ES2304264A1 - Combination therapy for treating disease - Google Patents

Abstract

Disclosed are methods for treating cancer comprising administering a xenotypic monoclonal antibody and a chemotherapeutic drug to a patient suffering from cancer. Also disclosed is a method for inducing a host immune response in a patient against a multi-epitopic in vivo tumor antigen in present in the host serum, which antigen does not elicit a host immune response, comprising administering to the patient a chemotherapeutic drug and a composition comprising a binding agent that specifically binds to a first epitope on the antigen and allowing the binding agent to form a binding agent/antigen pair, wherein a host immune response is elicited against a second epitope on the antigen.

Description

Combination therapy to treat diseases.

Background of the invention Field of the Invention

The invention relates to immunology. Plus particularly, the invention relates to the use of immunotherapy in Combination with chemotherapy.

Summary of related technique

Despite the progress that modern medicine has made made to treat cancer, it remains a concern the onset of cancer For a majority of cancers, the treatment Typical includes surgery followed by high dose chemotherapy. A majority of these patients relapse and do not respond to others chemotherapeutic treatments These patients resort then to experimental or last resort treatments.

The current experimental regimes are focused on mixing chemotherapeutic agents in an attempt of overcoming resistance problems. Most of these treatments result in serious blood toxicities such as neutropenia and thrombocytopenia. Other severe and frustrating symptoms For the patient include hair loss and nausea. The researchers are currently looking for ways to improve the system immune through less toxic means than at the same time still eliminate cancer.

Many have returned to the use of chemotherapy in conjunction with antibody treatments. Many of these have also presented toxicities similar to chemotherapy.

Therefore, there remains a need for identify new treatments that not only treat symptoms initials of a disease, but also relieve and / or prevent the reappearance of those symptoms.

Brief summary of the invention

In a first aspect, the invention provides a method of treating cancer, which comprises administering concurrently a xenotypic monoclonal antibody and a drug Chemotherapeutic to a patient suffering from cancer. Preferably This patient is a human being.

In a second aspect, the invention provides a method to treat cancer, which includes excision Surgical cancer, concurrent administration of a drug Chemotherapeutic and a xenotypic monoclonal antibody in one dose equal to or less than 2 mg.

In a third aspect, the invention provides a method to treat cancer, which includes excision Surgical cancer, administration of an antibody xenotypic monoclonal at weeks 1, 3, 5 and 9 followed by the concurrent administration of a chemotherapeutic drug and a Xenotypic monoclonal antibody at week 12 in an equal dose or less than 2 mg.

In a fourth aspect, the invention provides a method for inducing a host immune response in a patient against a multiepitopic in vivo tumor antigen, an antigen that does not elicit an effective immune response from the host, comprising concurrently administering to the patient a chemotherapeutic drug and a composition comprising a binding agent that specifically binds to a first epitope in the antigen and that allows the binding agent to form a binding agent / antigen pair, where an immune response of the host against a second epitope is elicited. in the antigen.

In a fifth aspect, the invention provides a method of treating cancer, which comprises administration concurrent of a chemotherapeutic drug, a binding agent and an antigen

In a sixth aspect, the invention provides a method for inducing a host immune response in a patient against a multiepitopic in vivo tumor antigen, an antigen that does not elicit an effective immune response from the host, comprising concurrently administering to the patient chemotherapeutic drug and a composition comprising a binding agent present in an amount of 0.1 µg to 2 mg per kg body weight of the host, and wherein the binding agent specifically binds to an epitope in the antigen and an immune response is elicited effective host against a second epitope in the antigen.

Brief description of the drawings

Figure 1 is a table showing the results of three clinical studies in which it is administered Alt-2 concurrently with a drug Chemotherapeutic

Figure 2 is a diagram showing a non-limiting embodiment of the invention.

Figure 3 is a graph showing the difference in numbers between those who responded to Ab2 (squares whites) (effective immune response) and those who did not respond to Ab2 (black squares) (ineffective immune response) over time.

Figure 4 is a table showing the different disease characteristics of those who responded to  Ab2 and those who did not respond to Ab2.

Detailed description

The present invention is based on the discovery that a combination of immunotherapy with Traditional chemotherapy and / or radiation therapy relieves and / or prevents reappearance of cancer The presence of an antibody response host anti-xenotypic in a patient It will stimulate an immune response. The inventors have exploited this discovery to develop therapeutic products that contain binding agents useful in immunotherapy and drugs chemotherapeutic or radiotherapeutic, as well as methods to use These therapeutic products. The patents and publications cited in this specification they reflect the level of knowledge in this field and are incorporated herein descriptive as a reference in its entirety to the same extent as if each one was specific and individually indicated for Be incorporated as a reference. In the case of any conflict between a cited reference and this specification, prevail This descriptive report.

Consequently, in a first aspect, the invention provides a method for treating cancer, which comprises concurrently administering a monoclonal antibody xenotypic and a chemotherapeutic drug to a patient suffering from Cancer. In some embodiments of the invention, the binding of the Xenotypic monoclonal antibody of a first single epitope exposes a second different epitope in the antigen. In some embodiments of the invention, the xenotypic monoclonal antibody, when bound to the antigen, it forms an immunogenic complex. Examples of Xenotypic monoclonal antibodies ("MAb"), includes preferably IgG1 antibodies; monoclonal antibodies chimeric ("C-MAb"); humanized antibodies; monoclonal antibodies treated by genetic engineering ("G-MAb"); antibody fragments monoclonal (including, but not limited to, "F (Ab) 2", "F (Ab)" and "Dab"); and unique chain representing the antibody reactive part monoclonal ("SC-MAb"). Binding agent It can be marked or unmarked.

When the patient is a human being, the Preferred xenotypic monoclonal antibodies include, without limitation, murine monoclonal antibodies. Antibodies particularly preferred murine monoclonal include Alt-1 (murine IgG1, which specifically binds to MUC-1; ATCC No. PTA-975; American Type Culture Collection, Manassas, VA).

The methods according to the invention are useful for provide a therapeutic advantage to patients suffering from cancer. As used herein, the term "cancer" is used to indicate a state in which a cell in a patient's body experiences uncontrolled proliferation abnormal. The abnormal cell can proliferate to form a tumor solid, or it can proliferate to form a multitude of cells (by example, leukemia). It should be noted that since cancer is the uncontrolled and abnormal proliferation of a patient's cells, the term does not cover the normal proliferation of a cell, such as a stem cell or a sperm cell.

By the expression "treat a patient who suffers from cancer "means that the patient's symptoms they are relieved following the treatment according to the invention. In a non-limiting example, a patient suffering from a highly cancer metastatic (for example, breast cancer), when treated, does not an additional metastasis occurs, or is reduced in number compared to a patient who does not receive treatment. In another non-limiting example, when a patient is treated, the solid cancer of the patient is reduced in size or not increases in size compared to a patient who does not receive the treatment. Still, in another non-limiting example, the number of cancer cells (for example, leukemia cells) in a treated patient does not increase or is reduced compared to the number of cancer cells in a patient who does not receive the treatment. In preferred embodiments, the patient is a being. human.

It will be appreciated that a "patient who suffers cancer "of the invention can express the mutant protein and not Be still symptomatic for the disease. For example, when the cancer is a colon cancer (which is associated with protein mutant K-ras), a patient with a mutant protein  K-ras in some colon cells is a patient according to the invention even though that patient is not yet symptomatic for colon cancer. "Associated with a protein mutant "means that the signs or symptoms of the disease in a majority of patients are present when the mutant protein is present in the patient's body, but in which the signals or disease symptoms are absent when protein mutant is absent from the patient's body. "Signs or symptoms of the disease "are the manifestations or indications Clinically recognized disease.

Preferably, the therapeutic compositions of the invention further comprise a vehicle pharmaceutically acceptable. By "pharmaceutically vehicle acceptable "means a vehicle that is physiologically acceptable to the patient administered. An example of a vehicle Pharmaceutically acceptable is physiological saline. Others pharmaceutically acceptable vehicles and their formulations are fine known and generally described, for example, in Remington's Pharmaceutical Sciences (18 th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, PA, 1990).

"Administration", as used in the Present specification means providing the composition to the patient in a way that results in the composition being The inside of the patient's body. This administration can be by any means that includes, but are not limited to, the parenteral, subcutaneous, percutaneous, intravenous, intra-arterial, intraperitoneal and intramuscular.

In certain embodiments of the invention, the Used chemotherapeutic drug is commercially available. Some non-limiting examples include carboplatin, cisplatin, docetaxel, paclitaxel, doxorubicin injection HC1-liposomes, topotecan hydrochloride, gemcitabine, cyclophosphamide and etoposide or any combination of the same.

In preferred embodiments, the drug Chemotherapeutic is administered one week before or after murine monoclonal antibody.

In a second aspect, the invention provides a method of treating cancer comprising surgery, administration of a chemotherapeutic drug, administration of an antibody xenotypic monoclonal in a dose equal to or less than 2 mg provided by intravenous infusion for 20 minutes during weeks 1, 3, 5, 9 and then every 8 weeks, followed by the administration of a chemotherapeutic drug within 5 days of binding agent administration.

In certain non-limiting embodiments of the invention, the xenotypic agent, for example, Alt-2 it is administered in the form of a dose of 2 mg dissolved in 50 ml of saline solution and administered slowly by infusion, preferably for about 20 minutes. If it occurs an allergic reaction or another that may limit the completion of the dose, then a lower dose can be used at that time or with subsequent treatments, so that the interval of Expected dose will be 1-2 mg per treatment. Usually a previous medication with 25 to 50 mg is administered of oral or intravenous diphenhydramine to decrease the risk of allergic reaction to protein. The scheme used to Alt-2 and chemotherapy combined comprise administer Alt-2 at the previous dose in weeks 1, 3, 5, 7 and 9 and chemotherapy given with Alt-2 weeks 12 to 26. The Alt-2 Can be started after recovery from any surgery It needs to be done prior to chemotherapy, and it can be continued until and during the treatment period of chemotherapy. Chemotherapy can be provided in cycles 3-4 weeks or other schemes, according to the Optional physician and common clinical practice. Chemotherapy can continue up to six cycles following the administration of the xenotypic antibody every twelve weeks until two years.

In a third aspect, the invention provides a method to treat cancer, which includes surgery followed in seven days after administration of a monoclonal antibody xenotypic in a dose equal to or less than 2 mg provided by intravenous infusion over 20 minutes during the weeks 1, 3, 5, 9 and then every 8 weeks with the administration concurrent of a chemotherapeutic drug at week 3 and later.

In another non-limiting example, the antibody murine is administered in week 1 after completing the standard surgery, but when the chemotherapy. The murine antibody is administered in a dose. equal to or less than 2 mg through an intravenous infusion of 20 minutes followed by a second treatment and administration Concurrent of a chemotherapeutic drug in 6 weeks and more there. "Concurrent administration" means the administration in a relatively short period of time of one Regarding another. Preferably, this period of time is shorter. than 2 weeks, more preferably less than 7 days, most preferably less than 1 day and could even be administered simultaneously.

Survival times without progress Expected can be measured in months to years, depending on prognostic factors that include the number of relapses, phase of The disease and other factors. Overall survival is measured. also in months to years. In the case of ovarian cancer, the addition of the xenotypic monoclonal antibody, Alt-2, is expected to increase the time of recurrence or progress, and may also prolong the time of survival. Any improvement of 2 months or more is usually considered as clinically significant.

In a fourth aspect, the invention provides a method for inducing a host immune response in a patient against a multi-epitopic in vivo tumor antigen present in the host serum, an antigen that does not elicit an host immune response, which comprises administering to the patient. a chemotherapeutic drug and a combination comprising a binding agent that specifically binds to a first epitope in the antigen and that allows the binding agent to form a binding agent / antigen pair, where an immune response from the host is elicited. against a second epitope in the antigen. Examples of multi-epitope antigens are described and incorporated by reference in the present specification in the publications Nicodemus CF et al , Expert Rev. Vaccines 1 (1), 34-48 (2002), Qi et al , Hybridoma and Hybridomics 20,313 -323 (2001), and Berlyn et al ., Clin. Immunol 101, 276-283, (2001).

A "binding agent", as used in the This specification refers to a member of a pair of union, which includes an immune pair, for example, a remainder of binding that is capable of binding to an antigen, preferably a single epitope expressed in the antigen, as a tumor antigen predetermined. In some embodiments of the invention, the joint of a first single epitope exposes a second different epitope in the antigen. In some embodiments of the invention, the agent binding, when bound to the antigen, forms an immunogenic complex. Examples of binding agents include, but are not limited to: antibodies, monoclonal antibodies ("MAb"), preferably IgG1 antibodies; chimeric monoclonal antibodies ("C-MAb"); humanized antibodies; antibodies monoclonal treated by genetic engineering ("G-MAb"); antibody fragments monoclonal (including, but not limited to, "F (Ab) 2", "F (Ab)" and "Dab"); unique chains that represent the antibody reactive part monoclonal ("SC-MAb"); peptide binding antigens; tumor binding peptides; a protein, which includes receptor proteins; peptides; polypeptides; glycoproteins; lipoproteins, or the like, for example, growth factors; lymphokines and cytokines; enzymes, immune modulators; hormones, for example, somatostatin; any of the above joined to a molecule that mediates an effector function; and emulators or Fragments of any of the above. Binding agent It can be marked or unmarked.

Preferred binding agents of the invention They are monoclonal antibodies. When the patient is a human being, these xenotypic monoclonal antibodies include, without limitation, murine monoclonal antibodies. Monoclonal antibodies Particularly preferred murines include Alt-1 (Murine IgG1, specifically binds to MUC-1; ATCC No. PTA-975; American Type Culture Collection, Manassas, VA), Alt-2 (OvaRex®) MAb B43.13, IgG1 murino specifically binds to CA125; ATCC No. PTA-1883), Alt3 (murine IgG3, binds specifically to CA19.9; ATCC No. PTA-2691), Alt-4 (murine IgM, specifically binds to CA19.9; ATCC No. PTA-2692), Alt-5 (IgG1 murine, specifically binds to CA19.9; ATCC No. PTA-2690); and Alt-6 (murine IgG1, it specifically binds prostate specific antigen (PSA); ATCC No. HB-12526).

A "multi-epitope in vivo tumor antigen" is an antigen that has multiple epitopes on its surface. Some non-limiting examples of these antigens include CA125, MUC-1, PSA, CA19.9 and TAG-72.

"Induce an immune response of host "means that the patient experiences relief or reduction of disease signs or symptoms, and includes specifically, without limitation, prolongation and survival. In certain preferred embodiments of the methods according to the invention, a CD8 + IFN-? that produces T cells is activated to induce an immune response of T lymphocytes cytotoxic (CTL) in the patient administered with the antibody murine monoclonal. In certain embodiments of the methods according to the invention, a CD4 + IFN-? that produces cells T is activated to induce an immune response of T cells helper in the patient administered with the composition. These CD4 + IFN-γ activated producing T cells (it is ie, helper T cells) provide immune support necessary (for example, by releasing cytokines) to induce and maintain not only CTL, but also a response humoral immune mediated by B cells. Therefore, in certain embodiments of the methods according to the invention, a response humoral antigen is activated in the patient administered with the composition.

The activation of T cells that produce CD8 + and / or CD4 + IFN-? Means to cause T cells that they have the ability to produce IFN-? for actually produce IFN-?, or to increase its IFN-γ production. "CTL induction" means to cause potentially cytotoxic T lymphocytes to exhibit antigen specific cytotoxicity. "Cytotoxicity antigen specific "means a cytotoxicity against a cell that presents an antigen that is associated with the antigen associated with cancer that is greater than an antigen that is not associated with cancer. "Cytotoxicity" refers to the ability of cytotoxic T lymphocyte to destroy the target cell. Preferably, this cytotoxicity specific for the antigen is at least 3 times, more preferably 10 times greater, more preferably more than 100 times greater than cytotoxicity against a cell that does not have the antigen not associated with the Cancer.

In a fifth aspect, the invention includes a method of treating cancer, which comprises administration concurrent of a chemotherapeutic drug, a binding agent and an antigen

In a sixth aspect, the invention provides a method for inducing a host immune response in a patient against a multi-epitopic in vivo tumor antigen, an antigen that does not elicit an effective immune response from the host, comprising concurrently administering to the patient a chemotherapeutic drug and a composition comprising a binding agent present in an amount of 0.1 µg to 2 mg per kg body weight of the host, and wherein the binding agent specifically binds to an epitope in the antigen and an immune response is elicited effective host against a second epitope in the antigen.

Example I Clinical and immunological results of patients with cancer recurrent epithelial ovaries (EOC) treated with B43.13 and Chemotherapy (Ct) - provisional immunology and clinical results of the OVA-Gy-12 study

Patients with recurrence after therapy with platinum and a first surgery were registered if they were Candidates for a second surgery and continued chemotherapy. Alt-2 was administered by 20 minute infusion at weeks 1, 3, 5 and 9 before the start of chemotherapy, and then an option to continue every 8 weeks x 2 doses concurrent with chemotherapy at weeks 12 and 26. The humoral immune responses including HAMA, Ab2 and antibody anti-CA125 were assessed at baseline and serially. Using an ELISPOT trial of gamma-interferon, the T cell responses were evaluated for activation using Alt-2, CA125 or autologous tumor.

20 patients were registered; monitoring Median was 6 months varying in the interval up to 2 years. He Alt-2 was well tolerated and produced no reactions serious adverse effects related to the drug. In 14 of 19 patients evaluable (71%), humoral responses were observed arising from a energetic treatment to the constant zone (HAMA) and variable antibody (Ab2). To date, 5 of 8 patients (62.5%) tested demonstrated functionally active, stimulated T cells by CA125 or by autologous tumor. T cell responses to Alt-2 were demonstrated in 4 patients. The T cell responses were restricted from class I and II MHC, indicating the activation of CTL (cytotoxic T lymphocytes) and cells helper T. Immune responses were commonly induced in the week 12 after 4 doses, and were generally kept in patients who continued a combined treatment with Alt-2 and chemotherapy. 75% are still alive and median survival had not been reached at 120 weeks

Conclusions: Alt-2 is well tolerated and induces specific immune responses for multiple antigens, even when combined with chemotherapy. In advanced EOC, these data are among the first to demonstrate induction of tumor-specific T cells.

Claims (17)

1. Use of a xenotypic monoclonal antibody and a chemotherapeutic drug for the manufacture of a medicine or medications to treat a patient suffering from cancer, in the that the antibody and the chemotherapeutic drug are intended to be administered concurrently. 2. The use of claim 1, wherein the medicine (s) also includes a antigen that is specifically recognized by the antibody Xenotypic monoclonal. 3. The use of any of the preceding claims, wherein the xenotypic monoclonal antibody binds to an epitope of a multiepitopic in vivo tumor antigen, an antigen that does not trigger an effective immune response from the host. 4. The use of claim 3, wherein the Xenotypic monoclonal antibody specifically binds to a first epitope of the antigen and triggers an effective immune response of the host against a second epitope of the antigen. 5. The use of any of the claims precedents, in which the xenotypic monoclonal antibody is murine 6. The use of any of the preceding claims, wherein the medicament (s) are intended
Do (s) to be administered in a dosage amount equal to or less than 2 mg. 7. The use of any of the claims precedents, in which the medicament comprises 2 mg of the antibody Xenotypic monoclonal. 8. The use of any of the claims precedents, in which the xenotypic monoclonal antibody is present in an amount of 0.1 µg to 2 mg per kg of weight body of a host. 9. The use of any of the claims precedents, in which the antibody is selected from the group that consists of Alt-1, Alt-2, Alt-3, Alt-4, Alt-5 and Alt-6. 10. The use of any of the claims precedents, in which the patient is a human being. 11. The use of any of the claims precedents, in which the chemotherapeutic drug is administered within one week before the monoclonal antibody. 12. The use of any of the claims precedents, in which the chemotherapeutic drug is administered within one week after the antibody monoclonal 13. The use of any of the claims precedents, which also includes the surgical removal of the Cancer. 14. Use according to any of the preceding claims, wherein the administration of the antibody is performed in an intravenous infusion of 20 minutes 15. The use of claim 11 or 12, in the that the chemotherapeutic drug is administered every four weeks in six cycles 16. The use of claim 15, wherein the use further comprises the step of administering the antibody xenotypic monoclonal every twelve weeks for a period of up to two years. 17. The use of claim 16, wherein the Xenotypic monoclonal antibody and chemotherapeutic drug are administered at weeks 1, 4 and 8, followed by administration additional chemotherapeutic drug only at weeks 12 and 16, followed by concurrent administration of the drug chemotherapeutic and the xenotypic monoclonal antibody in the week 20