COMBINED PREPARATIONS COMPRISING ANTITUMOR AGENTS

Abstract: There are provided the combined use of 4-demethoxy-3'-deamino-3'-aziridinyl-4'-methansulfonyl daunorubicin or 4-demethoxy-N,N-bis(2-chloroethyl)-4'-methansulfonyl daunorubicin and a recombinant humanized anti-HER2 antibody, preferably trastuzumab, in the treatment of tumors and the use of said combination in the treatment and/or prevention of tumor metastasis.

Description: Title: "Combined preparations comprising antitumor agents' The present invention pertains to the field of neoplastic disease therapy. Particularly, this invention provides an antitumor composition comprising an alkylating anthracycline and a recombmant humanized antι-HER2 antibody, for example the recombmant humanized monoclonal antibody (rhuMab) anti- HER2, trastuzumab (Herceptm™) , having a synergistic or additive antmeoplastic effect. The present invention provides, in a first aspect, a pharmaceutical composition for use antmeoplastic therapy m mammals, including humans, comprising - an alkylating anthracycline of formula la or lb a recombmant humanized antι-HER2 antibody and a pharmaceutically acceptable carrier or excipient . The recombmant humanized antι-HER2 antibody is preferably, the recombmant humanized monoclonal antibody antι-HER2 trastuzumab . The chemical names of the alkylating anthracyclmes of formula la and lb are 4-demethoxy-3' -deamιno-3' -azιrιdmyl- ' - methansulfonyl daunorubicin (la) and 4-demethoxy-N, N-bis (2- chloroethyl ) -4 ' -methansulfonyl daunorubicin (lb). These alkylating anthracyclmes were described in Anticancer Drug Design (1995), vol. 10, 641-653, and claimed respectively in US-A-5, 532, 218 and US-A-5, 496, 800. Both compounds intercalate into DNA via the chromophore and alkylate guanine at N 7 position n DNA minor groove via their reactive moiety on position 3' of the ammo sugar. Compounds la and lb are able to circumvent the resistance to all major classes of cytotoxics, indicating that the compounds represent a new class of cytotoxic antitumor drugs. The recombmant humanized monoclonal antibody antι-HER2 trastuzumab (Herceptin™) is described in various scientific publications, for example Cancer Res., 1998, 58:2825-2831. The present invention also provides a product comprising an alkylating anthracycline of formula la or lb as defined above and a recombmant humanized antι-HER2 antibody, preferably the recombmant humanized monoclonal antibody antι-HER2 trastuzumab, as combined preparation for simultaneous, separate or seguential use m antitumor therapy. A further aspect of the present invention is to provide a method of treating a mammal, including a human, suffering from a neoplastic disease comprising administering to said mammal an alkylating anthracycline of formula la or lb as defined above and a recombmant humanized antι-HER2 antibody, preferably the recombmant humanized monoclonal antibody anti- HER2 trastuzumab, in amounts effective to produce a synergistic antmeoplastic effect. A still further aspect of the present invention is to provide a method for lowering the side effects caused by antmeoplastic therapy with an antmeoplastic agent a mammal, including a human, in need thereof, the method comprising administering to said mammal a combined preparation comprising an alkylating anthracycline of formula la or lb as defined above, and a recombmant humanized antι-HER2 antibody, preferably the the recombmant humanized monoclonal antibody antι-HER2 trastuzumab, in amounts effective to produce a synerqistic antmeoplastic effect. By the term "a synergistic antmeoplastic effect" as used herein is meant the inhibition of the growth tumor, preferably the complete regression of the tumor, administering an effective amount of the combination of an alkylating anthracycline of formula la or lb as defined above and a recombmant humanized antι-HER2 antibody to mammals, including humans. By the term "administered" or "administering" as used herein is meant any acceptable manner of administering a drug to a patient which is medically acceptable including parenteral and oral administration. By "parenteral" is meant intravenous, subcutaneous and intramuscular administration. Oral administration includes administering the costituents of the combined preparation m a suitable oral form such as, e.g., tablets, capsules, suspensions, solutions, emulsions, powders, syrups and the like. Parenteral administration includes administering the costituents of the combined preparation by subcutaneous, intravenous or intramuscular injections. The actual preferred method and order of administration of the combined preparations of the invention may vary according to, inter alia, the particular pharmaceutical formulation of the alkylating anthracycline of formula la or lb as defined above being utilized, the particular pharmaceutical formulation of the recombmant humanized antι-HER2 antibody being utilized, the particular cancer being treated, and the particular patient being treated. The dosage ranges for the administration of the combined preparation may vary with the age, condition, sex and extent of the disease in the patient and can be determined by one of skill m the art. The dosage regimen must therefore be tailored to the particular of the patient's conditions, response and associate treatments m a manner which is conventional for any therapv, and may need to be adjusted in response to changes in conditions and/or in light of other clinical conditions. In the method of the subject invention, the alkylating anthracycline may be administered simultaneously with the recombmant humanized antι-HER2 antibody, or the compounds may be administered sequentially, in either order. In the method of the subject invention, for the administration of the alkylating anthracycline of formula la or lb as defined above, the course of therapy generally employed is from about 0.1 to about 200 mg/m of body surface area. More preferably, the course therapy employed is from about 1 to about 50 mg/m 2 of body surface area. In the method of the subject invention, for the administration of the recombmant humanized antι-HER2 antibody, for example for the administration of the recombmant humanized monoclonal antibody antι-HER2 trastuzumab, the course of therapy generally employed is from about 1 to about 1000 mg/m 2 of body surface area. More preferably, the course therapy employed is from about 50 to about 500 mg/m 2 of body surface area. The antmeoplastic therapy of the present invention is, in particular, suitable for treating breast, ovary, lung, colon, kidney, stomach, pancreas, liver, melanoma, leukemia and brain tumors m mammals, including humans. More in particular, the combined use of an alkylating anthracycline according to the invention and a recombmant humanized antι-HER2 antibody, for example the recombmant humanized monoclonal antibody anti- HER2 trastuzumab, can be suitable for the treatment of patients with cancers over-expressing the HER2 protein, for example, for patient with metastatic breast cancer over- expressing the HER2 protein. The antmeoplastic therapy according to this invention also comprises the prevention and/or treatment of tumor metastasis. A still further aspect of the present invention is the use of an alkylating anthracycline of formula la or lb as defined above and a recombmant humanized antι-HER2 antibody, preferably the recombmant humanized monoclonal antibody anti- HER2 trastuzumab, for the treatment of tumors by angiogenesis inhibition . As stated above, the effectiveness of an alkylating anthracycline of formula la or lb and a recombmant humanized antι-HER2 antibody is significantly increased without a parallel increased toxicity. In other words, the combined therapy of the present invention enhances the antitumoral effects of the alkylating anthracycline of formula la or lb as defined above and of a recombmant humanized antι-HER2 antibody and thus yields the most effective and least toxic treatment for tumors. The synergistic action displayed by the combined preparations according to the present invention can be shown, for instance, by testing the activity of the combination m mice bearing human tumor xenografts overexpressmg HER2 protein, following, for example, the method described in Cancer Research, 1998, 58:2825-2831. Suitable modifications and adaptations of a variety of conditions and parameters normally encountered in clinical therapy which are obvious to those skilled m the art are within the scope of this invention.

Claims: CLAIMS 1. Products containing an alkylating anthracycline of formula la or lb: and a recombmant humanized antι-HER2 antibody as a combined preparation for simultaneous, separate or sequential use in antitumor therapy. 2. Products according to claim 1, wherein the recombmant humanized antι-HER2 antibody is the recombmant humanized monoclonal antibody antι-HER2 trastuzumab. 3. Products according to claim 1 or 2, wherein the alkylating anthracycline is 4-demethoxy-3' -deammo-3' -azιrιdιnyl-4 ' - methansulfon 1 daunorubicin. 4. Products according to any one of claims 1 to 3, wherein the antitumor therapy is for treating cancers over-expressing HER2 protein. 5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and, as active ingredient, an alkylating anthracycline of formula la or lb as defined m claim 1 and a recombmant humanized antι-HER2 antibody. 6. A pharmaceutical composition according to claim 5 wherein the recombmant humanized antι-HER2 antibody is the recombmant humanized monoclonal antibody antι-HER2 trastuzumab . 7. Use of an alkylating anthracycline of formula la or lb as defined in claim 1 and a recombmant humanized antι-HER2 antibody in the preparation of a medicament for use in the treatment of tumors, wherein the alkylating anthracycline and the recombmant humanized antι-HER2 antibody are administered simultaneously, separately or sequentially. 8. Use according to claim 7 wherein the recombmant humanized antι-HER2 antibody is the recombmant humanized monoclonal antibody antι-HER2 trastuzumab. 9. Use of an alkylating anthracycline of formula la or lb as defined m claim 1 and a recombmant humanized antι-HER2 antibody m the preparation of a medicament for use in the prevention and/or treatment of tumor metastasis, wherein the alkylating anthracycline and the recombmant humanized anti- HER2 antibody are administered simultaneously, separately or sequentially. 10. Use according to claim 9 wherein the recombmant humanized antι-HER2 antibody is the recombmant humanized monoclonal antibody antι-HER2 trastuzumab. 11. A method of treating a mammal, including a human, suffering from a neoplastic disease comprising administering to said mammal an alkylating anthracycline of formula la or lb as defined above and a recombmant humanized antι-HER2 antibody, in amounts effective to produce a synergistic antmeoplastic effect. 12. A method according to claim 11, wherein the recombinant humanized antι-HER2 antibody is the recombinant humanized monoclonal antibody anti-HER2 trastuzumab. 13. A method for lowering the side effects caused by antmeoplastic therapy with an antineoplastic agent in a mammal, including a human, in need thereof, the method comprising administering to said mammal a combined preparation comprising an alkylating anthracycline of formula la or lb as defined above, and a recombinant humanized anti-HER2 antibody, in amounts effective to produce a synergistic antineoplastic effect . 14. A method according to claim 13, wherein the recombinant humanized anti-HER2 antibody is the recombinant humanized monoclonal antibody anti-HER2 trastuzumab.

Inventors: CARUSO MICHELE, GERONI CRISTINA, RIPAMONTI MARINA, SUARATO ANTONINO, CARUSO, MICHELE, GERONI, CRISTINA, RIPAMONTI, MARINA, SUARATO, ANTONINO
Applicants: CARUSO MICHELE, GERONI CRISTINA, PHARMACIA & UPJOHN SPA, RIPAMONTI MARINA, SUARATO ANTONINO, CARUSO, MICHELE, GERONI, CRISTINA, PHARMACIA & UPJOHN S.P.A., RIPAMONTI, MARINA, SUARATO, ANTONINO
Application year: 2000
Main classification: A61K39
IPC codes: A61K31, A61K39, A61P35, C07K16