2. Activity of Cytolytic T-lymphocytes In Vitro
5.9.3. Levels of Tumor Specific Antigens
5.9.4. Computed Tomographic (CT) Scan
5.9.5. Measurement of Putative Biomarkers
5.9.6. Sonogram
6. Example: Mehylcholanthrene (Meth A)-Induced Sarcoma Model
6.1. Prevention Modality
7. Examples: Adoptive Transfer of Sensitized Macrophages, Alone or in Combination with Administration of Hsp-Peptide Complexes
7.1. Materials and Methods
7.2. Treatment of Hepatocellular Carcinoma
8. Example: Administration of Hsp-Peptide Complexes in the Treatment of Colorectal Cancer
1. INTRODUCTION
The present invention relates to methods and compositions for the prevention and treatment of infectious diseases, primary and metastatic neoplastic diseases, including, but not limited to human sarcomas and carcinomas. In the practice of the prevention and treatment of infectious diseases and cancer, compositions of complexes of heat shock/stress proteins (hsps) including, but not limited to, hsp70, hsp90, gp96 alone or in combination with each other, noncovalently bound to antigenic molecules, are used to augment the immune response to genotoxic and nongenotoxic factors, tumors and infectious agents. In the practice of the invention, hsp-antigenic molecule complexes may be administered alone or in combination with the administration of antigen presenting cells sensitized with an hsp-antigenic molecule complex.
2. BACKGROUND OF THE INVENTION
The era of tumor immunology began with experiments by Prehn and Main, who showed that antigens on the methylcholanthrene (MCA)-induced sarcomas were tumor specific in that transplantation assays could not detect these antigens in normal tissue of the mice (Pre.hn, R. T., et al., 1957,
J. Natl. Cancer Inst.
18:769-778). This notion was confirmed by further experiments demonstrating that tumor specific resistance against MCA-induced tumors can be elicited in the autochthonous host, that is, the mouse in which the tumor originated (Klein, G., et al., 1960,
Cancer Res.
20:1561-1572).
In subsequent studies, tumor specific antigens were also found on tumors induced with other chemical or physical carcinogens or on spontaneous tumors (Kripke, M. L., 1974,
J. Natl. Cancer Inst.
53:1333-1336; Vaage, J., 1968,
Cancer Res.
28:2477-2483; Carswell, E. A., et al., 1970,
J. Natl. Cancer Inst.
44:1281-1288). Since these studies used protective immunity against the growth of transplanted tumors as the criterion for tumor specific antigens, these antigens are also commonly referred to as “tumor specific transplantation antigens” or “tumor specific rejection antigens.” Several factors can greatly influence the immunogenicity of the tumor induced, including, for example, the specific type of carcinogen involved, immunocompetence of the host and latency period (Old, L. J., et al., 1962,
Ann. N.Y. Acad. Sci.
101:80-106; Bartlett, G. L., 1972,
J. Natl. Cancer Inst.
49:493-504).
Most, if not all, carcinogens are mutagens which may cause mutation, leading to the expression of tumor specific antigens (Ames, B. N., 1979,
Science
204:587-593; Weisburger, J. H., et al., 1981,
Science
214:401-407). Some carcinogens are immunosuppressive (Malmgren, R. A., et al., 1952,
Proc. Soc. Exp. Biol. Med.
79:484-488). Experimental evidence suggests that there is a constant inverse correlation between immunogenicity of a tumor and latency period (time between exposure to carcinogen and tumor appearance) (Old, L. J., et al., 1962,
Ann. N.Y. Acad. Sci.
101:80-106; and Bartlett, G. L., 1972,
J. Natl. Cancer Inst.
49:493-504). Other studies have revealed the existence of tumor specific antigens that do not lead to rejection, but, nevertheless, can potentially stimulate specific immune responses (Roitt, I., Brostoff, J and Male, D., 1993, Immunology, 3rd ed., Mosby, St. Louis, pps. 17.1-17.12).
2.1. Tumor-Specific Immunogenicities of Heat Shock/Stress Proteins hsp70, hsp90 and gp96
Srivastava et al. demonstrated immune response to methylcholanthrene-induced sarcomas of inbred mice (1988,
Immunol. Today
9:78-83). In these studies it was found that the molecules responsible for the individually distinct immunogenicity of these tumors were identified as cell-surface glycoproteins of 96 kDa (gp96) and intracellular proteins of 84 to 86kDa (Srivastava, P. K., et al., 1986,
Proc. Natl. Acad. Sci. USA
83:3407-3411; Ullrich, S. J., et al., 1986,
Proc. Natl. Acad. Sci. USA
83:3121-3125. Immunization of mice with gp96 or p84/86 isolated from a particular tumor rendered the mice immune to that particular tumor, but not to antigenically distinct tumors. Isolation and characterization of genes encoding gp96 and p84/86 revealed significant homology between them, and showed that gp96 and p84/86 were, respectively, the endoplasmic reticular and cytosolic counterparts of the same heat shock proteins (Srivastava, P. K., et al., 1988,
Immunogenetics
28:205-207; Srivastava, P. K., et al., 1991,
Curr. Top. Microbiol. Immunol.
167:109-123). Further, hsp70 was shown to elicit immunity to the tumor from which it was isolated but not to antigenically distinct tumors. However, hsp70 depleted of peptides was found to lose its immunogenic activity (Udono, M., and Srivastava, P. K., 1993,
J. Exp. Med.
178:1391-1396). These observations suggested that the heat shock proteins are not immunogenic per se, but are carriers of antigenic peptides that elicit specific immunity to cancers (Srivastava, P. K., 1993,
Adv. Cancer Res.
62:153-177).
2.2. Pathobiology of Cancer
Cancer is characterized primarily by an increase in the number of abnormal cells derived from a given normal tissue, invasion of adjacent tissues by these abnormal cells, and lymphatic or blood-borne spread of malignant cells to regional lymph nodes and to distant sites (metastasis) Clinical data and molecular biologic studies indicate that cancer is a multistep process that begins with minor preneoplastic changes, which may under certain conditions progress to neoplasia.
Pre-malignant abnormal cell growth is exemplified by hyperplasia, metaplasia, or most particularly, dysplasia (for review of such abnormal growth conditions,
Chandawarkar Rajiv Y.
Srivastava Pramod K.
Bansal Geetha P.
Fordham University
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