Potentiation of cytotoxicity caused by anti-cd38-immune toxin

FIELD: medicine, oncology, immunology, tumor biology.

SUBSTANCE: invention relates, in particular, to methods for enhancing cytotoxicity based on applying anti-CD38-immune toxins. Method involves carrying out the treatment of patient with pathophysiological state taken among the group including myelomas and leukosis and involves the following stages: a) administration to the indicated patient the pharmacologically effective dose of retinoid that enhances expression of antigen CD38; and b) administration to the indicated patient the pharmacologically effective dose of immune toxin acting against effectively expressing antigen CD38. Method provides enhancing the cytotoxicity with respect to above said diseases in their resistance to anti-tumor medicinal agents.

EFFECT: enhanced and valuable method for treatment.

6 cl, 1 tbl, 9 dwg, 10 ex

 

The scope of the invention

The present invention relates primarily to the field of immunology and tumor biology. More specifically, the present invention relates to processing leading to increased expression of CD38 protein in the tumor cell target, with the aim of increasing the cytotoxicity based on anti-D38-immunotoxins.

Description of the prior art

The use of monoclonal antibodies for the development of drugs or toxins in order to identify molecular structures expressed on the surface of the unwanted tumor cells, is an attractive and potentially applicable strategy. Theoretically, such a targeted approach to the treatment of malignant tumors can provide a great advantage for the selective elimination of tumor cells as well as reducing toxicity effects on normal tissues, were not targeted. However, in practice there are many problems that need to be addressed in order for therapy with immunotoxins or drugs based on antibodies could be really effective in vivo.

One potential limitation on the road to success of any targeted approach to therapy is heterogeneity in the expression of antigens of target populations of tumor cells. From this the following is the duty to regulate, what if a small number of tumor cells was negative in relation to the target antigen or Express the antigen is very weak, these cells may be able to avoid damage from disorders mediated by antibody education cytotoxic agent in these special cells. A possible way of overcoming this problem may be the identification of agents that induce high levels of cell surface target molecules in the expectation that the tumor target cells that were previously negative for the antigen will be able to Express these target molecules in excess.

All-TRANS-retinoic acid (RK) is the agent that induces a high level of expression of cell surface antigen CD38 in some myeloid and lymphoid leukemic cells. The CD38 expression induced by retinoic acid in these cells is specific, rapid, dose-dependent and highly sensitive, with 4-fold induction at such a low dose retinoic acid as 10-13M. it has Been shown that the induction of CD38 expression by retinoic acid involves RARα-receptor retinoids. The RAR receptors form heterodimers with RXR receptors; then RXR/RAR-heterodimer interacts with DNA sequences, known as response elements on linaeve acid (RARE), which are involved in transcription induced by retinoids.

CD38 is a cell surface protein with a mass of 45 kDa, which is expressed mainly on activated cells-precursors and Mature cells of the blood. He is a transmembrane glycoprotein with a short N-terminal cytoplasmic domain and a long C-terminal extracellular domain. It was shown that the extracellular domain is a bifunctional enzyme with both ADP-ribosylates and ADP-rebuildrate activity, thereby catalyzing the conversion of NAD+in cadp-ribose (cyclase) and may further hydrolyze it to ADP-ribose (hydrolase). cadp-ribose involved in the mobilization of calcium from intracellular reserves, which has the activity of second messenger that is important for cell proliferation, differentiation and apoptosis. It is believed that CD38 acts as a receptor for an unidentified ligand and acts as a cell adhesion molecule by interaction with CD31. In the experiments, in which the feature is activated CD38 produced against him by the antibodies, it was shown that CD38 is involved in the proliferation of Mature b lymphocytes and myeloid leukemia cells, protecting cells germinal center from apoptosis and suppression of growth support with the Roma cultures of precursor b-cells, and in the induction of cytokines IL-6, IGN-g, GM-CSF and IL-10. In addition, it was shown that it signals the increased levels of TNF-α, IL-1, IL-6 and transcription of IL-8 in cells of myeloid leukemia.

In the prior art lacks a method of inducing expression of a target molecule for immunotherapy of tumors and other causes of disease cells. The present invention fills this long-standing need in the art.

The invention

The present invention demonstrates the ability induced by retinoids in the expression of CD38, which serves as a target for the action of anti-D38-gelonin. The obtained results confirm the fact that the treatment of leukemia cells with retinoic acid even in very low concentrations (subnanomolar) makes these cells are extremely sensitive to immunotoxin-induced death.

The present invention relates to a method of treatment of subjects with the presence of pathophysiological conditions, including the stage of introduction of a specified subject a pharmacologically effective dose of an agent that increases the expression of cellular targets, as well as the introduction of a pharmacologically effective dose of immunotoxin acting against cellular targets.

The present invention also relates to a method of treatment of subjects with available pathophysiologic the civil state, resistant to the effects of retinoids, including the stage of introduction of a specified subject a pharmacologically effective dose of the metabolite retinoic acid and pharmacologically effective dose of immunotoxin.

Other and the following aspects, features and advantages of the present invention will become apparent in the subsequent description of the preferred in the present embodiments of the invention. These embodiments are given for the purpose of disclosing the essence of the present invention.

Brief description of figures

In order for the object, which will become apparent to the above features, advantages and objectives of the present invention, was carried out and could be thoroughly understood, a more detailed description of the present invention, briefly described above, may be given on the example of the specific embodiments that are illustrated in the attached figures. These figures form part of the description of the invention. However, it should be noted that the attached figures are only illustrative of preferred embodiments of the invention, and therefore should not be construed as limiting the scope of the claims.

The figure 1 shows a dot blot of mRNA from various human tissues, after hybridization with a labeled radioactive isotope samples D38-specific nucleic acid man. Relatively low EC is major depression CD38 mRNA was observed only in the tissues of the thymus [as an adult (E5), and fetal (G6)], while the lowest level of expression was observed in normal prostate (C7).

The figure 2 shows the effects of 5 nm all-TRANS-retinoic acid (RK) on the cytotoxicity of immunotoxins and the effects of increasing the added concentration of unconjugated anti-D38 monoclonal antibody (IB4). Point C shows the effect of one immunotoxin. The point RK+it shows the effect of 5 nm all-TRANS-retinoic acid (RK) on the cytotoxicity of immunotoxins. In the rest of the samples separately added increasing concentrations of IB4 with immunotoxin and 5 nm all-TRANS-retinoic acid (RK). After 3 days incubation, cell survival was determined using the MTS assay. The results are presented on the basis of % of surviving cells.

The figure 3 shows the effect of pre-treatment with retinoic acid on the cytotoxicity of anti-D38 immunotoxin on cell line HL-60. Cell line HL-60 were incubated overnight in the presence or in the absence of retinoic acid. After removal of the medium and twice washing of cells cell re-incubated with increasing concentrations of immunotoxin (represented as ng per well) in the presence or absence of 100-fold excess of unconjugated anti-D38 monoclonal antibody IB4. After three days to determine the survival rate of cells, the results of which before is taulani based on % of surviving cells, used MTS-analysis.

The figure 4 shows the effect of treatment or immunotoxin, or gelonida on the survival of the cell line HL-60. Cell line HL-60 were incubated for three days with increasing concentrations of immunotoxin or gelonin (presented as ng of toxin per well) in the presence or absence of 5 nm retinoic acid. Cell survival was determined using the MTS-analysis, the results of which are presented here based on the percentage of surviving cells relative to the control sample (without toxin).

The figure 5 shows the effect of increasing concentrations of all-TRANS-retinoic acid (RK) (in nm) on the survival of cells. Cell line HL-60 were incubated with or immunotoxin or with unconjugated anti-D38 monoclonal antibody in the absence or in the presence of increasing concentrations of retinoic acid (shown in nm). After three days using the MTS assay was determined cell survival, the results of which are shown on the basis of the percentage of surviving cells relative to untreated control sample.

In figure 6A and 6B shows the effect of increasing concentrations of immunotoxin (shown in ng per well) in the presence or absence of 5 nm all-TRANS-retinoic acid (RK) on the survival of cells of different cell lines, including lines Daudi, THP-1, K562 (which are resistant to induced the To the expression of CD38 and RARα -expressing variant line HL60. Cell survival was determined using the MTS analysis after three days and the results were reported based on the percentage of surviving cells relative to untreated control sample.

The figure 7 shows the immunotoxin induced death of Doxo-resistant cell line HL-60, which are resistant to adriamycin-induced death. Cells were incubated with increasing concentrations of immunotoxin (shown in ng per well) in the presence or absence of 5 nm RK. Cell survival was analyzed after three days using the MTS analysis.

The figure 8 shows the immunotoxin-mediated cell death line non-Hodgkin's lymphoma MZ(NHL), which have high initial expression D38-antigen. The cells were incubated with increasing concentrations of immunotoxin (shown in ng per well) in the presence or absence of 5 nm retinoic acid. After three days, the cell survival was analyzed using the MTS-analysis, the results of which were presented based on the percentage of surviving cells.

The figure 9 shows the immunotoxin-mediated destruction resistant to the action of retinoic acid variant cell line HL60 (HL60R). These cells are resistant to induced retinoic acid on the expression of CD38 antigen due to scatter the mutation of the gene alpha retinoic acid receptor (RARα ). The cell line was cultured with increasing concentrations of immunotoxin (ng/ml) under different conditions. After three days, the cell survival was analyzed using the MTS analysis, the results of which were expressed in optical density. The presence of retinoic acid did not stimulate immunotoxin-induced death of these cells due to their inability to Express D38-antigen in response to treatment with retinoic acid.

Detailed description of the invention

The immunotoxin is defined as any immunological molecule such as an antibody, which was conjugated with a toxin, preferably a cytotoxin.

The present invention relates to a method of treatment of a subject with the presence of pathophysiological conditions, including the stage of introduction of a specified subject a pharmacologically effective dose of an agent that increases the expression of cellular targets. This introduction is followed by the introduction of a pharmacologically effective dose of immunotoxin acting against cellular targets. Preferably administered agent selected from the group consisting of differentiation factors, cytokines, interleukin-2, tumor necrosis factor, interferon-α, interferon-γ and peptide hormones.

In one embodiment of the invention is the introduction pharmacologic the ski effective dose of a retinoid. Preferably, the retinoid induces the expression of CD38 antigen in cells. If so, enter pharmacologically effective dose of anti-D38 immunotoxin. Characteristic pathophysiological conditions that can be treated using the methods of this embodiment of the invention, include RARα-selective acute myeloid leukemia, acute promyelocytic, lymphoma and myeloma.

Characteristic metabolites retinoic acid, which can be used in methods of the present invention include all-TRANS-retinoic acid (ROK); 9-CIS retinoic acid (9-CIS RK); (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid (TNPB); (E)-4-[2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-1-propenyl]benzoic acid (3-met TNPB); and other retinoids, which can bind and activate RARα-receptor. Preferably, the retinoid is introduced in a dose of from approximately 0.1 mg/kg to about 2 mg/kg

The immunotoxin used in the methods of the present invention, specifically purposefully acts on cells expressing D38-antigen. Preferably, the immunotoxin is a monoclonal antibody that acts against D38-antigen conjugated to a toxin molecule. Although a specialist in the art can use any toxin, the preferred toxin used in these methods, is gelonin. Although a specialist in the art can use any monoclonal antibody specific to D38-antigen, to demonstrate these techniques were used here antibody IB4 or IB6. Preferably, the immunotoxin was administered in a dose of from about 0.05 mg/kg to about 2 mg/kg

Further examples are provided to illustrate various embodiments of the invention and are in no way intended to limit the present invention.

Example 1

The CD38 expression in normal tissues is limited mainly to the thymus.

Tissue specificity CD38 was investigated using labeled with radioactive labeled probe nucleic acid CD38 against commercial tissue-specific dot blot mRNA (CLONTECH). The hybridization results are presented in figure 1.

It was shown that CD38 is expressed mainly in the thymus with a significantly lower level of expression in the prostate.

Example 2

Retinoic acid (RK) enhances the cytotoxic effect of immunotoxin by enhancing the expression of CD38.

Cell line HL-60 were incubated or only with immunotoxin or in the presence of 5 nm retinoic acid (RK). To the cells, inquireys with immunotoxin and retinoic acid, was added increasing concentrations of unconjugated monoclonal antibodies is and IB4. After three days cells were analyzed on survival using the MTS assay. Briefly, about 6.5 mg/ml MTS [(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy)-2-(4-sulfophenyl)-2H-tetrazole] and 0.5 mm PMS solution (methosulfate phenazine) were mixed in a ratio of 20:1. 20 μl of the combined solution of MTS/PMS was placed in each well of 96-well plates containing samples of the tested cells. The plates were incubated for 1-4 hours at 37°C in an atmosphere of 5% CO2, after which the number of formazan produced by living cells by cell MTS recovery, measured by the magnitude of the absorption at 490 nm. The results are presented in figure 2.

Separately immunotoxin had little effect on cell survival (point C). However, incubation of cells with an immunotoxin in the presence of 5 nm retinoic acid showed a significant decrease in the survival rate of cells. Increasing the concentration of unconjugated monoclonal antibody IB4 blocked the cytotoxic effect of immunotoxin and retinoic acid. The fact that unconjugated monoclonal antibody IB4 blocked the ability of immunotoxin to kill cells, shows that the immunotoxin specifically interacts with surface marker CD38 and that the effect of retinoic acid is the increased expression of D38-antigen.

Example 3

Cell line HL-60 pre-incubated overnight in the presence or absence of 5 nm all-TRANS-retinoic acid. Cells were twice washed, and incubated with increasing concentrations of immunotoxin in the presence or in the absence of unconjugated anti-D38 monoclonal antibody IB4. After three days the cells were analyzed for survival. The results are presented in figure 3.

After inactivated with all-TRANS-retinoic acid followed by treatment with immunotoxin, which led to the deaths of more than action just immunotoxin cells. The presence of 100-fold excess of unconjugated monoclonal antibodies anti-D38 IB4 blocked immunotoxicity of immunotoxin in both cases by competition with immunotoxin for binding to the marker CD38 in the cells. These results show that all-TRANS-retinoic acid (RK) caused some changes in the cells, which likely made them more susceptible to the action of immunotoxin condition than played a direct role in the death of the target cells.

Example 4

To achieve a toxic effect on target cells gelonin should be anywhereman with anti-D38-antibodies.

Cell line HL-60 were incubated for 3 days with increasing concentrations or immunotoxin or gelonin in presets is under or in the absence of 5 nm retinoic acid. The cells are then analyzed for survival using the MTS assay. As can be seen in figure 4, separately gelonin had no toxic effect or in the presence or absence of 5 nm retinoic acid. Therefore, the toxic effect gelonin depends on anywhereman, whether it is with anti-D38 monoclonal antibody to deliver the toxin to the cell.

Example 5

Even a small amount of all-TRANS-retinoic acid (RK) lead to increased toxicity of immunotoxins.

Cell line HL-60 were incubated with or immunotoxin or with unconjugated monoclonal antibody IB4 in the presence of increasing concentrations of monoclonal antibodies. The figure 5 shows that even small amounts of all-TRANS-retinoic acid (RK) (1 nm) resulted in almost complete destruction of the target cells under the action of immunotoxin. This effect was not observed with unconjugated monoclonal antibody. This result shows that it is rather gelonin conjugated with a monoclonal antibody in the immunotoxin leads to increased levels of cell death than any effect of the antibodies.

Example 6

Retinoic acid can induce the expression of marker CD38 in some cell lines.

Cell lines Daudi, THP-1, K562 and HL60-RARα was treated with increasing concentrations of immunotoxin in the presence or the absence of 5 nm all-TRANS-retinoic acid (RK). After three days, the cell survival was investigated using MTS-analysis, the results of which are presented in figure 6. In cell lines THP-1 and HL60-RARα, all-TRANS-retinoic acid induced cell death, while cells that were grown in the absence of all-TRANS-retinoic acid, the immunotoxin is almost not affected. The cell line Daudi, which is characterized by a high initial level of expression of CD38, action immunotoxin resulted in almost complete cell death regardless of the presence of retinoic acid. On the other hand, on the cell line K562, which is resistant to induced retinoic acid on the expression of CD38, the immunotoxin had no effect regardless of the presence of retinoic acid.

Example 7

Immunotoxin induces loss of cell line HL-60, resistant to adriamycin.

Clone cell line HL-60, resistant to adriamycin-induced death, were grown either with separate immunotoxin, or in the presence of 5 nm all-TRANS-retinoic acid. After three days to assess the survival rate of cells used MTS analysis. The figure 7 presents the obtained results. The death of a certain number of cells was observed in the presence of only immunotoxin and significantly increased by adding 5 nm all-TRANS-retinoic acid.

Use the 8

Cells with high initial expression of CD38, killed in action immunotoxin regardless of the presence or absence of all-TRANS-retinoic acid (RK).

MZ, a line of non-Hodgkin lymphoma cells with high initial expression of CD38, was treated with increasing concentrations of immunotoxin in the presence or absence of 5 nm all-TRANS-retinoic acid. Add immunotoxin led to a high level of cell death regardless of the presence or absence of retinoic acid (figure 8). There is reason to believe that retinoic acid enhances the toxicity of immunotoxins by increasing the content of CD38 on other cell lines that do not have a high level of CD38 expression.

Example 9

Retinoids increase the expression of CD38 in some lines of lymphoid tumor cells.

Table 1 lists potential targets for impacts associated with anti-CD38 toxin. Some of the various lines of lymphoid tumor cells were treated with 5 nm all-TRANS-retinoic acid (RK). After that, the expression of CD38 in untreated cells compared with treated cells was measured using flow cytometry. The significant increase in CD38 expression was observed in cells in acute myeloid leukemia (AML), acute promyelocyte (OPML), lymphoma and myeloma. Growth expr the hurt CD38 varied from 2.5 to 20 times. Therefore, retinoic acid can be used for all data types of tumors to increase the vulnerability of tumor cells to the action of immunotoxin.

Example 10

Immunotoxin no effect on cells that are resistant to the action of all-TRANS-retinoic acid (RK).

Cell line HL-60 with the mutated gene RARαthat makes cells resistant to retinoic acid, was treated with immunotoxin in the presence or absence of 5 nm retinoic acid. In these cells the addition of retinoic acid did not affect the toxicity of immunotoxins. As shown in figure 9, there was little loss of cells treated with all-TRANS-retinoic acid (RK) with non-conjugated IB4 and gelonida or only gelonida. This is proof that the immunotoxin kills cells that are affected by retinoic acid retinoic acid induces the expression of CD38 target for immunotoxin.

Any patents or publications mentioned in this description of the invention, testify to the level of those skilled in the art to which this invention relates. These patents or publications are included here as a reference to the same extent as if each individual publication was specifically and individually marked for inclusion of potemski.

Specialists in this field will readily understand that the present invention is well applicable for implementation and achievement of the above results and benefits, and related. These examples along with the methods described herein, procedures, treatments, molecules, and specific compounds are currently characteristic of the preferred embodiments are illustrative and are not intended to limit the scope of the claims. Specialists in this field can change or find other applications that fall within the scope of the invention as defined by the scope of the claims.

1. A method of treating a patient pathophysiological condition is selected from the group consisting of myeloma, and drug-resistant leukemia, which includes the following stages:

an introduction to a specified patient a pharmacologically effective dose of a retinoid, which increases the expression of CD38 antigen, and

b) the introduction of a specified patient a pharmacologically effective dose of immunotoxin acting against the strongly expressed antigen CD38.

2. The method according to claim 1, where the specified drug-resistant leukemia is a resistant to adriamycin leukemia.

3. The method according to claim 1, where the specified retinoid selected from the group consisting of all-TRANS-retinoic the acid (ROK); 9-cisretinoic acid (9-CIS RK); (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid (TNPB); (E)-4-[2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-1-propenyl]benzoic acid (3-met TNPB).

4. The method according to claim 1, where the specified immunotoxin is a monoclonal antibody against CD38 antigen conjugated to a toxin molecule.

5. The method according to claim 4, where the indicated toxin is gelonida.

6. The method according to claim 4, where the monoclonal antibody is selected from the group consisting of IB4 or IB6.



 

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