Immunogenic composition based on tlp

 

(57) Abstract:

The present invention relates to medicine, in particular to cancer, and is associated with immunogenic composition based on TLP. The invention includes at least one protein of the TLP (Tumor Liberated Particles or particles that are released by the tumor or its fragment, in particular, to compositions in which these fragments may include at least one of the claimed peptides are given 3 sequences intended for the treatment of cancer, in particular, the treatment of non-small cell lung cancer and cancer of the genitourinary system in mammals. The advantage of the invention is to develop new therapeutic agents that are able to direct the immune response against the tumour cells. 13 C. and 8 C.p. f-crystals, 5 tab., 2 Il.

Background of the invention

The present invention relates to the field of immunotherapy of malignant diseases.

Prior art

Cancer science has repeatedly directed its efforts toward problems immunotherapy of malignant diseases in search of a therapeutically-effective solution capable of regulation immunoanalytical reaction, which aapologise, as you can see from earlier publications (I. S. Irlin, Virolody 1967, 32:725; E. Klen et al., Nat. Cancer Inst. 1964, 32:547; G. J. Pasternak J. Nat. Cancer Inst., 1965, 34:71, S. S. Tevethia et al., Immunol, 1968, 100:358; R. Nishioka et al., Monograph 1968, 7: 49), observation, discovered the phenomenon of stimulating specific cellular and humoral antibodies antigens of neoplastic cells in animals and humans.

Immunological manipulation, as well as attempts to develop immunotherapy approaches, reflected the level of knowledge achieved in the field of fisiopatologia cancer, as well as knowledge about the immune system of the host; however, these attempts have been very difficult due to the lack of suitable immunogenic agents or in connection with numerous challenges associated with the prevalence of blockade of cellular immunity that occurs in cancer patients.

In fact, initially developed in two directions:

a) a nonspecific activation of the host immune system in relation of enhancing oncolytic reactions (immunoadjuvant);

b) specific activation of the host immune system in relation to the electoral stimulate the production of antibodies with oncolytic effect.

A specific advantage of the approach is the possibility of more specific and more eevich cells under the action of the immune system mediated by direct cytotoxic mechanisms (NK-cells), and more complex, but more specific and more effective cytotoxic mechanisms, including recognition of antigens on the surface of tumor cells and the presence of antibodies (ADCC-cytotoxicity, predominantly mediated by the cells of the CD8+). The functioning of the immune system is always associated with a complex network of cytokines, modulating the activity of effector cells involved in a "cascade" mechanism by inhibition or stimulation.

Still undertakings in the field of immunotherapy were focused on the overall amplification of nonspecific immune response mediated by cells, either by expanding (hormones of the thymus, IL-2 (interleukin-2) or activation (BCG, PPD (purified protein derivative), IFN (interferon), IL-2, NF factors, tumor necrosis), and so on) populations of lymphocytes. The solver was carried out at the level of the effects of each of these substances (IL-2, IFN, and so on), but to identify the individual effect of each of them had much to increase the dose of a test substance that would inevitably lead to significant toxic effects and too costly (Mule JJ, Shu, S., Swarz SL., Rosenberg SA. , Science, 225:1478, 1984; Hadden JW., in "Advances inimmunomodulation", 1988, Ed. B. Bizzini and E. Bonmasser, Pitagora Roma Press).

The previous and the doses interferon-alpha or interleukin-2) can cause a synergistic effect on the cytotoxic activity of lymphocytes (natural killer cells, lymphokineactivated killer cells, cytotoxic lymphocytes) against tumor cells of a particular type in vitro (Favalli, C., Mastino, A., Jezzi, T., Grelli, S., Goldestein, A. L. and Garaci, E. , Int. J. Immunopharmacol., 11, 443-450, 1989; Mastino, A., Favalli, C., Grelli, S., Innocenti, F. and Garaci, E., Cell. Immunol., 133, 196-205, 1991).

However, the increase of the cytotoxic activity did not meet adequate antitumor response in vivo, nor increase the degree of survival of cells (Favalli, C. , Mastino, A., Grelli, S., Pica, F., Rasi, G., Garaci, E. , Combination Therapits, pp. 275-280 Ed. by A. Goldstein and E. Garaci, Plenum Press, NY, 1992; Mastino, A., Favalli, C., Grelli, S., Rasi, G. , Pica, F., Goldestein, A. L. and Garaci, E., Int. J. Cancer. 50, 493-499, 1992; Garaci, E., Pica, F., Mastino, A., Palamara, A. T., Belardelli, F., and Favalli, C., J. Immunother., 13, 7-17, 1993).

Conversely, when combined immunotherapy was preceded by chemotherapy (even when using unspectacular doses), observed complete recovery from the tumor (Mastino, A., Favalli, C., Grelli, S., Rasi, G., Pica, F., Goldestein, A. L. and Garaci, E., Int. J. Cancer. 50, 493-499, 1992; Garaci, E., Pica, F., Mastino, A., Palamara, A. T., Belardelli, F., and Favalli, C., J. Immunother., 13, 7-17, 1993; Rasi, G., Sinibaldi-Vallebona P., Favalli, C., Pierimarchi, P., et al., 2nd International Symposium on Combination Therapies, documents, 1-3 May, 1992 - Santa Tecla CT).

Gave monogenea neoplasia and that the main purpose of chemotherapy (used in inefficient quantities) is the transformation of neoplasia in immunogenic tumor (Rasi, G., Sinibaldi-Vallebona P., Favalli, C., Pierimarchi, P., et al., 2nd International Symposium on Combination Therapies, documents, 1-3 May, 1992 - Santa Tecla CT; Sinibaldi-Vallebona P., Pierimarchi, P., Ravagnan, G. P., Rasi, G., Third International Symposium on Combination Therapies, documents, 29-31 October, 1993, Houston, Texas; Sinibaldi-Vallebona P., Pierimarchi, P., Lucertini, L. Ravagnan, G. P., Rasi, G., Fourth International Symposium on Combination Therapies, 14-17 June, 1994, documents, p. 105; Rasi, G., Siltcchia, G. F., Sinibaldi-Vallebona P. , Pierimarchi, P., Sivilia, M., Tremiterra, S., Garaci, E., Int. J. Cancer. 57, 701-705, 1994).

Currently, this strategy proved to be effective also in respect of solid human tumors (Rasi, G., Favalli, C., Terzoli, E., Izzo, F., Sinibaldi-Vallebona P., Pierimarchi, P., P., Sivilia, M., Garaci, E., Biomedicine &pharmacotherapy, 47-292, 1993).

So, in experimental models we have been able to demonstrate no effect or little effect of each of the effects separately (chemotherapy, hormones of the thymus, cytokines), no antitumor effect even with a significant increase in cellular immune activity and lysis of tumor cells only in the presence of specific modulated by immune system cells, cytotoxic activity against neoplastic cells. Based on these studies it can be concluded that the role of antigen is crucial in terms of induction of a cytotoxic immune response with znacie response are very important as the ability of antigens to induce and modulate the immune response, and knowledge about the immunological relationships within each system target/effector" (neoplastic cells/lymphocytes).

Complexes TLP are protein complexes that are present in tumor cells. Among these TLP-proteins described protein with a molecular mass of 240 kilodaltons (Tarro G., Oncology 40, 248-253, 1983). TLP isolated from tumor tissues, as described in European patent 0 283 443. In the European patent 649 433 identified protein TLP received from cancer of the lung. In the Italian patent application RM96A 000 496 shown that the TLP received from cancers of the urogenital system, contains peptides that differ in sequence from the previously identified TLP. The protein fragments of the TLP can be obtained and also synthetically using known methods.

In 1993 identified a new tumor antigen with a molecular mass of 240 kilodaltons extracted from neoplastic tissue non-small cell lung cancer (NSCLC), and named TLP (Tumor Liberated Particles, or particles that are released by the tumor). In laboratories, Cold Spring Harbor, new York, USA) has already undertaken a structural analysis of the lung cancer antigen extracted antigen with a molecular massappeal, CSH 275) and the resulting antibody (CSH 419).

Using the methods of Western blotting after thus and immunohistochemistry (R. A. P.) showed that this antibody (CSH419) are able to identify the sequence of the antigen in homogenates obtained from all protestirovannyx today neoplastic tissues (NSCLC).

Peptide declared in the sequence Seq. ID N1), as well as others derived from antigenic region TLP were described and protected in the European patent 649 433, in accordance with the International application WO-A-001 458.

Summary of the invention

The present invention relates to a pharmaceutical composition comprising at least one protein from a complex TLP (Tumor Liberated Particles, or particles that are released by the tumor) for therapeutic and immunogenic use.

The author of the present invention has at this moment of complete and accurate documentation on clinical use of TLP as an immuno-modulating agent is capable of stimulating the immune response of the host) used to struggle with neoplastic pathologies (immunotherapy), and to prevent the occurrence of cancer (vaccination).

On the basis of experience, became the first TLP, could be used for therapeutic purposes should meet the following main conditions:

1) the presence of antigen on the surface of tumor cells;

2) the ability to pharmacologically induce or increase the expression of antigen on the cell surface;

3) the ability of the antigen to stimulate the lymphocytes with specific antitumor activity (the ability to blastogenesis and activity of cytotoxic thymus-dependent lymphocytes);

4) the presence of TLP in serum (indicates a possible correlation between serum levels and expression of antigen on the cell surface) and the absence of systems (kidney or other urinary system, such as the skin or gut), providing a rapid clearance from the blood.

When all these four conditions apply (TLP) is shown as a therapeutic agent, and as a vaccine, due to its strictly proven immunogenicity.

The object of the present invention, therefore, is immunogenic composition and its use as a vaccine and as a medicinal product, respectively, in the cases of prevention and treatment of cancer, particularly lung cancer and cancers of makepolo the first fragment.

Immunogenic fragments of the protein TLP predominantly contain at least one of the following amino acid sequence (Seq):

ArgThrAsnLysGluAlaSerIle (Seq ID No. 1; WO-A-001458).

GlySerAlaXPheThrAsn (Seq ID N2; WO-A-001458).

AsnGlnArgAsnArgAsp (Seq ID N3; WO-A-001458).

Alternatively, the immunogenic composition according to the invention includes an immunogenic fragment comprising the following amino acid sequence:

GlyProProGluValGlnAsnAlaAsn (Seq ID N1; Italian patent application RM96A000496).

A brief description of the drawings.

In Fig.1 shows the result of the experiment carried out on neoplastic cells derived from explants of non-small cell lung cancer, a method of running cytofluorimetry (Facscan-BD).

On the right histogram peak indicates the binding of anti-TLP-antibodies with the corresponding antigen on the cell surface.

In Fig. 2 shows the result of the same experiment as in Fig.1, performed on the same cells from the same explants treated preimmune serum as a negative control.

The peak shown in Fig.1, including the values of fluorescence between 103and 104and indicating the binding of the antigen with anti-L cells.

Antigen TLP was studied using flow cytofluorimetry (Facscan-BD) on the surface of fresh neoplastic cells derived from small cell lung cancer (NSCLC).

Labeled cells were made using a monoclonal anti-L antibodies (CSH # 419, Cold Spring Harbor Lab. NY, USA) conjugated (second stage) with a secondary goat antibodies against IgG-RPE rabbit.

The binding specificity TLP with anti-TLP was evaluated using a non-specific antisera or preimmune serum. The specificity of cell phenotype was assessed by marking the cells stable tumor lines or fresh cells from neoplastic tissues (except NSCLC) antibodies against TLP.

The possibility of drug induction or increased expression of the antigen on the cell surface.

Cells were processionary fresh and after preparation of primary cultures (complete culture medium RPMI 1640 with the addition of 10% bovine fetal serum).

Were also studied, depending on variations in the TLP, and other possible modifications of the phenotype (IL-2 HPP (interleukine receptors), HLA-Dr (antigen of human leukocytes), CD16 (sub-populations of lymphocytes), and so on), induced by processing one or not is whether when surgery patients with non-small cell lung cancer; 24 hours after seeding deleted fibroblasts, and the desired cells resuspendable for immunohistochemical and cytofluorimetrically research; in short: CSH419-anticigarette labeled with PE-conjugated antibodies against rabbit IgG, incubated with cells. To obtain negative controls used preimmune serum of the rabbit, and for a positive control for immunohistochemical analysis) - method serial dilutions up to 500 times; observed no reactions at colouring or conjugation with C and two cell lines of melanoma in women. TLP was found in 75% of all the studied cell lines NCLC.

Preliminary research using confocal microscopy revealed cytoplasmic and membrane localization TLP in tumor cells. Showed that the expression of antigen TLP can enhance or induce in vitro chemotherapeutic effects: primary cell culture NSCLC TLP becomes positive after exposure to CIS-platinum or etoposide.

Freezing TLP in the culture supernatant controlled using test EL ISA.

Simultaneously, we conducted an experiment consisting in assigning CIS-platinum and etoposide serum negatively antigen to stimulate the lymphocytes with specific antitumor activity (blastolene ability and activity of cytotoxic thymus-dependent lymphocytes).

Lymphocytes obtained from peripheral blood of patients who had explanitory tumor cells (autologous cells), were analyzed by the method of flow cytofluorimetry (the phenotypes of CD4/CD25, CD8/CD25, CD56-16-3/CD25) before and after treatment TLP in vitro, individually or in conjunction with chemotherapy and/or cytokines.

Cytotoxic activity of autologous lymphocytes (treated and untreated) were determined after 4 hours on release of the51SG, using tumor cells derived from explants of tumors of the same patient as the target cells.

Lymphocytes of healthy donors and patients suffering from other neoplastic pathologies, were used as effectors against neoplastic cell lines (sensitive and resistant targets natural killer cells) as a control to establish the specific nature of tumor lysis.

The presence of TLP in serum

To establish the presence of TLP and in serum of patients with non-small cell lung cancer, and in the serum of patients suffering from other diseases, neoplastic diseases, non-non-small cell lung cancer; not neoplastic pathology of the lungs), and in the control savor the P on the surface of tumor cells.

The presence of antigen TLP on the cell surface of non-small cell lung cancer has been shown using the described method. The data shown in Fig. 1 are an example of positive tumor. You will notice that processing preimmune serum does not lead to the formation of the signal, while the label anti-L#419 identifies TLP-positive cell population.

The ability to drug induction or increased expression of antigen on the cell surface.

Two TLP-positive tumor cell population treated within 48 hours of CIS-platinum and etoposide (10 μg/ml):

2 TLP-negative cell population became TLP-positive after treatment with etoposide;

1 TLP-negative cell population became TLP-positive after treatment with CIS-platinum;

TLP-positive cell population remained TLP-positive after treatment with CIS-platinum and etoposide.

The results of the test EL ISA used to check for a (possible) freezing TLP in cell supernatant cell cultures, comparable to the data presented in tables II-IV on the availability of TLP in the serum of patients with non-small cell lung cancer.

The same chemotherapeutic protosenia TLP test EL ISA.

The ability of the antigen to stimulate the lymphocytes with specific antitumor activity (the ability to blastogenesis and activity of cytotoxic thymus-dependent lymphocytes).

Treatment in vitro lymphocytes of patients with non-small cell lung cancer using TLP causes blast activity, in particular against certain phenotypes of activated cells that Express high-affinity receptor for interleukin-2 (CD3+/CD25+), natural killer cells (NK-cells, CD56+/CD16+/CD3); activated cytotoxic cells CD25+/CD8+ (table 1).

Processing lipocytes using TLP also able to induce the lytic activity of NK-cells (natural killer cells, target cells C) and cytotoxic thymus-dependent lymphocytes (in relation to their own cells of the tumor). The activity of natural killer cells also depends on the dose, as observed for CD8+CD25+) cells, and correlates closely with the number of these cells. This observation, together with the absence of lytic activity (either spontaneous or induced TLP) LAK-type (activated lymphokines killer cells targeted NK-cells, Daudi cells) indicates the specific nature of the activation.

Shows the ZG cells, originating from non-small cell lung cancer.

The presence of TLP in serum

The results, obtained by the method of EL ISA with the analytical scheme "sandwich", are given in tables 2-5.

Moreover, measurement of the levels of TLP in patients with non-small cell lung cancer results in 56% (see table II); this result should be compared with 35-40%, obtained by applying the "cyfra", another marker proposed for lung cancer. Moreover, data on the binding specificity give 100% for TLP against 60-70% for "cyfra".

Similarly, the synthetic polypeptide (Seq. ID N1; W-A-001458) demonstrates exceptional immunogenic capabilities, the study identified specific stimulation of cytotoxic CD8 lymphocytes only in patients with non-small cell lung cancer.

Experiments conducted on mice "skid", showed that vaccination with the sequence Seq. ID N1, W-A-001 458 protects animals from growth from 1.800.000 up to 6,000,000 the tumor cells.

Similar results were obtained for other claimed peptides.

The final conclusion

The results of the studies conducted on TLP derived peptides and peptide GlyProProGluValGlnAsnAlaAsn obtained from analogicopoesie action directed against them.

In fact, the presence of TLP on the cell surface of non-small cell lung cancer and its ability to stimulate specific antitumor activity of lymphocytes (the ability to blastogenesis and activity of cytotoxic thymus-dependent lymphocytes) clearly demonstrate the immunogenicity of this protein. Similar results were obtained for peptides with sequences Seq. ID N1 (W-A-001 458) and the other two peptides Seq. ID N2 and Seq. ID N3, also derived from the antigenic region of the protein TLP.

The value and significance of this approach is confirmed also by the fact of detection of the TLP in the serum of patients with non-small cell lung cancer, indicating a direct link between the presence of tumor and the level of TLP in the blood. Therefore, therapeutic use of TLP or peptides can be very useful and promising, because, as it turned out, their immunogenetic active sequence has no homology among other human proteins.

The purpose of TLP or derivative peptides, therefore, should be more specific and effective than nonspecific activation of the immune system of the host, and less destructive than assigning some of the step TLP in connection with the discovery of the ability of chemotherapeutic drugs to induce the production of antigen in cell culture, and in patients with non-small cell lung cancer, whose source is not the TLP in the serum.

This is a direct consequence of the experimental results obtained by applying the individual or combination of chemotherapeutic agents. As shown previously, in fact, the use of etoposide and CIS-platinum in the cultures of tumor cells stimulates production TLP, a comparable level to that recorded in patients with non-small cell lung cancer with positive serum reaction to the antigen, and the appointment of the same chemotherapy drugs to patients with initial TLP-negative serum response (EL ISA) makes these patients intensively TLP-positive after two cycles of chemotherapy.

J peptide GlyProProGluValGlnAsnAlaAsn derived from protein, similar TLP extracted from infected tissues in cancer of the genitourinary system, studies have found similar immunotherapy effect for all cancers of the genitourinary system.

All these data indicate both therapeutic and preventive (vaccination) the use of these peptide molecules, blah is s, suitable both for humans and for animals. The same applies to the peptides described in the experimental part.

In fact, the immune response may be caused by how to combat the growth and expansion of the tumor (application effectively also in the case of metastasis, as was previously shown), and to protect healthy people from the possible development of the disease. This, in particular, confirm the data previously obtained in mice "skid".

1. Immunogenic composition comprising at least one protein obtained from TLP, or at least one immunogenic fragment that includes at least one amino acid sequence selected from the group comprising sequence

ArgThrAsnLysGluAlaSerlle

GlySerAlaXPheThrAsn

AsnGlnArgAsnArgAsp

or an alternative sequence

GlyProProGluValGlnAsnAlaAsn

in pharmaceutically effective and acceptable dose.

2. Protein TLP or at least its immunogenic fragment that includes at least one of the amino acid sequences referred to in paragraph 1, for the manufacture of a vaccine for the prevention of cancer in mammals.

Kislotnyh sequences specified in paragraph 1, for the manufacture of immunogenic drugs for active specific immunotherapy of cancer in mammals.

4. Protein TLP under item 2 or 3, where the specified cancer is a lung cancer.

5. Protein TLP under item 4, where the specified cancer is a non-small cell lung cancer (NSCLC).

6. Protein TLP under item 2 or 3, where the specified cancer is a cancer of the genitourinary system.

7. Immunogenic fragment TLP containing at least one amino acid sequence selected from the group comprising sequence

ArgThrAsnLysGluAlaSerlle

GlySerAlaXPheThrAsn

AsnGlnArgAsnArgAsp

for the manufacture of a vaccine for the prevention of lung cancer in a mammal, is effective to generate a specified mammalian immune response against the specified lung cancer.

8. Immunogenic fragment TLP containing at least one amino acid sequence selected from the group comprising sequence

ArgThrAsnLysGluAlaSerlle

GlySerAlaXPheThrAsn

AsnGlnArgAsnArgAsp

for production of immunogenic drugs for active sparago active specific immune response against the specified lung cancer.

9. Immunogenic fragment of TLP under item 7 or 8, wherein the specified cell lung cancer is a non-small cell lung cancer (NSCLC).

10. Immunogenic fragment TLP containing the following amino acid sequence:

GlyProProGluValGlnAsnAlaAsn

for the manufacture of a vaccine for the prevention of cancer of the genitourinary system in mammals.

11. Immunogenic fragment TLP containing the following amino acid sequence:

GlyProProGluValGlnAsnAlaAsn

for production of immunogenic drugs for active specific immunotherapy of cancer of the urogenital system of a mammal, is effective to generate a specified mammal active specific immune response against the specified cancer.

12. The method of immunization of a mammal against cancer, including the introduction of a given mammal amount of protein TLP or at least one immunogenic fragment that includes at least one of the amino acid sequences referred to in paragraph 1, a pharmaceutically effective to generate a specified mammal an immune response against a specified cancer.

13. A method of treating cancer in plecoptera, the number of protein TLP or at least one immunogenic fragment that includes at least one of the amino acid sequences referred to in paragraph 1, a pharmaceutically effective to generate a specified mammal active specific immune response against the specified cancer.

14. The method according to p. 12 or 13, wherein the specified cancer is a lung cancer.

15. The method according to p. 14, wherein the specified cancer is a non-small cell lung cancer (NSCLC).

16. The method according to p. 12 or 13, wherein the specified cancer is a cancer of the genitourinary system.

17. The method of immunization of mammals against lung cancer, which includes the introduction of the specified mammal immunogenic fragment TLP containing at least one amino acid sequence selected from the group that includes

ArgThrAsnLysGluAlaSerlle

GlySerAlaXPheThrAsn

AsnGlnArgAsnArgAsp

in the amount pharmaceutically effective to generate a specified mammal an immune response against the specified lung cancer.

18. A method of treating lung cancer in a mammal by active specific therapy, including in the e one of the amino acid sequence, selected from the group which includes

ArgThrAsnLysGluAlaSerlle

GlySerAlaXPheThrAsn

AsnGlnArgAsnArgAsp

in the amount pharmaceutically effective to generate a specified mammal active specific immune response against the specified lung cancer.

19. The method according to p. 17 or 18, wherein the specified cell lung cancer is a non-small cell lung cancer (NSCLC).

20. The method of immunization of a mammal against cancer of the urogenital system, including the introduction of the mammal immunogenic fragment TLP, which includes the following amino acid sequence:

GlyProProGluValGlnAsnAlaAsn

in amounts effective to produce the specified mammal an immune response against cancer of the genitourinary system.

21. The method of treatment of cancer genito-urinary system in a mammal by active specific therapy comprising the administration to a mammal, if required, immunogenic fragment TLP, which includes the following amino acid sequence:

GlyProProGluValGlnAsnAlaAsn

in amounts effective to produce the specified mammal active specific immune response against the specified cancer genitourinary si is

 

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