Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Reexamination Certificate
2001-08-08
2004-07-06
Helms, Larry R. (Department: 1642)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
C424S130100, C424S137100, C424S138100, C424S141100, C424S155100, C424S001210
Reexamination Certificate
active
06759045
ABSTRACT:
BACKGROUND OF THE INVENTION
Chronic myelocytic leukemia (CML) is a highly specific disease that is defined by strict hematologic parameters that include a pathognomonic differential leukocyte count. Usually, CML is accompanied by the presence, in bone marrow cells, of the Ph chromosome, the first chromosomal anomaly to be regularly associated with a human neoplastic disease. Chronic myelocytic leukemia is a disease of worldwide distribution and predominantly appears during middle age. The disease is characterized by an initial chronic phase when it behaves as a differentiated neoplasm and responds very well to simple, nonintensive therapy. After a variable interval, CML metamorphosizes to a refractory phase that responds poorly or not at all to therapy, even when intensive. See Spiers,
Semin. Oncol.,
22(4):380-95 (1995). At the stage of metamorphosis a great variety of clinical and hematologic pictures occur, and CML may mimic a myeloproliferative disease, a myelodysplasia, a subacute leukemia, acute myelocytic leukemia (AML), or acute lymphocytic leukemia (ALL). The old concept of an abrupt, explosive transition from the chronic phase to a so-called blastic crisis is incorrect. See Spiers,
Semin. Oncol.,
22(4):380-95 (1995). In most cases, CML is observed to undergo two or more stepwise evolutions, e.g., from chronic phase to an accelerated myeloproliferative phase to a phase that resembles AML.
A variety of therapies have been used to treat CML. Traditional methods for treating leukemia, including chemotherapy and radiotherapy, have limited utility due to toxic side effects. The use of monoclonal antibodies to direct radionuclides, toxins or other therapeutic agents selectively to tumor sites has reduced the level of toxicity to normal tissues. However, due to the large quantities of conjugate which must be administered, such therapies continue to produce toxic side-effects. These aspects limit the effectiveness and duration of such treatments. Another therapy, allogeneic bone marrow transplants, has had the largest impact on survival among patients with CML. See Clarkson,
J. Clin. Oncol.,
3:135-139 (1985). Like the previous therapies, however, bone marrow transplants are poorly tolerated by patients.
Recent studies suggest that immunotherapy utilizing naked antibodies can be an effective tool for treating certain cancers. The use of naked, humanized, anti-CD33 antibodies has proved effective in treating acute myelocytic leukemia and in reducing the residual disease in patients. See Caron et al.,
Clin. Cancer Res.,
4:1421-1428 (1998); Jurcic et al.,
Clin. Cancer Res.,
6:372-380 (2000). Similarly, immunotherapy comprising naked, humanized, anti-HER2
eu antibodies has produced promising results in the treatment of breast cancer. See Baselga et al.,
Semin. Oncol.,
26:78-83 (1999); Weiner,
Semin. Oncol.,
26:43-51 (1999). Unconjugated immunoglobulins directed against CD20 have been shown to induce partial and complete responses in up to 50% of patients with advanced, indolent non-Hodgkin's lymphoma. See Weiner,
Semin. Oncol.,
26:43-51 (1999).
The use of naked antibodies for treating malignancies has several advantages. First, immunotherapy comprising solely naked antibodies lacks the toxic side-effects associated with other therapies, such as radioimmunotherapy (RAIT) or immunotherapy utilizing conjugated toxins. Second, circulating naked antibodies remain therapeutically active longer than other therapies. For example, the effectiveness of RAIT is limited by the half-life of the conjugated isotope, typically a week or less. Similarly, the efficacy of conjugated immunotoxins can be short-lived due to in vivo modification of the toxin. Third, since naked antibodies are well-tolerated by patients, multiple rounds of therapy can be administered. Fourth, combination therapy utilizing naked antibodies is better tolerated by patients because lower quantities of the toxic component of the combination are required to achieve effective results. Finally, the use of naked antibodies dramatically reduces the costs of treating cancer by reducing the need for expensive radioactive or therapeutic conjugates which possess short shelf-lives and whose administration typically requires special facilities and personnel. Thus, such cost reductions enable more patients to benefit from the therapy.
There is a need, therefore, to develop immunotherapies which utilize naked antibodies to treat CML. Such therapies would cost-effectively treat patients without inducing toxic side-effects.
SUMMARY OF THE INVENTION
Accordingly, it is one object of the present invention to provide methods of treating myelocytic leukemia using naked immunotherapy.
In accomplishing this and other objects, there is provided, in accordance with one aspect of the present invention, a method for treating chronic myelocytic leukemia (CML) in a patient, comprising administering to the patient a therapeutic composition comprising a pharmaceutically acceptable carrier and at least one naked anti-granulocyte antibody. A variety of anti-granulocyte antibodies can be used in the present invention. Examples include, but are not limited to, anti-NCA-90, anti-NCA-95, MN-2, MN-15, NP-1 and NP2. In one embodiment, a single, naked anti-granulocyte antibody is administered to a patient while, in another, more than one anti-granulocyte antibody is administered. In still another embodiment, at least one naked anti-granulocyte antibody is administered to a patient in combination with naked antibodies directed to antigens present on a single granulocyte precursor, such as anti CD33 or anti-CD15 antibodies.
In another embodiment of the present invention, naked anti-granulocyte antibodies are used in combination with other cancer therapies, e.g., an immunoconjugate or chemotherapy. Preferred immunoconjugates include radiolabeled antibody components and conjugates of an anti-granulocyte antibody component and an immunomodulator, such as a cytokine, stem cell growth factor, lymphotoxin or hematopoietic factor. In still another embodiment, combination therapy of the present invention can comprise antibody-toxin fusion proteins.
In yet another embodiment of the present invention, naked anti-granulocyte antibodies are administered in combination with inducing agents which either enhance or induce the expression of the targeted antigen. Such inducing agents enhance the efficacy of the administered therapy by up-regulating the expression of the target antigen on the surface of a cell of interest. In addition, inducing agents can extend the inventive therapy's tumor-killing potential to additional cell-types and cancers by inducing expression of antigens not normally displayed on the surface of these cells. Accordingly, the antibodies of the present invention can be used to treat AML, as well as CML.
Thus, in another embodiment of the present invention, there is provided a method for treating acute myelocytic leukemia (AML) or acute promyelocytic leukemia (APML) in a patient, comprising administering to the patient a therapeutic composition comprising a pharmaceutically acceptable carrier and at least one naked anti-granulocyte antibody and an inducing agent, wherein the inducing agent induces expression of antigens which are minimally displayed on the surface of myeloblasts. As described above, the inventive method can be further combined with other naked, anti-granulocyte antibodies, antibody-toxin fusion proteins and other cancer therapies, e.g., an immunoconjugate or chemotherapy.
Other objects, features and advantages of the present invention will become apparent from the following detailed description. The detailed description and specific examples, while indicating preferred embodiments, are given for illustration only since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. Further, the examples demonstrate the principle of the invention and cannot be expected to specifically illustrate the application of this invent
Goldenberg David M.
Hansen Hans J.
Heller Ehrman White and McAuliffe LLP
Helms Larry R.
Immunomedics Inc.
Yaen Christopher
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