Drug – bio-affecting and body treating compositions – Conjugate or complex of monoclonal or polyclonal antibody,... – Conjugate includes potentiator; or composition comprising...
Reexamination Certificate
1994-10-18
2001-07-10
Wortman, Donna C. (Department: 1648)
Drug, bio-affecting and body treating compositions
Conjugate or complex of monoclonal or polyclonal antibody,...
Conjugate includes potentiator; or composition comprising...
C424S152100, C424S155100, C424S174100, C435S188500, C514S049000, C514S050000, C536S027400, C536S028550
Reexamination Certificate
active
06258360
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides methods and compounds for providing suitable prodrugs of cytotoxic agents that are activated by enzymes or catalytic antibodies.
BACKGROUND OF THE INVENTION
Many pharmaceutical compounds such as antiviral, immunosuppresive, and cytotoxic cancer chemotherapy agents generally have undesirable toxic effects on normal tissues. Such effects, which include damage to bone marrow (with consequent impairment of blood cell production) and gastrointestinal mucosa, alopecia, and nausea, limit the dose of pharmaceutical compound that can be safely administered and thereby reduce the potential efficacy.
Prodrugs Of Antineoplastic Agents
a. Nucleoside Analogs
A number of nucleoside analogs have utility as antitumor agents, including fluorouracil, fluorodeoxyuridine, fluorouridine, arabinosyl cytosine, mercaptopurine riboside, thioguanosine, arabinosyl fluorouracil, azauridine, azacytidine, fluorcytidine, fludarabine. Such drugs generally act by conversion to nucleotide analogs that either inhibit biosynthesis of important nucleotides or that are incorporated into nucleic acids, resulting in defective RNA or DNA.
5-Fluorouracil (5-FU) is a major antineoplastic drug with clinical activity in a variety of solid tumors, such as cancers of the colon and rectum, head and neck, liver, breast, and pancreas. 5-FU has a low therapeutic index. The size of the dose that is administered is limited by toxicity, reducing the potential efficacy that would be obtained if higher concentrations could be attained near tumor cells.
5-FU must be anabolized to the level of nucleotides (e.g., fluorouridine- or fluorodeoxyuridine-5′-phosphates) in order to exert its potential cytotoxicity. The nucleosides corresponding to these nucleotides (5-fluorouridine and 5-fluoro-2′-deoxyuridine) are also active antineoplastic agents, and in some model systems are substantially more potent than 5-FU, probably because they are more readily converted to nucleotides than is 5-FU.
AraC, also called arabinosylcytosine, 1-&bgr;-D-arabinofuranosylcytosine, cytarabine, cytosine-&bgr;-D-arabinofuranoside and &bgr;-cytosine arabinoside, is a widely used anti-cancer drug, albeit with some major disadvantages (see below). Currently AraC is used to treat both myelogenous and lymphocytic leukemias and non-Hodgkin's lymphomas. Used alone it has resulted in a 20-40% remission of acute leukemia and, in combination with other chemotherapeutic agents, has yielded greater than 50% remission (Calabresi, et al., “In The Pharmacological Basis of Therapeutics”. Eds. Gilman, A. G., et al., New York: Macmillian Publishing Company, (1985):1272).
One of the disadvantages of AraC as a cancer drug is its rapid catabolism by deaminases. Human liver contains high levels of deoxycytidine deaminase which converts AraC to Ara-Uracil, an inactive metabolite. This rapid catabolism results in a t
½
in humans of 3-9 minutes following parenteral administration (Baguley, et al.,
Cancer Chemotherapy Reports
55 (1971):291-298). Compounding this problem, only cells undergoing DNA synthesis are susceptible to the drug's effect and therefore, one must maintain a toxic concentration until all cells of an asynchronously growing tumor pass through S-phase. Unfortunately, this means that the optimum dose schedule of AraC involves a slow intravenous infusion over many hours on each of 5 days, thus requiring a hospital stay. Prolonged application leads to the major problem of general toxicity among rapidly dividing normal cells, leading to bone marrow suppression, infection, and hemorrhage. Another problem encountered using this drug is the resistance to AraC eventually developed by cells, presumably due to selection of cells with low kinase activity, or an expanded pool of deoxy CIP.
Prodrug derivatives of AraC have been synthesized in order to: 1) protect AraC from rapid degradation by cytidine deaminase; 2) act as molecular depots of AraC and thereby simplify drug dose schedules; 3) act as carrier molecules for transport on serum proteins and facilitate cellular uptake; or 4) overcome resistance of cells with low linase activity. AraC derivatives substituted at the 5′ position of the arabinose or the N4 position of the cytidine ring have been found to be cytidine deaminase-resistant. Acting as carrier molecules that protect AraC from degradation by cytidine deaminase, lipophilic 5′-ester derivatives (Neil, et al.,
Biochem. Pharmacol.
21 (1971):465-475; Gish, et al.,
J. Med. Chem.
14 (1971):1159-1162) and N4-acyl derivatives (Aoshima, et al.,
Cancer Res.
36 (1976):2726-2732) of AraC have been shown to possess higher antitumor activity than AraC in leukemic mice.
All of the above prodrug derivatives are designed to be administered systemically as the parent drug itself is administered. The side effects of the prodrug arising out of the non-tumor-specific toxicity are very similar, if not identical to the systemic application of the parent drug, Ara-C. These prodrugs are presumably acting as molecular depots of Ara-C and thus prolonging the time of drug availability.
Some prodrugs of other antineoplastic nucleoside analogs are also known. Such prodrugs are generally acyl derivatives of the nucleoside analogs; the acyl groups are removed by endogenous esterase activity following administration. Some of these prodrugs of arabinosyl cytosine (Neil, et al.,
Cancer Research
30 (1970):1047-1054; Neil, et al.,
Biochem Pharmacol.
20 (1971):3295-3308; Gish, et al.,
J. Med. Chem.
14 (1971):1159-1162; Aoshima, et al.,
Cancer Research
36 (1976):2762-2732 or fluorodeoxyuridine (Schwendener, et al.,
Biochem. Biophys. Res. Comm.
126 (1985):660-666) provide active drug for a period longer than would occur after administration of the parent drug.
However, such prodrugs do not selectively deliver the drug to tumor tissue; enhanced toxicity often accompanies enhanced antitumor efficacy (Schwendener, et al.,
Biochem. Biophy. Res, Comm.
126 (1985):660-666).
Like 5Fu and Ara-C, the size of the dose of other antineoplastic nucleoside analogs (including but not limited to fluorouracil arabinoside, mercaptopurine riboside, arabinosyl adenine, or fluorodeoxyuridine) or their prodrugs that is administered is limited by toxicity, reducing the potential efficacy that would be obtained if higher concentrations could be attained near tumor cells.
Previous suggestions for targeted prodrugs of antineoplastic nucleoside analogs are unsatisfactory. Bagshawe, et al., Patent Application WO 88/07378, proposed that the corresponding nucleotides of antineoplastic nucleosides could be converted back to the nucleoside with an appropriate enzyme; Senter, et al., Patent Application EP 88112646, similarly suggest the use of fluorouridine monophosphate to be activated by the enzyme alkaline phosphatase conjugated to an antibody that binds to a tumor cell surface antigen. These proposals fail to take into account the high and ubiquitous activity of enzymes which convert nucleotides to nucleosides (e.g., 5′nucleotidase) in blood and tissues. Nucleotides (nucleoside phosphates) are therefore not useful for targeted delivery of antineoplastic nucleoside analogs.
b. Alkylating Aunts
Nitrogen mustard alkylating agents are an important class of antineoplastic drugs. Examples of antineoplastic alkylating agents with clinical utility are: cyclophosphamide, melphalan, chlorambucil, or mechlorethamine. These agents share, as a common structural feature, a bis-(2-chloroethyl) grouping on a nitrogen which can alkylate and thereby damage nucleic acids, proteins, or other important cellular structures. The cytotoxic activity of alkylating agents is less dependent upon the cell cycle status of their targets than is the case for antimetabolites that affect nucleic acid synthesis. For this reason, the cytotoxicity of alkylating agents can be less selective for rapidly dividing cells (e.g., many tumors) relative to normal tissues, but on the other hand, it is more completely effective against populations of cells that ar
Casadei Jan M.
Kamireddy Balreddy
Kenten John Henry
Martin Mark T.
Massey Richard J.
Evans, Esq. Barry
IGEN International Inc.
Kramer Levin Naftalis & Frankel LLP
Wortman Donna C.
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