Pharmaceutical compositions able to induce cancer cell apoptosis for diagnosing and treating b-cell chronic lymphocytic leukaemia

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, and concerns pharmaceutical compositions able to induce cancer cell apoptosis for diagnosing and treating B-cell chronic lymphocytic leukaemia. Substance of the inventions involves the pharmaceutical compositions for treating B-cell chronic lymphocytic leukaemia containing an active ingredient presented by a humanised monoclonal antibody T1h from a secreting hybridoma IOR-TIA under depositary No. ECACC 96112640, identifying a leukocyte differentiation antigen CD6. A diagnostic reagent also contains said antibody.

EFFECT: advantage of the group of inventions consists in higher specific activity.

11 cl, 4 ex, 4 dwg

 

The technical field

The present invention relates to pharmaceutical compositions containing humanitariannet monoclonal antibody that recognizes differencirovany antigen CD6 of cells capable of inducing apoptosis in tumor cells, which are suitable for the treatment of b-cell chronic lymphocytic leukemia.

Description of the prior art

therapeutic significance of monoclonal antibodies (MAB) has been proven in practice. In particular, in the case of cancer of the Mat belong to the modern instruments used for the treatment of patients with various cancers (Weiner, L.M. et al. (2006) Hum Antibodies 15(3): 103; Imai, K. et al. (2006) Nat Rev Cancer 6(9):714).

Apoptosis is a natural biological mechanism of cell death, apoptosis may be caused by therapeutic means. Apoptosis represents an important way of controlling the growth of tumor cells is the mechanism of action stated for certain medications, including Mat, for therapeutic application in patients suffering from certain types of cancer. In medical Oncology, therefore, becomes important to search for drug compounds that can cause cell death through apoptosis (Cartron, G. et al. (2004) Blood 104:2635).

One of the modern problems common who care are lymphoproliferative syndromes, in particular b-cell chronic lymphocytic leukemia (B-CLL). B-CLL is the most common leukemia in the Western world, and today there are no of drugs, get rid of it (Chiorazzi, N. et al. (2005) N Engl J Med 352(8):804; Herishanu, Y. et al. (2005) Transfus Apher Sd 32(1):85). Currently one of the most important methods of treatment of such patients is the use of the Mat is capable of removing the tumor cells (Robak, T. (2005) Transfus Apher Sci 32(1):33). However, the main disadvantage of this approach based on the use of specific Mat to CD52 and CD20, is that it has very limited antitumor therapeutic effect, while also causing the destruction of normal lymphocytes of the individual (Nuckel, H. et al. (2005) Eur J Pharmacol 514(2-3):217; Cartron, G. et al. (2004) Blood 104:2635). The lack of specific recognition of causes prolonged lymphopenia constituting a risk factor for frequent occurrence of infections in patients receiving treatment, which is already to them susceptible due to the inherent characteristics of the cancer (Boye, J. et al. (2003) Ann Oncol 14(4):520; Cartron, G. et al. (2004) Blood 104:2635; Potter, M.(1999) 12(4):359; Ravandi, F. et al. (2006) Cancer Immunol Immunother 55(2): 197).

Tumor cells of patients with B-CLL Express the cell surface markers characteristic of normal b-lymphocytes (e.g., CD19 and CD20). Specifically, the occurrence of tumor glue is OK associated with B-lymphocytes of peripheral blood, which coexpression differencirovany the CD5 antigen leukocyte (Herishanu, Y. et al. (2005) Transfus Apher Sci 32(1):85). CD5 is a distinctive marker for B-CLL, but not essential, as it may represent a secondary marker of a subpopulation of tumor cells, and has not yet been proven whether these cells from the bone marrow, or the source is outside the bone marrow (Caligaris-Cappio, F. et al. (2004) Hematol Oncol Clin N Am 18:849).

Differencirovany antigen CD6 leukocytes is little known and poorly characterized molecule. CD6 is a surface glycoprotein expressed predominantly T-lymphocytes. Basically I believe that CD6 in these cells is receptor performing co-stimulating functions, but the underlying mechanism remains unknown (Aruffo, A. et al. (1997) Immunol Today 18(10):498; Patel, D.D. (2000) J Biol Regul Homeost Agents 2000 14(3):234). Its expression in Mature thymocytes is associated with resistance to apoptosis in the process of maturation of lymphocytes in the lymphoid organ (Singer, N.G. et al. (2002) Int Immunol. 14(6):585).

Interestingly, the CD6 molecule is expressed in a minor subpopulation In the peripheral blood lymphocytes of healthy individuals, however, information about the origin and the functional characteristics of these cells is very limited. In addition, mononuclear cells from peripheral blood of patients with B-CLL also expressio the t CD6 molecule. I believe that the CD6 molecule coexpressed with the CD5 molecule, but unlike it in the end CD6 was found only in samples of patients with B-CLL.

In addition, the recognition molecules CD5 specific monoclonal antibody induces apoptosis in tumor cells of patients with B-CLL, but only part of them (Pers, J.O. et al. (2002) Leukemia 16:44).

The CD6 molecule recognizes mouse Mat ior-t1A. In the previous study samples of patients with B-CLL was found that mouse Mat ior-t1A inhibits apoptosis caused by anti-IgM antibody in b-lymphocytes (Osorio, L. M. et al. (1997) Blood, 89(8):2833). On the other hand, therapeutic compositions of this mouse Mat to CD6 have a therapeutic effect on psoriasis (Montero, E. et al. (1999) Autoimmunity 29(2): 155).

Subsequently, by using genetic engineering methods (EP 0699755) was obtained humanitariannet version of this mouse monoclonal antibody CD6 man named T1h (EP 0807125).

The authors found that humanitariannet Mat T1h recognizes the CD6 molecule expressed on tumor cells in peripheral blood and, unexpectedly, also on the bone marrow cells of patients with B-CLL. Moreover, the Mat T1h also recognize the tumor cells that do not Express CD5 molecule that makes CD6 tumor marker, including CD5-subpopulation. Moreover, humanitariannet monoclonal Mat T1h causes apoptosis of tumor cleto the patients with b-cell chronic lymphocytic leukemia, but not normal lymphocytes.

The novelty of the present invention to provide therapeutic compositions containing anti-CD6 monoclonal antibodies for use in patients with lymphoproliferative syndromes and, in particular, in patients with b-cell chronic lymphocytic leukemia. Surprisingly, the recognition molecules CD6 humanized monoclonal antibody T1h causes apoptotic death of tumor cells of patients with lymphoproliferative syndromes expressing CD6 molecule, and, in particular, neoplastic b-lymphocytes of patients with b-cell chronic lymphocytic leukemia that allows you to use the Mat T1h for the treatment of this type of tumors. In addition, the impact Mat T1h can sensitize cancer cells to the cytotoxic drugs that can promote the combined use of gumanitarnogo monoclonal antibody T1h together with radiation therapy, chemotherapeutic agents or other biological products.

Detailed description of the invention

The present invention relates to therapeutic compositions of monoclonal antibodies that recognize the antigen CD6 man, is effective for the treatment of patients with lymphoproliferative diseases. More specifically, the present invention includes the em in the use of pharmaceutical compositions containing humanitariannet monoclonal antibody T1h, which recognizes differencirovany antigen CD6 of human leukocytes, and their use for diagnosis and treatment of b-cell chronic lymphocytic leukemia.

The term "humanitariannet monoclonal antibody" refers to monoclonal antibody obtained by genetic engineering methods, as described in patent No. 0699755 (European patent Bulletin). The object of the present invention is a therapeutic composition comprising humanitariannet Mat T1h (which is obtained from hybridoma IOR-T1A with Depository number ESAS 96112640 and is able to induce apoptosis of malignant cells of patients with b-cell chronic lymphocytic leukemia by recognition molecules CD6) separately or in conjunction with any of the agents selected from the group:

chemotherapeutic agents such as fludarabine;

monoclonal antibodies specific to surface molecules of cancer cells, such as anti-CD20 antibodies.

The pharmaceutical compositions of the present invention also contain a suitable filler, which may represent a physiological buffer solution, and they can be administered by injection in the range of doses from 0.05 to 1 mg/kg of body weight. On the other hand, the present invention relates to a diagnostic tool for what they reagent, contains anti-CD6 monoclonal antibody, for use in the diagnosis of b-cell chronic lymphocytic leukemia.

1. Creation of pharmaceutical compositions containing humanitariannet monoclonal antibody T1h to CD6 man

Humanitariannet monoclonal antibody T1h to CD6 person received from hybridoma IOR-T1A with Depository no ESAS 96112640, as described in EP 0807125 A2. The pharmaceutical composition of the present invention contains humanitariannet monoclonal antibody T1h, in addition, this composition contains as a suitable auxiliary filler physiological buffer solution, similar to the other solutions used in the compositions of monoclonal antibodies for intravenous use, as described in EP 0807125. The composition of the present invention is administered by injection in the range of doses from 0.05 to 1 mg/kg body weight.

2. Characteristics specific recognition gumanitarnogo monoclonal antibody T1h

Mononuclear cells of peripheral blood and bone marrow cells of patients with b-cell chronic lymphocytic leukemia were stained with FITC-conjugated Mat to human CD19. After that, cells were incubated with the following monoclonal antibodies: conjugated with Biotin monoclonal antibody to CD6 person (T1h) or con is Giovanni with PE-Cy5 antibody to CD5 person (Pharmingen) or conjugated with Biotin antibody to CD20 person (Rituximab-Rx). Binding of biotinylated antibodies were detected using streptavidin conjugated to PE-Cy5.5. On a flow cytometer FACScan collected at least 10000 of living cells. Dead cells were excluded by staining of propecia the iodide.

3. Characterization of antitumor action gumanitarnogo monoclonal antibody T1h cells of patients with b-cell chronic lymphocytic leukemia.

Mononuclear cells from peripheral blood of healthy individuals and patients with b-cell chronic lymphocytic leukemia treatedin vitro0.1 mg/ml humanized monoclonal antibody T1h or ezotericheskim control (monoclonal antibody R3h) for 18 hours at 37°C and 5% CO2. Then cells were washed and incubated with annexin-V conjugated with FITC for 10 minutes at room temperature. After that, cells were stained with propedia the iodide (PI) and collected on a flow cytometer FACScan. Apoptotic cells were defined as cells annexin-V+/PI.

EXAMPLES

The following examples are intended to illustrate the invention. Humanitariannet monoclonal antibody T1h to CD6 person received from hybridoma IOR-T1A with Depository no ESAS 96112640, as described in EP 0807125 A2.

Example 1: Humanitariannet monoclonal antibody T1h to CD6 human resposne the malignant t cells from the peripheral blood of patients with b-cell chronic lymphocytic leukemia.

Assessed recognition Mat T1h mononuclear cells in the peripheral blood of 19 patients with b-cell chronic lymphocytic leukemia and determined the expression of CD6 molecule on b cells, limited expression markers CD19 and CD20. Moreover, we compared the expression of these cellular markers with samples from healthy individuals (figure 1). The study was performed using flow cytofluorimetry using FACScan analysis of samples. Normal values are shown as red solid squares in figure 1.

Example 2: Humanitariannet monoclonal antibody T1h to CD6 person recognize malignant cells from the bone marrow of patients with b-cell chronic lymphocytic leukemia.

Assessed recognition Mat T1h mononuclear cells in the peripheral blood of 4 patients with b-cell chronic lymphocytic leukemia and determined the expression of CD6 molecule on b cells, limited expression markers CD19 and CD20. Moreover, we compared the expression of these cellular markers with samples from healthy individuals (figure 2). The study was performed using flow cytofluorimetry using FACScan analysis of samples.

Example 3: Humanitariannet monoclonal antibody T1h to CD6 person recognizes malignant cell is patients with b-cell chronic lymphocytic leukemia, which does not Express CD5 molecule.

Assessed recognition Mat T1h mononuclear cells of peripheral blood (figure 3A) and bone marrow cells (figure 3b) patients with b-cell chronic lymphocytic leukemia and is defined coexpressed molecules CD6 and CD5 in malignant cells. Sample 1 represents a patient with tumor cells CD6+CD5+, and sample 2 is the patient with tumor cells CD6+CD5-. The study was performed using flow cytofluorimetry using FACScan analysis of samples.

Example 4: Humanitariannet monoclonal antibody T1h causes apoptotic cell death of malignant cells of patients with b-cell chronic lymphocytic leukemia.

Assessed ability gumanitarnogo monoclonal antibody T1h to cause apoptotic cell death of malignant cells of patients with b-cell chronic lymphocytic leukemia. After incubationin vitrotumor cells from humanized monoclonal antibody T1h was determined the percentage of apoptotic cells according to the following criteria: cells positively stained with annexin-V and not stained propecia the iodide. As positive controls used dexamethasone (Dex) and rituximab (Rx, anti-CD20 monoclonal antibody). In quality the ve negative control used humanitariannet monoclonal antibody R3h (isotype IgG1; specific receptor for epidermal growth factor (human). The results (figure 4) was compared with cells not treated with the exposure (without processing). The study was performed using flow cytofluorimetry using FACScan analysis of samples.

Brief description of drawings

Figure 1:

The figure 1 presents the expression of CD6 defined using gumanitarnogo monoclonal antibody T1h, in mononuclear cells of peripheral blood of patients with b-cell chronic lymphocytic leukemia. Potential specific to the tumor antigen.

Figure 2:

The figure 2 shows the expression of CD6 defined using gumanitarnogo monoclonal antibody T1h, in bone marrow cells of patients with b-cell chronic lymphocytic leukemia. Potential specific to the tumor antigen.

Figure 3:

The figure 3 presents the expression of CD6 defined using gumanitarnogo monoclonal antibody T1h, in mononuclear cells of peripheral blood of patients with b-cell chronic lymphocytic leukemia who lack expression of the CD5 molecule.

Figure 4:

The figure 4 shows the induction of apoptotic cell death of malignant cells of patients with b-cell chronic lymphocytic leukemia with OSU gumanitarnogo monoclonal antibody T1h.

1. Pharmaceutical composition suitable for the diagnosis of b-cell chronic lymphocytic leukemia, where the composition comprises humanitariannet monoclonal antibody that recognizes differencirovany antigen CD6 of cells capable of inducing apoptosis in tumor cells, and a suitable filler, in which humanitariannet monoclonal antibody to CD6 is a humanized antibody T1h from secreting hybridoma IOR-T1A with Depository no ESAS 96112640.

2. The pharmaceutical composition according to claim 1, in which a suitable filler is a physiological buffer solution.

3. Pharmaceutical composition suitable for the treatment of b-cell chronic lymphocytic leukemia, where the composition comprises humanitariannet monoclonal antibody that recognizes differencirovany antigen CD6 of cells capable of inducing apoptosis in tumor cells, and a suitable filler, in which humanitariannet monoclonal antibody to CD6 is a humanized antibody T1h from secreting hybridoma IOR-T1A with Depository no ESAS 96112640.

4. The pharmaceutical composition according to claim 3, containing humanitariannet antibody T1h, which causes apoptosis of malignant b-lymphocytes, separately or in conjunction with any of the agents selected from the group of chemotherapeutic agents, monoclonal antibodies is, specific to surface molecules of malignant lymphocytes.

5. The pharmaceutical composition according to claim 4, in which the chemotherapeutic agent is fludarabine phosphate.

6. The pharmaceutical composition according to claim 4, in which a monoclonal antibody specific to surface molecules of malignant lymphocytes, is anti-D20 antibody.

7. The pharmaceutical composition according to claim 3, in which a suitable filler is a physiological buffer solution.

8. The pharmaceutical composition according p-7, where the composition has a therapeutic effect within the dosages of anti-D6 monoclonal antibodies from 0.05 to 1 mg/kg body weight.

9. Diagnostic reagent containing humanitariannet antibody T1h from secreting hybridoma IOR-T1A with Depository no ESAS 96112640, for use in the diagnosis of b-cell chronic lymphocytic leukemia.

10. Application gumanitarnogo antibody T1h from secreting hybridoma IOR-T1A with Depository no ESAS 96112640 for the diagnosis of b-cell chronic lymphocytic leukemia.

11. Application gumanitarnogo antibody T1h from secreting hybridoma IOR-T1A with Depository no ESAS 96112640 for the treatment of b-cell chronic lymphocytic leukemia.



 

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