DRUG CONTAINING RECOMBINANT MISTLETOE LECTINS FOR TREATING

Abstract

The invention relates to a drug and/or pharmaceutical composition for treating metastatic tumors, in particular of malignant melanoma, above all of stage IV malignant melanoma, and to the use of said drug, in particular the use of said drug in select patient populations.

Claims

1-14. (canceled)

15. A drug containing purified recombinant mistletoe lectin for treating metastatic tumors or skin cancer, wherein the purified recombinant mistletoe lectin is selected from the group of amino acid sequences of SEQ ID Nos. 1-12, or is a combination thereof.

16. The drug according to claim 15, wherein the purified recombinant mistletoe lectin polypeptide is a mistletoe lectin A-chain selected from the group of amino acid sequences of SEQ ID No. 1-3, or is a combination thereof.

17. The drug according to claim 15, wherein the purified recombinant mistletoe lectin polypeptide is a mistletoe lectin B-chain selected from the group of amino acid sequences of SEQ ID No. 4-12, or is a combination thereof.

18. The drug according to claim 15, wherein the metastatic tumor or skin cancer is malignant melanoma.

19. The drug according to claim 15, wherein the drug is selected for non-responders and therapeutic failures of a standard tumor therapy.

20. The drug according to claim 15, wherein the drug is selected for the treatment of stages Ill and IV of a metastatic tumor or skin cancer.

21. The drug according to claim 20, wherein the metastatic tumor or skin cancer is malignant melanoma.

22. The drug according to claim 15, wherein the drug is used after a first standard treatment for tumors.

23. The drug containing a purified recombinant mistletoe lectin polypeptide according to claim 15, optionally in combination with a pharmaceutically compatible carrier.

24. The drug containing a purified recombinant mistletoe lectin polypeptide according to claim 15 for the specific treatment of malignant melanoma in humans, wherein the drug is used in a dosage in a range of 3-7 ng recombinant mistletoe lectin per kg body weight.

25. The drug according to claim 24, wherein the drug is used in a dosage of 5 ng recombinant mistletoe lectin per kg body weight.

26. The drug containing a purified recombinant mistletoe lectin polypeptide according to claim 15 for the specific treatment of malignant melanoma in humans, wherein the dosage of recombinant mistletoe lectin is 200-500 ng, independently of body weight.

27. The drug according to claim 26, wherein the dosage of purified recombinant mistletoe lectin is 350 ng, independently of body weight.

28. The drug according to claim 15, wherein the drug is administered at least once a week.

29. The drug according to claim 15, wherein the drug is administered at least twice a week, or at least three times per week.

30. A pharmaceutical composition containing at least one recombinant mistletoe lectin according to claim 15, in combination with a pharmaceutically compatible carrier or, optionally, additional inactive ingredients and additives.

31. A drug containing purified recombinant mistletoe lectin for treating metastatic tumors or skin cancer, wherein the purified recombinant mistletoe lectin is selected from the group of amino acid sequences of SEQ ID Nos. 2, 3, and 5-12, or is a combination thereof.

Description

EXAMPLES AND FIGURES

Example 1 of a Composition of the Drug

[0044]

TABLE-US-00001 Solution for injection: 1 mL ampule with 0.5 mL/1.0 mL injection solution Aviscuminum 200-500 ng Sodium 2.8 mg 5.6 mg monohydrogen phosphate dihydrate Sodium dihydrogen 0.078 mg 0.155 mg phosphate dihydrate Sodium chloride 3.3 mg 6.7 mg Polyoxyethylene 0.1 mg 0.1 mg sorbitan ester (polysorbate) Glutaminic acid 0.1 mg 0.1 mg Water for injection to make 0.5 ml to make 1.0 mL

Example 2 of a Composition of the Drug

[0045]

TABLE-US-00002 Powder for making a solution for injection, 2R glass vial with Aviscuminum 20-500 ng Trehalose 40.0 mg Sodium chloride 1.0 mg Tris(hydroxymethyl)aminomethane (TRIS) 0.6 mg Polyoxyethylene sorbitan ester (polysorbate) 0.1 mg Hydrochloric acid for adjusting the pH value for administration, the powder is dissolved in 0.5 mL or 1.0 mL water for injection.

[0046] A clinical study was conducted to investigate whether recombinant mistletoe lectin (Aviscumin, “rML” according to EP 0 751 221) can halt the progression of the disease in patients with stage IV metastatic malignant melanoma after failure of standard therapy, or whether the survival of the patient can be prolonged. The study involved 31 evaluatable patients. Although the progression-free survival was changed, surprisingly, the survival of the patients was significantly increased. The median survival of the patients was 11.0 months, and the one-year survival rate was 45.0%. The prolongation of the survival time was independent of the number of pretreatments and independent of the general condition (ECOG status 0 or 1). The one-year survival rate of a comparable control group, which can be calculated on the basis of the criteria of gender, brain metastases present/not present, the type of metastases (visceral/non-visceral), and general condition (ECOG) according to the data of Korn et al. 2008 (supra), is 33.1%. No side effects occurred over the course of treatment with rML that had a severity of >2 according to the CTC criteria. Therefore, the use of rML is very well tolerated.

TABLE-US-00003 TABLE 1 Demographic data Patients, n = 31 Sex n (%) Male 16 (51.6) female 15 (48.4) ECOG n (%) 0 17 (54.8) 1 14 (45.2) Age Mean 65.32 (yrs) SD 13.53 Median 67.00 Range 20-86 Weight Mean 76.53 (kg) SD 12.42 Median 77.50 Type of n (%) cutaneous 26 (83.9) melanoma mucosal 3 (9.7) occult 1 (3.2) other 1 (3.2) No. of metastatic n (%) 1 13 (41.9) sites 2 13 (41.9) 3 4 (12.9) 4 1 (3.2) LDH (U/L) Mean 262.71 at BL SD 89.17 Median 245.00 LDH elevation n (%) yes 17 (54.8) no 14 (45.2) ECOG = Eastern Cooperative Oncology Group, LDH = Lactate dehydrogenase

[0047] Case Study 1:

[0048] Patient, female, age: 78 years, stage IV malignant melanoma, ECOG: 1,

[0049] Metastases in lymph nodes and lungs,

[0050] 2 pretreatments with dacarbazine,

[0051] 15 cycles (420 days) therapy with Aviscuminum (rML) 350 ng, 2× per week,

[0052] Stabilization of the disease (no tumor growth) for a period of 433 days,

[0053] survival time: 453 days

[0054] Case Study 2:

[0055] Patient, male, age: 79 years, stage IV malignant melanoma, ECOG: 0,

[0056] multiple metastases in the liver and lungs,

[0057] 5 pretreatments with dacarbazine, dacarbazine combined with interferon-alpha, dacarbazine combined with vindesine, treosulfan combined with gemcitabine, imatinib

[0058] 4 cycles (112 days) therapy with Aviscuminum (rML) 350 ng, 2× per week,

[0059] Stabilization of the disease (no tumor growth) for a period of 116 days,

[0060] survival time: 435 days

DESCRIPTION OF THE FIGURES

[0061] FIG. 1 describes the survival curve according to the Kaplan-Meier method that was evaluated with respect to the study data.