Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Structurally-modified antibody – immunoglobulin – or fragment...
Reexamination Certificate
2001-03-08
2003-11-25
Navarro, Mark (Department: 1645)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Structurally-modified antibody, immunoglobulin, or fragment...
C424S135100, C424S136100, C424S138100, C424S141100, C424S152100, C424S155100, C424S156100, C424S172100, C424S174100
Reexamination Certificate
active
06652853
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a combination of immunotherapy and chemotherapy to promote tumor regression, particularly colorectal cancer and gastric carcinomas by treating a patient in need thereof with a combination of a humanized antibody that binds to A33 antigen and one or more chemotherapeutic agents. The combination of immunotherapy and chemotherapy is also useful for treatment of tumors that are resistant to one or more chemotherapeutic agents.
BACKGROUND OF THE INVENTION
Colorectal cancer remains a major medical problem in the western world, with an estimated 130,000 new cases and 55,000 deaths in the United States in 1997 (Parker S. L., et al.,
Cancer statistics
(1997). CA Cancer J Clin., 47:5-27 (1997)). In recent years, dietary and genetic factors have been identified as playing a role in determining an individual's risk of developing the disease (Weisburger, “Causes, relevant mechanisms, and prevention of large bowel cancer”,
Seminars in Oncology,
18:316-336 (1991) and Lynch et al. “Hereditary colorectal cancer”,
Seminars in Onocology;
18:337-366 (1991).
Adjuvant chemotherapy, radiation therapy, and immunotherapy have shown some usefulness in the treatment of primary and advanced colorectal carcinoma but additional agents and regimens are needed to consistently treat these diseases successfully (Petrelli et al., “The modulation of flourouracil with leucovorin in metastatic colorectal carcinoma: A prospective randomized phase III trial”,
J Clin Oncol,
7:1419-1426 (1989); Laurie et al., “Surgical adjuvant therapy of large-bowel carcinoma: An evaluation of levamisole and the combination of levamisole and flourouracil”,
J Cin. Oncol.;
7:1447-1456 (1989); Byfield, et al., “Pharmacological requirements for obtaining sensitization of human cancer cells in vitro to combined 5-FU or ftorafur and X-rays”,
Int J Rad Oncol Biol Phys,
8:1923-1933 (1982); Mohiuddin and Marks, “Adjuvant radiation therapy for colon and rectal cancer”,
Sem. Oncol.
18:411-420 (1991); Krook, et al., “Effective surgical adjuvant therapy for high-risk rectal carcinoma”,
N Engl. J. Med.,
324:709-815 (1991) U.S. Pat. No. 5,851,526 and U.S. Pat. No. 5,958,412).
Chemotherapy alone has limitations in that the cancer cells often become resistant to a broad spectrum of structurally unrelated chemotherapeutic agents. Such resistance, termed “multidrug resistance” (MDR), is not an uncommon problem in the treatment of patients with cancer and while significant efforts have been made to understand the mechanisms responsible for MDR, that understanding has not fulfilled the expectations for eradicating chemoresistant cancer cells.
Immunotherapy, alone or in combination with radiotherapy, has also been investigated as a method for inhibiting or eradicating cancer cells. In such treatments the immunoglobulin molecules are preferably specific for an antigen expressed on the cancer cells. In the case of colorectal cancers, radiolabelled antibodies specific for A33 antigen have shown promise for targeting colon cancer cells. The original mouse mAb A33 is an IgG
2
a antibody that detects an epitope that is specific to colorectal cancer cells. Biopsy-based radioimmunolocalization studies quantitatively demonstrated high levels of antibody targeting to colorectal cancer.
A33 is a novel glycoprotein with a molecular weight of 43 kD in its monomeric form in Western blots under non-reducing conditions. Extensive immunohistochemical analysis of malignant and normal tissues has demonstrated that the antigen is homogeneously expressed by more than 95% of colon cancers and in the normal colon mucosa but not in other epithelial tissues. Immunohistochemical staining of the normal colon mucosa with serially diluted samples of mAb A33 suggests that A33 antigen expression is greatest at the top of the crypt and minimal at the base. A subset of gastric carcinomas also express the A33 antigen, while normal gastric mucosa are antigen-negative. The A33 antigen has been purified from human colon cancer cells, the protein sequence determined, the cDNA cloned, and the mouse homolog identified. See, U.S. Pat. No. 5,712,369.
The biodistribution and imaging characteristics of
131
I-mAb A33 were studied in colon carcinoma patients with hepatic metastases. Control mAb TA99 studies showed that mAb A33 localization was antigen-specific, cancer:liver ratios were 2.3- to 45-fold higher for specific antibody as compared to non-specific antibodies. In metastatic lesions, the radioisotope is localized primarily in the viable periphery, but even the necrotic core concentrates mAb A33. External imaging shows isotope visualization in the bowel of some patients (Welt S. et al., “Quantitative analysis of antibody localization in human metastatic colon cancer”, A phase I study of monoclonal antibody A33,
J Clin. Oncol.;
8:1894-1906(1990)).
mAb A33 localization is specific with regard to cancer blood pool (as determined by ratios of cancer:liver of injected
99
Tc-HSA) and with regard to an isotype-matched control antibody. Autoradiographs of cancers and surrounding tissue of patients treated with radiolabeled antibody demonstrate that isotope accumulation in cancers corresponds to antibody binding specifically to the cancer cells while the surrounding stromal cells and vasculature do not concentrate the isotope.
A phase II study of
131
I-A33 radioimmunotherapy (Welt S. et al., “Phase I/II study of
131
I-labeled monoclonal antibody A33 in patients with advanced colon cancer”,
J Clin Oncol,
12:1561-1571 (1994)) demonstrated
131
I mAb-A33 had modest anticancer effects in heavily pre-treated patients who were no longer responding to chemotherapy. Of 23 patients treated, five had mixed responses: one patient displayed a disappearance of ascites and a drop in carcinoembryogenic antigen (CEA) levels from 4,200 ng/ml to 1,740 ng/ml, while other radiographic evidence of disease remained stable; in another patient with several pulmonary nodules, a single nodule disappeared while other evidence of disease remained stable; an additional patient with a nonmeasurable, pleura-based mass had a 30% decrease in CEA; and in another patient with progressive abdominal disease, several large lymph nodes of the neck disappeared. The fifth patient also showed a drop in CEA. These results show that murine
131
I-mAb A33 has modest anti-cancer activity in heavily pretreated patients even after a single dose.
Five patients were treated with a second course of
131
I-mAb A33 at 6-16 weeks; however, clearance of radiolabeled mAb was rapid, due to the human antimouse response (HAMA), and localization of isotope to the cancer sites was much less than after the first treatment, indicating that re-treatment is not practical.
An attractive feature of the A33 antigenic system for radioimmunotherapy is the in vitro evidence for rapid internalization of A33 antigen/antibody complexes into colon cancer cells (Daghighian et al., “Enhancement of radiation dose to the nucleus by vesicular internalization of
125
I-labeled A33 monoclonal antibody”,
J. Nucl. Med.;
37:1052-1057 (1996)) and the ability of
125
I-mAb A33-conjugates internalized into the cell to kill colon cancer cells in vitro and in a nu—nu mouse xenograft model.
125
I-mAb A33 exerts its cytotoxic effects primarily through short-range Auger electrons, which are most effective if generated in close proximity (<1-4 &mgr;m) to the cell nucleus. Compared to “
3
I-mAb A33, one of the expected benefits of
125
I-mAb A33 is reduced bone marrow toxicity, and this expectation has been confirmed in the nu—nu mouse cancer model.
In a phase I/II study, twenty-one patients with advanced measurable or evaluable colon cancer who had failed at least one 5-fluorouracil (5-FU) based therapy but had not received prior radiotherapy, were treated with a single dose of
125
I-labeled mAb A33 (Welt et al., “Phase I/II study of Iodine 125-labeled monoclonal antibody A33 in patients with advanced colon cancer”,
J. Clin. Oncol.,
14:1787-1797 (1996)). Of the 20 patients showing radiologic evidence of dise
Cohen Leonard
Jungbluth Achim A.
Kemeny Nancy
Old Lloyd J.
Ritter Gerd
Fulbright & Jaworski L.L.P.
Ludwig Institute for Cancer Research
Navarro Mark
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