Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector
Patent
1993-12-06
1997-01-21
Housel, James C.
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
4242771, 5303888, 435 723, 436 71, A61K 3120, A61K 3438
Patent
active
055957382
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Colorectal cancer is the second most prevalent cancer in the United States, affecting both men and women. Until recently, the only viable treatment for this disease has been surgery, which has a poor prognosis for patients with transmural extension of tumor and metastasis to regional lymph nodes. A dramatically improved prognosis was indicated in a recently reported randomized Phase II-active specific immunotherapy trial, which showed that immunization of patients with autologous tumor cells admixed with Tice BCG (Bacillus Calmette Guerin) (Institute for Tuberculosis Research, Chicago, Ill.) significantly increased delayed cutaneous hypersensitivity responses and, over a four year period of time, significantly decreased recurrence and mortality.
There have been numerous publications describing the identification of colon carcinoma-associated antigens. The majority of these antigens were identified using monoclonal antibodies generated by immunizing mice with some form of the colon tumor (extracts, dissociated cells, membrane preparations, and etc.) or colon tumor cell lines. These mouse antibodies identify a repertoire of antigens that were antigenic in the mouse. In addition to these studies, there are several reports of human monoclonal antibodies that show specific reactivity with tumor material.
Using peripheral blood B-cells from colorectal patients actively immunized with autologous tumor cells and BCG in immunotherapy protocols, we have successfully developed a strategy for producing human anti-tumor monoclonal antibodies. Unlike mouse monoclonal antibodies generated against human colon cancer, which often recognize tissue components also found in healthy individuals, such as CEA, our human monoclonal antibodies exhibit no reactivity with CEA, blood group determinants or histocompatibility antigens, indicating that these antibodies are characterized by a specificity confined to those epitopes that are recognized as immunogenic in the autologous host.
We have used these human monoclonal antibodies as probes to identify tumor antigens. We have identified a particular antigen in colon tumors, extracts of colon tumor cell lines and human tumor xenografts generated in nude mice. The subject antigen is characterized by containing an epitope recognized by human monoclonal antibody (MCA) 81AV78.
SUMMARY OF THE INVENTION
CTAA 81AV78 is a tumor associated antigen recognized by the human monoclonal antibody 81AV78 claimed in copending application U.S. Ser. No. 07/701,281 filed May 16, 1991 for Tumor Associated Monoclonal Antibody 81AV78, by Hanna et al., and included herein by reference. This IgM monoclonal antibody is found to be reactive with a cell surface antigen in various tumor cell lines. CTAA 81AV78 is found in lipid extracts of colon tumor cell lines, primary colon tumors, and colon tumor xenograft tissues. The antigen has been found to be acidic in nature and can be purified by various thin layer chromatographic and column chromatographic techniques.
The invention also relates to the use of antibodies to the antigen containing this epitope for diagnosis and monitoring of treatment of cancer and to the use of this antigen in the preparation of vaccines to elicit an immune response similar to that obtained against tumor cells containing this epitope.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGS. 1A-1D show two dimensional TLC of two sets of tumor FIGS. 1C and 1D) and normal tissue (FIGS. 1A and 1B). These figures show the CTAA 81AV78-4A and CTAA 81AV78-5 are present in tumor tissue extracts but were not found in normal colon tissue extract.
FIG. 2 Purity of CTAA 81AV78-4A and 5 By TLC.
FIG. 3 Immunoreactivity of CTAA 81AV78-4A and 5 With MCA 81AV78.
FIG. 4 CTAA 81AV78-4A and 5 purified by thin layer chromatography Are Positive For Phosphate Groups After TLC.
FIG. 5 is the NMR spectrum of CTAA 81AV78-4A. FIG. 5A is an expansion of the NMR of FIG. 5 between about 2.5 and 0.5 PPM to better show the unsaturated fatty acid side chain at 2.0 PPM. FIG. 5B is an expansion of the NM
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Pomato Nicholas
Ransom Janet H.
Akzo Nobel N.V.
Blackstone William M.
Gormley Mary E.
Housel James C.
Minnifield N. M.
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