CH696871A5 - Use of a chemotherapeutic drug and a composition comprising a binder, for producing a medicament for the treatment of disease. - Google Patents

Description

CH 696 871 A5

Description Background of the Invention Field of the Invention

The invention relates to immunology. In particular, the invention relates to the use of a chemotherapeutic drug and a composition comprising a binder for the manufacture of a medicament or medicaments for treating a patient's cancer or for eliciting a host immune response in a patient against a multi-epitomic tumor in vivo antigen which does not elicit an effective host immune response according to claim 1 or 2.

Summary of the Related Art

Despite the progress that modern medicine has made in the treatment of cancer, the recurrence of cancer remains a concern. For a majority of cancers, a typical treatment involves surgery, followed by chemotherapy in high dosages. A majority of these patients relapse and do not respond to other chemotherapeutic treatments. These patients then make use of experimental or rescue treatments.

Current experimental protocols focus on a mixture of chemotherapies in an attempt to overcome resistance problems. Most of these treatments lead to serious blood toxicity such as neutropenia and thrombocytopenia. Other serious and frustrating symptoms for the patient include hair loss and nausea. Researchers are now seeking ways to boost the immune system with less toxic agents, while still eliminating the cancer.

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

Thus, there remains a need to identify new treatments that not only treat the initial symptoms of a disease, but also mitigate and / or prevent recurrence of these symptoms.

Brief summary of the invention

[0006] In a first aspect, the invention provides a use of a chemotherapeutic drug and a composition comprising a binder for the manufacture of a medicament or medicaments for the treatment of cancer of a patient or for triggering a host immune response in a patient, against a multivariate drug. epitomic in vivo tumor antigen that does not elicit an effective host immune response, wherein the binding agent is capable of specifically binding to a first epitope on the tumor antigen to form a binding agent / antigen pair, and wherein a host Immune response is elicited against a second epitope on the antigen.

In a second aspect, the invention provides a use of a chemotherapeutic drug, a binding agent and an antigen for the manufacture of a medicament or medicaments for the treatment of cancer in a patient, wherein the antigen is a tumor antigen and the binding agent binds the antigen.

Brief description of the drawings

[0008]

Fig. 1 is a table showing the results of three clinical studies in which Alt-2 is co-administered with a chemotherapeutic drug.

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

Figure 3 is a graph showing the difference in numbers between Ab2 responders (white squares) (effective immune response) and Ab2 non-responders (black squares) (non-effective immune response) over time.

Fig. 4 is a table showing the different disease characteristics of Ab2 responders and Ab2 non-responders.

Detailed description

[0009] The present invention stems from the discovery that a combination of immunotherapy with conventional chemotherapy and / or radiotherapy mitigates and / or prevents the recurrence of cancer. The presence of a host response in a patient to a xenotypic antibody will stimulate an immune response. The inventors have exploited this discovery to develop therapeutics containing excipients useful in immunotherapy and chemotherapeutic or radiotherapeutic drugs, as well as the use of the same.

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these binders and chemotherapeutic or radiotherapeutic drugs in the manufacture of medicaments for the treatment of cancer or for inducing a host immune response to an in vivo tumor antigen. The patents and publications cited herein reflect the level of skill in the art and are hereby incorporated in their entirety, to the same extent as if each would be specifically and individually indicated to be incorporated by reference , In the event of a conflict between a cited document and this description, this description is authoritative.

[0010] According to a first aspect, the invention provides a use of a chemotherapeutic drug and a composition comprising a binder for the manufacture of a medicament or medicaments for the treatment of cancer of a patient or for triggering a host immune response in a patient, against a multivariate drug. epitaxial in vivo tumor antigen that does not elicit an effective host immune response, wherein the binding agent is capable of specifically binding to a first epitope on the tumor antigen to form a binding agent / antigen pair, and wherein a host immune response is conferred a second epitope is produced on the antigen.

In a second aspect, the invention provides a use of a chemotherapeutic drug, a binding agent and an antigen for the manufacture of a medicament or medicaments for the treatment of cancer in a patient, wherein the antigen is a tumor antigen and the binding agent binds the antigen.

In some embodiments of the invention, the tumor antigen alone, without the binding agent, does not elicit an effective host immune response.

In some embodiments of the invention, the binder is present in an amount of from 0.1 μg to 2 mg per kg body weight of the patient.

In some embodiments of the invention, the binding agent is a xenotic antibody, such as a xenotic, monoclonal antibody or a mouse-derived xenotypic antibody. In some embodiments of the invention, the antibody is from a mouse and the host is human.

In some embodiments of the invention, binding of the xenotypic monoclonal antibody to a first single epitope releases a second distinct epitope on the antigen. In some embodiments of the invention, the xenotypic monoclonal antibody, when bound to the antigen, forms an immunogenic complex. Examples of xenotypic monoclonal antibodies ("MAb") preferably include IgG1 antibodies, chimeric monoclonal antibodies ("C-MAb"), humanized antibodies, engineered monoclonal antibodies ("G-MAb"), fragments of monoclonal antibodies (including, but not limited to "F (Ab) 2", "F (Ab)" and "Dab"), and single chains representing the reactive portion of monoclonal antibodies ("SC-MAb"). The binder may be labeled or unmarked.

In some embodiments of the invention, the binding agent and the chemotherapeutic drug are to be administered in the same drug or administered simultaneously.

In some embodiments of the invention, the binding agent (such as the xenotypic antibody) is to be co-administered with the chemotherapeutic drug at a dose equal to or less than 2 mg.

In some embodiments of the invention, the binder (such as the antibody) is to be administered at a dose of less than or equal to 2 mg.

In some embodiments of the invention, the binder (such as the antibody) is to be administered via a 20 minute intravenous infusion.

In some embodiments of the invention, the patient is a human.

In some embodiments of the invention, the binders, such as the xenotypic monoclonal antibodies, include, without limitation, murine monoclonal antibodies. Particularly preferred murine monoclonal antibodies include Alt-1 (mouse IgG1 specifically binds to MUC-1, ATCC No. PTA-975, American Type Culture Collection, Manassas, VA), Alt-2 (OvaRex® mAb B43.13, IgG1 from mouse, binds specifically to CA125, ATCC No. PTA-1883), Alt3 (murine lgG3, binds specifically to CA19.9, ATCC No. PTA-2691), Alt-4 (mouse IgM binds specifically to CA19 9, ATCC No. PTA-2692), mouse Alt-5 (lgG1, binds specifically to CA19.9, ATCC No. PTA-2690), and mouse Alt-6 (IgG1) specifically binds to prostate-specific antigen (PSA); ATCC No. HB-12526).

The medicaments according to the invention are suitable for providing a therapeutic benefit to patients suffering from cancer. As used herein, the term "cancer" means a condition in which a cell in the body of a patient undergoes abnormal, uncontrolled proliferation. The abnormal cell may proliferate to form a solid tumor or may proliferate to form a variety of cells (e.g., leukemia). It should be noted that the term does not encompass the normal proliferation of a cell, such as a stem cell or a spermatocyte, because cancer is the abnormal, uncontrolled proliferation of a patient's cell.

By "treating a patient suffering from cancer" or "treating cancer in the patient" it is understood that the symptoms of the patient are alleviated after treatment according to the invention. By way of non-limiting example, a patient suffering from a highly metastatic cancer (e.g., breast cancer) is treated with either no additional metastases or reduced numbers as compared to a non-treated patient. In another non-limiting example, a patient becomes

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which either reduces the size of the solid tumor of the patient or does not increase in size as compared to a non-treated patient. In yet another non-limiting example, the number of cancer cells (e.g., leukemia cells) in a treated patient either does not increase, or is reduced in comparison to the number of cancer cells in a patient who is not receiving treatment. In preferred embodiments, the patient is a human.

It will be appreciated that a "patient suffering from cancer" or a "patient" according to the invention may express the mutated protein and yet need not be symptomatic of the disease. For example, if the cancer is a colon cancer (associated with the mutant K-ras protein), a patient with a mutant K-ras protein in some cells of the colon is a patient according to the invention, although the patient is not yet symptomatic of colon cancer have to be. "Associated with a mutant protein" means that in a majority of patients disease signs or symptoms are present when the mutant protein is present in the body of the patient, but where there are no disease signs or symptoms when the mutant protein is not present in the body the body of the patient is present. "Disease Signs or Symptoms" are clinically recognized manifestations or indications of a disease.

Preferably, the therapeutic compositions of the invention further comprise a pharmaceutically acceptable carrier.

By "pharmaceutically acceptable carrier" is meant a carrier that is physiologically acceptable to the patient to whom it is administered. An example of a pharmaceutically acceptable carrier is physiological saline. Other pharmaceutically acceptable carriers and their formulations are well known and generally described in, for example, Remington's Pharmaceutical Sciences (18th ed., Ed. A. Gennaro, Mack Publishing Co., Easton, PA, 1990).

As used herein, "administering" means delivering the composition to the patient in a manner that results in the composition being within the body of the patient. Such administration may be by any route including, without limitation, parenteral, subcutaneous, intradermal, intravenous, intraarterial, intraperitoneal, and intramuscular.

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

In preferred embodiments, the binding agent and the chemotherapeutic drug are to be administered in the same drug or simultaneously. For example, the chemotherapeutic drug is administered within one week before or after the binding agent (such as the mouse monoclonal antibody).

In certain embodiments of the invention, the medicaments of the present invention are to be used in a method of treating cancer comprising surgery, administering a chemotherapeutic drug, administering a xenotypic monoclonal antibody in a dose equal to or less than 2 mg administered by intravenous infusion over 20 minutes during weeks 1, 3, 5, 9, then every 8 weeks, followed by administration of a chemotherapeutic drug within 5 days of administration of the vehicle.

In certain non-limiting embodiments of the invention, the binder (such as the xenotypic antibody), e.g. Alt-2, administered as a 2 mg dose dissolved in 50 ml saline and slowly infused preferably for approximately 20 minutes. If an allergic reaction or other reaction occurs which may limit the complete administration of the dose then a lower dose may be used at that time, or with subsequent treatments, so that the expected dose range would be 1-2 mg per treatment. Typically, premedication with 25 to 50 mg of diphenhydramine is administered orally or intravenously to reduce the risk of allergic reactions to the protein. The treatment regimen used for a combination of Alt-2 and chemotherapy involves the administration of Alt-2 at the above dose at weeks 1, 3, 5, 7, 9, with chemotherapy with Alt-2 being administered at weeks 12 to 26 , Alt-2 may be started after recovery from any required surgery performed prior to chemotherapy, and will continue thereafter until and during the treatment period of chemotherapy. Chemotherapy may be given in cycles of 3-4 weeks, or other treatment regimens, according to the attending physician and standard clinical practice. Chemotherapy can be continued for up to six cycles, followed by administration of the xenotype antibody every twelve weeks for up to two years.

In certain embodiments of the invention, the medicaments of this invention are to be used in a method of treating cancer, including surgery, followed within seven days by administration of a xenotypic monoclonal antibody in a dose equal to or less than 2 mg administered by intravenous Infusion over 20 minutes during weeks 1, 3, 5, 9, then every 8 weeks, with concomitant administration of a chemotherapeutic drug at week 3 or thereafter.

In another non-limiting example, the vehicle (such as the antibody from a mouse) is administered at week 1 after standard surgery has been completed but chemotherapy has not yet begun.

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The mouse antibody is administered at a dose equal to or less than 2 mg by a 20 minute intravenous infusion, followed by a second treatment and coadministration of a chemotherapeutic drug at week 6 and later. "Simultaneous administration" means administration in a relatively short period of time to each other. Preferably, such a period is less than 2 weeks, more preferably less than 7 days, most preferably less than 1 day and the administration could even be simultaneous.

The expected survival times without progression of the disease can be measured in months to years, depending on prognostic factors including the number of relapses, the stage of the disease and other factors. Total survival times are also measured in months to years. In ovarian cancer, the addition of the xenotypic monoclonal antibody Alt-2 is expected to increase the time it takes for the disease to reoccur or progress, and also to prolong survival. Any improvement of 2 months or longer is usually considered clinically meaningful.

Examples of multi-epitope antigens are described in Nicodemus C.F. 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), and incorporated herein by reference.

A "binder" as used herein refers to a component of a binding pair comprising an immunological pair, e.g. a binding moiety capable of binding an antigen preferably a single epitope expressed on the antigen, such as a predetermined tumor antigen. In some embodiments of the invention, binding of a first single epitope exposes a second distinct epitope on the antigen. In some embodiments of the invention, when bound to the antigen, the binding agent forms an immunogenic complex. Examples of binders include, but are not limited to: antibodies, monoclonal antibodies ("MAb"), preferably IgG1 antibodies, chimeric monoclonal antibodies ("C-MAb"), humanized antibodies, genetically engineered monoclonal antibodies ("G-MAb"). ), Fragments of monoclonal antibodies (including but not limited to "F (Ab) 2", "F (Ab)" and "Dab"), single chains representing the reactive portion of monoclonal antibodies ("SC-MAb") Antigen-binding peptides, tumor-binding peptides, a protein comprising receptor proteins, peptide, polypeptide, glycoprotein, lipoprotein or the like, eg Growth factors, lymphokines and cytokines, enzymes, immunomodulators, hormones, for example somatostatin, any of the foregoing bound to a protein conferring effector function, and compounds mimicking any of the above, or fragments of any of the foregoing. The binder may be labeled or unmarked.

Preferred binders of the invention are monoclonal antibodies. If the patient is a human, these xenotypic monoclonal antibodies include, without limitation, murine monoclonal antibodies. Particularly preferred murine monoclonal antibodies include Alt-1 (mouse IgG1 specifically binds to MUC-1, ATCC No. PTA-975, American Type Culture Collection, Manassas, VA), Alt-2 (OvaRex® mAb B43.13, IgG1 from mouse, binds specifically to CA125, ATCC No. PTA-1883), Alt-3 (mouse IgG3, binds specifically to CA19.9, ATCC No. PTA-2691), Alt-4 (murine IgM binds specifically ATCC No. PTA-2692), mouse Alt-5 (lgG1, binds specifically to CA19.9, ATCC No. PTA-2690), and mouse Alt-6 (IgG1) binds specifically to prostate specific antigen (PSA); ATCC No. HB-12526).

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

[0039] "Inducing a host immune response" means that the patient is experiencing a mitigation or reduction of disease signs or symptoms, and specifically, without limitation, extends the survival time. In certain preferred embodiments of the methods of the invention, a CD8 + IFN-γ producing T cell is activated, wherein an immune response of cytotoxic T lymphocytes (CTL) is induced in the patient to whom the mouse monoclonal antibody has been administered. In certain embodiments of the methods of the invention, a CD4 + IFN-γ producing T-cell is activated, wherein an immune response of helper T-cells is induced in the patient to whom the composition has been administered. These activated CD4 + IFN-γ producing T cells (ie, helper T cells) provide immunological support (eg, by the release of cytokines) to not only induce and maintain CTL, but also a humoral immune response mediated by B cells is mediated. Thus, in certain embodiments of the inventive method, a humoral response to the antigen is activated in the patient to whom the composition has been administered.

Activation of CD8 + and / or CD4 + IFN-γ producing T cells means that T cells that can produce IFN-γ are caused to actually produce IFN-γ or to increase their production of IFN-γ increase. "CTL induction" means causing potentially cytotoxic T lymphocytes to actually exhibit anti-gene specific cytotoxicity. An "antigen-specific cytotoxicity" means a cytotoxicity against a cell presenting an antigen associated with the antigen associated with the cancer that is greater than against an antigen not associated with the cancer. "Cytotoxicity" refers to the ability of the cytotoxic T lymphocyte to kill the target cell. Preferably, such antigen-specific cytotoxicity is at least 3-fold, more preferably 10-fold greater, more preferably more than 100-fold greater than the cytotoxicity to a cell that does not present the antigen associated with the cancer.

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Example I

Clinical and immunological outcomes of patients with recurrent ovarian epithelial cancer (EOC) after treatment with B43.13 and chemotherapy (CT)

Immunological and clinical interim results from the study OVA-Gy-12

Patients with a relapse after platinum therapy and a first surgery were enrolled if they were candidates for a second surgery and continued chemotherapy. Alt-2 was administered by infusion for 20 minutes at weeks 1, 3, 5, and 9 prior to initiation of chemotherapy, and then optionally continued every 8 weeks x 2 dose levels, concurrently with chemotherapy at weeks 12 and 26. Humoral immune responses, comprising the antibodies HAMA, Ab2 and CA125, were measured as baseline and serially. Using the gamma-interferon ELISPOT assay, T-cell responses were assessed for activation by Alt-2, CA125 or autologous tumor.

20 patients were enrolled, the mean follow-up period was 6 months and lasted up to 2 years. Alt-2 was well tolerated and did not produce any serious drug-related adverse reactions. In 14 of 19 evaluable patients (71%), robust humoral treatment emergent responses to the antibody constant (HAMA) and variable region (Ab2) were observed. So far, 5 out of 8 patients tested (62.5%) showed functionally active T cells stimulated by CA125 or autologous tumor. T cell responses to Alt-2 were shown in 4 patients. The T cell responses were restricted to MHC class I and II, indicating the activation of CTL (cytotoxic T lymphocytes) and T helper cells. Immune responses were usually induced at week 12 after 4 doses and were generally maintained in patients who continued combination treatment with Alt-2 and chemotherapy. 75% are still alive and after 120 weeks a median survival time has not been reached.

Conclusion: Alt-2 is well tolerated and induces multiple antigen-specific immune responses, even when combined with chemotherapy. For advanced EOC, these data are among the first to show the induction of tumor-specific T cells.

Claims (13)

claims Use of a chemotherapeutic drug and a composition comprising a binder for the manufacture of a medicament or medicaments for eliciting a host immune response in a patient against a multi-epitopic in vivo tumor antigen which does not elicit an effective host immune response wherein the binding agent is capable of specifically binding to a first epitope on the tumor antigen to form a binimient / antigen pair and causing a host immune response against a second epitope on the antigen. Use of a chemotherapeutic drug, a binding agent and an antigen for the manufacture of a medicament or medicaments for the treatment of cancer in a patient, wherein the antigen is a tumor antigen and the binding agent binds the antigen. Use according to claim 2 wherein the tumor antigen alone, without the binding agent, does not elicit an effective host immune response. Use according to any one of the preceding claims, wherein the binder is present in an amount of from 0.1 μg to 2 mg per kg body weight of the patient. 5. Use according to one of the preceding claims, wherein the binder is a xenotypic antibody. Use according to any one of the preceding claims, wherein the binder is a xenotypic monoclonal antibody. 7. Use according to one of the preceding claims, wherein the binder and the chemotherapeutic drug to be administered in the same drug or to be administered simultaneously. Use according to any one of claims 5 to 7, wherein the xenotypic antibody is to be administered simultaneously with the chemotherapeutic drug in a dose equal to or less than 2 mg. Use according to any one of claims 5 to 8, wherein the xenotypic antibody is from the mouse. 10. Use according to one of the preceding claims, wherein the binder is selected from the group consisting of Alt-1 (ATCC No. PTA-975), Alt-2 (ATCC No. PTA-1883), Alt-3 (ATCC no. PTA-2691), Alt-4 (ATCC No. PTA-2692), Alt-5 (ATCC No. PTA-2690) and Alt-6 (ATCC No. HB-12526). Use according to any one of the preceding claims, wherein the patient is a human. Use according to any one of claims 5 to 11, wherein the antibody is to be administered at a dose of less than or equal to 2 mg. 6 CH 696 871 A5 Use according to any one of claims 5 to 12, wherein the antibody is to be administered via a 20 minute intravenous infusion. 7