WO2005070026A2 - Drug immunoconjugate combination therapy - Google Patents

Drug immunoconjugate combination therapy Download PDF

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WO2005070026A2
WO2005070026A2 PCT/US2005/002406 US2005002406W WO2005070026A2 WO 2005070026 A2 WO2005070026 A2 WO 2005070026A2 US 2005002406 W US2005002406 W US 2005002406W WO 2005070026 A2 WO2005070026 A2 WO 2005070026A2
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dox
cytostatic
inhibitor
agent
hours
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PCT/US2005/002406
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French (fr)
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WO2005070026A3 (en
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Michael Mcdonald
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Seattle Genetics, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6807—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense
    • A61K47/6809—Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6855—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from breast cancer cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6863—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from stomach or intestines cancer cell

Definitions

  • the present invention is directed to combination therapy of a drug immunoconjugate, an antibody-drug conjugate comprising an antibody reactive with Lewis Y antigen conjugated to doxorubicin, administered in combination with a cytotoxic or cytostatic agent, hi particular, the invention is directed to the pre- administration of an antibody-drug conjugate comprising an antibody reactive with Lewis Y antigen conjugated to doxorubicin, followed by the administration of a cytotoxic or cytostatic agent, such as paclitaxel (TAXOL®) or docetaxel (TAXOTERE®).
  • TAXOL® paclitaxel
  • TXOTERE® docetaxel
  • NSCLC nonsmall cell carcinoma
  • Anthracyclines including doxorubicin, have shown activity in early combination chemotherapy for NSCLC, and doxorubicin was included in one of the first chemotherapy regimens to show a survival benefit in this disease.
  • the anthracyclines have been largely supplanted in recent combination chemotherapy regimens in favor of the platinum compounds.
  • taxanes a novel class of anti-microtubule agents, the taxanes, has had an impact on both disease response and survival.
  • the taxanes affect polymerized tubulin and promote formation of abnormally stable microtubules and inhibit their disassembly. This prevents the formation of a functional spindle apparatus, leading to cell cycle arrest in the G2/M phase of mitosis.
  • the taxanes, and TAXOTERE® (docetaxel) in particular, have significantly improved response rates in multiple solid tumors, especially in advanced stage breast cancer, both as single agents and in combination with other anti- cancer agents.
  • TAXOTERE® exhibits significant anti-tumor activity in a number of tumors including squamous cell carcinoma and adenocarcinomas such as NSCLC.
  • TAXOL® (Pacitaxel) and TAXOTERE® are approved as therapy for NSCLC.
  • TAXOL® is approved in combination with cisplatin as first line therapy for advanced stage NSCLC.
  • TAXOTERE® is now approved as a single agent for patients who have failed first line chemotherapy. Because it is a phase specific agent, frequent administration offers a possible improvement in response with decreased toxicity.
  • Recent trials with TAXOTERE® in adenocarcinomas have demonstrated tolerability with weekly administration and maintained high response rates.
  • Targeted immunotherapy combines the specificity of mAbs with the greater tumor killing activity of toxins or chemotherapeutic agents.
  • this strategy has also been limited by normal tissue toxicity at the doses required to achieve meaningful anti-tumor activity.
  • a method for treating patients having a tumor type known to express the Lewis Yantigen (Le y ) including the administration of an antibody-drug conjugate comprising an antibody reactive with Lewis Y antigen conjugated to doxorubicin, followed by a cytotoxic or cytostatic agent.
  • the cytotoxic or cytostatic agent can be administered from about 4 hours to about 24 hours, to greater than 24 hours (i.e., at least 28 hours), to about 30 hours, to about 36 hours, to about 48 hours or to about 72 hours after administration of the antibody drug conjugate.
  • the therapeutic effect of administering the antibody drug conjugate followed by administration of a cytostatic or cytostatic agent is additive, hi other embodiments, the therapeutic effect of administering antibody drug conjugate followed by administration of a cytostatic or cytostatic agent is synergistic.
  • the cytostatic or cytotoxic agent is a tubulin inhibitor or an agent that inhibits, reduces or interferes with endocytosis.
  • the cytostatic or cytostatic agent can be, for example, a taxane such as paclitaxel and docetaxel.
  • the cytostatic agent or cytostatic agent is administered at least 28 hours after administration ofBR96-Dox.
  • the (Le y ) antigen can be expressed, for example, on a tumor, such as a epithelial tumor.
  • a tumor such as a epithelial tumor.
  • the epithelial tumor can be, for example, a lung, colorectal, esophageal, gastric or ovarian tumor.
  • Figure 1 shows drug sensitivity as a function of cell-cycle position.
  • the cell division of L2987 lung carcinoma cells was synchronized by double thymidine block and release and pulse-titrated with Taxol® or BR96-Dox at progressive stages of the cell cycle.
  • IC 50 for each population was determined at 96 hr.
  • the cell-cycle position of each population was determined by flow cytometery for DNA content using PI and the Cellfit program (Becton Dickenson).
  • the relative levels of Le antigen in each population was determined by labeled BR96-Dox binding.
  • Figures 2 A and 2B show the effect of timing on matrix titrations of BR96-Dox and Taxol®.
  • L2987 lung carcinoma cells were titrated with combinations of SGN-15 (an antibody drug conjugate composed of the BR96 mAb conjugated by a hydrazone linker to doxorubicin), at varying concentrations of Taxol®. hi all cases each drug was combined with cells for 1 hr, replaced with fresh media and cell viability was determined 96 hr after all combined drug treatments.
  • Figure 2A shows IC 50 S produced by matrix combination of Taxol® preceding SGN-15 by 24 hr
  • Figure 2B shows IC 50 s produced by matrix combination of Taxol® and SGN-15 given simultaneously.
  • Figure 3 shows the response to therapy with BR96-Dox, docetaxel, or combinations of both agents.
  • Each study group contained 9 animals with L2987 NSCLC tumor xenografts.
  • Figure 4 shows combined response results from multiple BR96-Dox/docetaxel combination therapy studies. The number of mice receiving each therapeutic regimen is listed above each bar.
  • the cytotoxic or cytostatic agent can be administered from about 4 hours to about 24 hours, to greater than 24 hours (i.e., at least 28 hours), to about 30 hours, to about 36 hours, to about 48 hours or to about 72 hours after administration of the antibody drug conjugate.
  • the antibody drug conjugate in the manufacture of a medicament for the treatment of a tumor type known to express the Lewis Y antigen, wherein the antibody drug conjugate is administered to a subject having the tumor, followed by administration of a cytotoxic agent or cytostatic agent from about 4 hours to about 24 hours, to greater than 24 hours (i.e., at least 28 hours), to about 30 hours, to about 36 hours, to about 48 hours or to about 72 hours after administration of the antibody drug conjugate.
  • BR96-Dox is an immunoconjugate comprised of the chimeric anti-Lewis Y (Le y ) mAb BR96, conjugated to doxorubicin by an acid cleavable linker.
  • Le y chimeric anti-Lewis Y
  • doxorubicin by an acid cleavable linker.
  • Humanized anti-Le(y) antibody hu3 SI 93 is another antibody that can be conjugated to Dox.
  • the Le y antigen is a tetrasacharide found as a glycoprotein at the cell surface on over 75% of epithelial cancers, such as carcinomas of the breast, gastrointestinal (GI) tract (e.g., colorectal, esophageal or gastric), lung, prostate, pancreatic, ovarian, and kidney, head and neck, and other cancers.
  • GI gastrointestinal
  • BR96 is capable of inducing tumor regression in animal models in its native form, it is even more effective as a drug immunoconjugate.
  • BR96-Dox induces its anti-tumor effect through binding to the cell surface Le y antigen.
  • the immunoconjugate After binding to the cell surface antigen, the immunoconjugate is rapidly internalized with release of doxorubicin through acid hydrolysis inside the cell. This mechanism of targeted drug delivery allows for relative sparing of tissues normally affected by non-specific chemotherapy, and represents an attractive strategy for the treatment of Le y -expressing tumors.
  • the BR96-Dox is SGN-15 (an antibody drug conjugate composed of the BR96 mAb conjugated by a hydrazone linker to doxorubicin).
  • cytotoxic chemotherapeutics are cell cycle-dependent. As a result, rapidly dividing cells are more sensitive to the killing activity than resting cells. Since the cell surface expression of the Le y tumor antigen is invariant throughout the cell cycle, the rate of BR96-Dox-mediated intemalization and release of free doxorubicin into the cytosol is relatively constant. As BR96-Dox delivers doxorubicin, the anti-tumor activity of the targeted agent is cell cycle-specific and similar to that of free doxorubicin, as shown in Fig. 1. Cells in the S-phase are the most sensitive to BR96-Dox exposure with those in G2/Mitosis being least sensitive.
  • Doxorubicin is a potent DNA intercalating agent and impairs normal DNA synthesis at several steps. Following exposure to doxorubicin, cells arrest in G2 as a consequence of inhibition of topoisomerase II activity. The G2 arrest can sensitize cells to subsequent treatment with a cytostatic or cytotoxic agent that can preferentially act in G2. hi contrast, when Taxol® precedes BR96-Dox an additive (or slightly antagonistic) effect is observed (Fig. 2A). When the two agents are applied together the result is antagonistic (Fig. 2B).
  • the cytostatic or cytotoxic agent can be, for example, a microtubule inhibitor, an agent that reduces (e.g., inhibits or interferes) with endocytosis, a DNA alkylating agent, DNA topoisomerase inhibitors, plant alkaloids, anti-metabolites, pyrimidine analogs, receptor antagonists, or retinoids/deltoids.
  • Suitable cytostatic or cytotoxic agents include, but are not limited to, methotrexate, taxol, L-asparaginase, mercaptopurine, thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide, nitrosoureas, cisplatin, carboplatin, mitomycin, dacarbazine, procarbizine, topotecan, nitrogen mustards, cytoxan, etoposide, 5-fluorouracil, BCNU, irinotecan, camptothecms, bleomycin, doxorubicin, idarubicin, daunorubicin, dactinomycin, plicamycin, mitoxantrone, asparaginase, vinblastine, vincristine, vinorelbine, paclitaxel, and docetaxel.
  • the cytostatic or cytotoxic agent includes, but is not limited
  • the cytostatic or cytotoxic agent can be a taxane.
  • a taxane such as doxorubicin can act in G2 to arrest the cell cycle by causing ineffective spindle formation.
  • a taxane such as paclitaxel (TAXOL®), which in contrast to doxorubicin is less effective in Gl, can also cause a block in G2/M.
  • TAXOL® paclitaxel
  • BR96-Dox and Taxol® are able to target complementary populations of growing cells.
  • cytostatic or cytotoxic agent is not a taxane. hi certain specific embodiments, the taxane is not paclitaxel or docetaxel.
  • the therapeutic effect of administering the antibody-drug conjugate (comprising an antibody reactive with Lewis Y antigen conjugated to doxorubicin) followed by administration of a cytostatic or cytotoxic agent is additive.
  • the therapeutic effect of administering the antibody drug conjugate followed by administration of a cytostatic or cytostatic agent is synergistic.
  • “synergistic” means that the combined therapeutic effect of the antibody drug conjugate and the cytostatic or cytotoxic agent exceeds the sum of their individual effects.
  • the antibody drug cognate and cytostatic or cytotoxic agent are administered to a subject having an Le y -expressing cancer.
  • subject as used herein means any mammalian patient to which the antibody drug conjugate can be admimstered, including, e.g., humans and non-human mammals, such as primates, rodents, and dogs. Subjects specifically intended for treatment using the methods described herein include humans.
  • the antibody drug conjugate and cytostatic or cytotoxic agent can be administered for the treatment and/or prophylaxis of an Le y -expressing cancer.
  • Various delivery systems are known and can be used to administer the antibody drug conjugate and cytostatic or cytotoxic agent.
  • Methods of introduction include but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes.
  • the antibody drug conjugate and cytostatic or cytotoxic agent can be administered, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, and the like).
  • each of the antibody drug conjugate and cytostatic or cytotoxic agent is administered by injection, by means of a catheter, by means of a suppository, or by means of an implant, the implant being of a porous, non-porous, or gelatinous material, including a membrane, such as a sialastic membrane, or a fiber.
  • the implant being of a porous, non-porous, or gelatinous material, including a membrane, such as a sialastic membrane, or a fiber.
  • materials to which the antibody drug conjugate or cytostatic or cytotoxic agent does not absorb are used.
  • the antibody drug conjugate and/or cytostatic or cytotoxic agent is delivered in a controlled release system.
  • a pump maybe used (see, e.g., Langer, 1990, Science 249:1527-1533; Sefton, 1989, CRC Crit. Ref Biomed. Eng. 14:201; Buchwald et al, 1980, Surgery 88:507; Saudek et al, 1989, N. Engl. J. Med. 321:574).
  • polymeric materials can be used.
  • the antibody drug conjugate and/or cytostatic or cytotoxic agent can be administered as pharmaceutical compositions comprising a therapeutically effective amount of the antibody drug conjugate and/or cytostatic or cytotoxic agent and one or more pharmaceutically compatible ingredients.
  • the pharmaceutical composition typically includes one or more pharmaceutical carriers (e.g., sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like). Water is a typical carrier when the pharmaceutical composition is admimstered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
  • Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, and the like.
  • the composition if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like.
  • the composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides.
  • Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E.W. Martin. Such compositions will contain a therapeutically effective amount of the antibody drug conjugate or the cytostatic or cytotoxic agent, typically in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulations correspond to the mode of administration.
  • each pharmaceutical composition e.g., BR96-Dox or the cytostatic or cytotoxic agent
  • a pharmaceutical composition adapted for intravenous administration is solutions in sterile isotonic aqueous buffer.
  • the pharmaceutical can also include a solubilizing agent and a local anesthetic such as lignocaine to ease pain at the site of the injection.
  • the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent.
  • the pharmaceutical is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
  • an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.
  • a pharmaceutical composition can be provided as a pharmaceutical kit comprising (a) a container containing the antibody drug conjugate (e.g., BR96-Dox) in lyophilized form, (b) a container containing a cytostatic or cytotoxic agent, (c) a container containing a pharmaceutically acceptable diluent (e.g., sterile water) for the antibody drug conjugate (e.g., BR96-Dox), and (d) a container containing a pharmaceutically acceptable diluent (e.g., sterile water) for the cytotoxic or cytostatic agent.
  • a pharmaceutically acceptable diluent e.g., sterile water
  • the pharmaceutically acceptable diluent can be used for reconstitution or dilution of the antibody drug conjugate and/or cytostatic or cytotoxic agent.
  • Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
  • the amount of the antibody drug conjugate and cytostatic or cytotoxic agent that is effective in the treatment or prevention of an Le y -expressing cancer can be determined by standard clinical techniques.
  • in vitro assays can optionally be employed to help identify optimal dosage ranges.
  • the precise dose to be employed in the formulation will also depend on the route of administration, and the stage of the Le y - expressing cancer, and should be decided according to the judgment of the practitioner and each patient's circumstances. Effective doses may be extrapolated from dose- response curves derived from in vitro or animal model test systems.
  • toxicity and therapeutic efficacy of the antibody drug conjugate and cytostatic or cytotoxic agent can be determined in cell cultures or experimental animals by standard pharmaceutical procedures for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD 50 /ED 50 .
  • a delivery system that targets the antibody drug conjugate and/or cytostatic or cytotoxic agent to the site of affected tissue can be used to minimize potential damage to reduce side effects.
  • the data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of the antibody drug conjugate and/or cytostatic or cytotoxic agent typically lies within a range of circulating concentrations that include the ED 50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC 50 (i.e., the concentration of the test compound that achieves a half-maximal inhibition of symptoms) as determined in cell culture.
  • IC 50 i.e., the concentration of the test compound that achieves a half-maximal inhibition of symptoms
  • levels in plasma can be measured, for example, by high performance liquid chromatography.
  • the dosage of an antibody drug conjugate (e.g., BR96-Dox) and/or cytostatic or cytotoxic agent administered to a patient with an Le y -expressing cancer is typically 0.1 mg/kg to 100 mg/kg of the subject's body weight. More typically, the dosage administered to a subject is 0.1 mg/kg to 50 mg/kg of the subject's body weight, even more typically 1 mg/kg to 30 mg/kg, 1 mg/kg to 20 mg/kg, 1 mg/kg to 15 mg/kg, or 1 mg/kg to 10 mg/kg of the subject's body weight.
  • an antibody drug conjugate e.g., BR96-Dox
  • cytostatic or cytotoxic agent administered to a patient with an Le y -expressing cancer is typically 0.1 mg/kg to 100 mg/kg of the subject's body weight. More typically, the dosage administered to a subject is 0.1 mg/kg to 50 mg/kg of the subject's body weight, even more typically 1 mg/kg to 30 mg/kg, 1 mg/
  • the invention is further described in the following examples, which are not intended to limit the scope of the invention.
  • the following examples describe a method of treating patients having a tumor type known to express Lewis Y antigen or any tumor type in which the majority of patients with a tumor type express Lewis Y antigen.
  • BR96-Dox may be administered prior to the administration of a taxane, particularly docetaxel, paclitaxel or any other taxane.
  • the BR96-Dox is administered prior to the TAXOTERE® to enable the BR96-Dox to circulate to the tumor site and reach the tumor cells.
  • BR96-Dox is a large molecule and circulation to the tumor cell particularly through the tumor microvasculature may be slow because of high interstitial pressure, abnormal vasculature and sticking of the protein to the vessel wall. Sufficient time must be given for BR96-Dox to be internalized into the tumor cell through the process of endocytosis.
  • TAXOTERE® 24 hours following BR96-Dox administration the TAXOTERE® is still administered during its pharmacological high point, yet conveniently for patient scheduling.
  • TAXOTERE® may be administered following BR96-Dox administration for about 4 days following or until the instability of the antibody drug conjugate would reduce the potential effectiveness of the combination.
  • the route of administration for both the BR96-Dox and the TAXOTERE® can be intravenous.
  • the monoclonal antibody portion may be given intraperitoneally.
  • hitraperitoneal administration may be used, for example, in tumors with a tendency to peritoneal spread.
  • tumors is ovarian tumors.
  • the administration of the monoclonal antibody portion and/or the cytotoxic or cytostatic agent may also be accomplished orally if the compounds are formulated for oral administration.
  • TAXOTERE® can be administered at a dose of about 25-35 mg/m 2 /week and BR96-Dox can be administered at a dosage at about 200 mg/m to about 350 mg/m .
  • a suboptimal dose of TAXOTERE® or the approved dose of TAXOTERE® according to the product label may be used. Additionally, any dose of TAXOTERE® which has been published in the literature as showing efficacy can be used for subsequent administration following BR96-Dox.
  • a suboptimal dosage of BR96-Dox and/or a dosage close to the maximally tolerated dose (MTD) may be used.
  • the number of courses of treatment are determined by patient response, according to one of skill in the art, such as the patient's treating physician.
  • Patients receiving TAXOTERE® can receive pretreatment with dexamethasone or another steroid. They may also receive pretreatment with an antihistamine and/or an antinausea drug, such as but not limited to, 5HT antagonist.
  • One method of confirming the dosage interval that confers added efficacy will be by biomarker and PET Positron Emission Tomography (PET) analysis. Such a method can also be used to confirm the dosage interval of about 4 to about 72 hours.
  • PET PET Positron Emission Tomography
  • Mouse xenograft models of human non-small cell lung cancer demonstrate that the efficacy of the BR96-Dox and docetaxel when administered in combination is dependent of the schedule of administration. For example, administering BR96-Dox approximately 48 hours prior to docetaxel results in consistently greater efficacy than when the two agents are administered with a shorter interval or when docetaxel is administered first.
  • an interval in mouse can be equivalent to a different interval in humans, allowing for differences in body mass, tumor mass, increased peri-tumor fibrosis and differences in time to full distribution and tumor penetration.
  • Study groups consisted of (1) untreated control, (2) BR96-Dox (also referred to as SGN-15) alone, (3) docetaxel alone, or a combination of BR96-Dox + docetaxel using the following schedules: (4) BR96-Dox + docetaxel administered on the same day; (5) BR96-Dox followed 24 hours later by docetaxel; (6) BR96-Dox followed 48 hours by docetaxel; (7) BR96-Dox followed 72 hours by docetaxel; (8) docetaxel followed 24 hours later by BR96-Dox; (9) docetaxel followed 48 hours later by BR96-Dox; and (10) docetaxel followed 72 hours later by BR96-Dox.
  • therapy was administered every 7 days for 3 weeks.
  • BR96-Dox was administered intraperitoneally at 15 mg/kg/dose and docetaxel was administered intravenously at 7.5 mg/kg/dose.

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Abstract

A method of treating patients having a tumor type known to express the Lewis Y antigen including the administration of BR96-Dox followed by a cytotoxic or cytostatic agent from about 4 hours to about 48 hour or to about 72 hours after administration of the BR96-Dox is described.

Description

DRUG IMMUNOCONJUGATE COMBINATION THERAPY
CONTINUITY [0001] This application claims the benefit of U.S. Provisional Application No. 60/538,705, filed January 23, 2004, and No. 60/576,734, filed June 3, 2004, the disclosures of which are incorporated by reference herein.
BACKGROUND OF THE INVENTION [0002] The present invention is directed to combination therapy of a drug immunoconjugate, an antibody-drug conjugate comprising an antibody reactive with Lewis Y antigen conjugated to doxorubicin, administered in combination with a cytotoxic or cytostatic agent, hi particular, the invention is directed to the pre- administration of an antibody-drug conjugate comprising an antibody reactive with Lewis Y antigen conjugated to doxorubicin, followed by the administration of a cytotoxic or cytostatic agent, such as paclitaxel (TAXOL®) or docetaxel (TAXOTERE®).
[0003] Current therapies for advanced stage or metastatic carcinoma continue to fall short of extending survival for the majority of patients. While response rates of 50% or more can be seen with newer anti-cancer agents, time to disease progression and overall mortality have not been dramatically improved in most cases. Consequently, continued effort to develop new agents and combinations is needed to improve the disease-free and overall survival for these cancer patients.
[0004] Lung cancer is now the worldwide leading cause of cancer-related deaths and accounted for an estimated 160,000 deaths in the US in 1999. Approximately 80% of lung cancer is nonsmall cell carcinoma (NSCLC). Due to the lack of early symptoms, most NSCLC patients are already in the advanced stages of the disease at the time of diagnosis. Combination chemotherapy regimens have produced clinical response or stabilization in many cases and newer drugs like gemcitabine, vinorelbine, and the taxanes have shown activity as single agents. However, effects on survival are modest. Treatment of stage iriB or IN ΝSCLC produces one year survival in the 20-40% range compared to 5-10% with supportive care alone. [0005] Anthracyclines, including doxorubicin, have shown activity in early combination chemotherapy for NSCLC, and doxorubicin was included in one of the first chemotherapy regimens to show a survival benefit in this disease. The anthracyclines have been largely supplanted in recent combination chemotherapy regimens in favor of the platinum compounds.
[0006] Recently, a novel class of anti-microtubule agents, the taxanes, has had an impact on both disease response and survival. The taxanes affect polymerized tubulin and promote formation of abnormally stable microtubules and inhibit their disassembly. This prevents the formation of a functional spindle apparatus, leading to cell cycle arrest in the G2/M phase of mitosis. The taxanes, and TAXOTERE® (docetaxel) in particular, have significantly improved response rates in multiple solid tumors, especially in advanced stage breast cancer, both as single agents and in combination with other anti- cancer agents. TAXOTERE® exhibits significant anti-tumor activity in a number of tumors including squamous cell carcinoma and adenocarcinomas such as NSCLC. TAXOL® (Pacitaxel) and TAXOTERE® are approved as therapy for NSCLC. TAXOL® is approved in combination with cisplatin as first line therapy for advanced stage NSCLC. TAXOTERE® is now approved as a single agent for patients who have failed first line chemotherapy. Because it is a phase specific agent, frequent administration offers a possible improvement in response with decreased toxicity. Recent trials with TAXOTERE® in adenocarcinomas have demonstrated tolerability with weekly administration and maintained high response rates.
[0007] Even for these newer drugs, however, the response rates remain very low (no better than 25% in phase III trials) and median survival is woefully short (less than 6 months from time to progression). Further, taxane-induced toxicity is a significant problem. The predominant toxicities are myelosuppression, which is dose related, and fluid retention. Consequently, there remains a significant unmet clinical need for patients with advanced stage NSCLC.
[0008] Toxicities to normal host tissue due to the lack of tumor specificity has been a major limitation of conventional chemotherapeutic agents, particularly with increasing dose intensity and in combination with other chemotherapeutic agents. Recently, a new class of biologic agents, monoclonal antibodies (mAb) has been developed that can target tumors and limit the associated toxicity to normal tissues. The success of agents such as Rituxan® (Rituximab), and Herceptin® (Trastuzumab) has underscored the utility of mAb-based therapeutics.
[0009] Despite the success of some therapeutic mAb (e.g., Herceptin®, Rituxan®, etc.), development of these biologic agents has been limited by a number of factors including: expression of target antigen on normal tissue, difficulties in the delivery of the mAb to the entire tumor burden, ineffective antibody-mediated tumor killing, and the immunogenicity of the murine mAbs. Therapeutic mAbs such as 17-1A used in colon carcinoma that have been effective in the adjuvant setting have not been effective in the metastatic setting. Other therapeutic mAbs such as Herceptin® have been associated with remarkable clinical activity in the metastatic breast cancer setting. Yet only a third of all breast cancers have Her-2/neu amplification, leaving a large number of patients with more limited treatment options.
[0010] Targeted immunotherapy combines the specificity of mAbs with the greater tumor killing activity of toxins or chemotherapeutic agents. However, this strategy has also been limited by normal tissue toxicity at the doses required to achieve meaningful anti-tumor activity. Thus, there is a need for a strategy that can be applied in a broader clinical setting and to a wider patient population that is not more toxic than conventional therapies.
[0011] These and other limitations and problems of the past are solved by the present invention.
BRIEF SUMMARY OF THE INVENTION [0012] A method is provided for treating patients having a tumor type known to express the Lewis Yantigen (Ley) including the administration of an antibody-drug conjugate comprising an antibody reactive with Lewis Y antigen conjugated to doxorubicin, followed by a cytotoxic or cytostatic agent. The cytotoxic or cytostatic agent can be administered from about 4 hours to about 24 hours, to greater than 24 hours (i.e., at least 28 hours), to about 30 hours, to about 36 hours, to about 48 hours or to about 72 hours after administration of the antibody drug conjugate. In some embodiments, the therapeutic effect of administering the antibody drug conjugate followed by administration of a cytostatic or cytostatic agent is additive, hi other embodiments, the therapeutic effect of administering antibody drug conjugate followed by administration of a cytostatic or cytostatic agent is synergistic.
[0013] In one embodiment, the cytostatic or cytotoxic agent is a tubulin inhibitor or an agent that inhibits, reduces or interferes with endocytosis. The cytostatic or cytostatic agent can be, for example, a taxane such as paclitaxel and docetaxel. In other embodiments, if the cytotoxic agent or cytostatic agent is paclitaxel or docetaxel, the cytostatic agent or cytostatic agent is administered at least 28 hours after administration ofBR96-Dox.
[0014] The (Ley) antigen can be expressed, for example, on a tumor, such as a epithelial tumor. The epithelial tumor can be, for example, a lung, colorectal, esophageal, gastric or ovarian tumor.
[0015] The invention will best be understood by reference to the following detailed description of the preferred embodiment, taken in conjunction with the accompanying drawings. The discussion below is descriptive, illustrative and exemplary and is not to be taken as limiting the scope defined by any appended claims.
BRIEF DESCRIPTION OF THE DRAWINGS [0016] Figure 1 shows drug sensitivity as a function of cell-cycle position. The cell division of L2987 lung carcinoma cells was synchronized by double thymidine block and release and pulse-titrated with Taxol® or BR96-Dox at progressive stages of the cell cycle. IC50 for each population was determined at 96 hr. The cell-cycle position of each population was determined by flow cytometery for DNA content using PI and the Cellfit program (Becton Dickenson). The relative levels of Le antigen in each population was determined by labeled BR96-Dox binding.
[0017] Figures 2 A and 2B show the effect of timing on matrix titrations of BR96-Dox and Taxol®. L2987 lung carcinoma cells were titrated with combinations of SGN-15 (an antibody drug conjugate composed of the BR96 mAb conjugated by a hydrazone linker to doxorubicin), at varying concentrations of Taxol®. hi all cases each drug was combined with cells for 1 hr, replaced with fresh media and cell viability was determined 96 hr after all combined drug treatments. Figure 2A shows IC50S produced by matrix combination of Taxol® preceding SGN-15 by 24 hr, and Figure 2B shows IC50s produced by matrix combination of Taxol® and SGN-15 given simultaneously.
[0018] Figure 3 shows the response to therapy with BR96-Dox, docetaxel, or combinations of both agents. Each study group contained 9 animals with L2987 NSCLC tumor xenografts.
[0019] Figure 4 shows combined response results from multiple BR96-Dox/docetaxel combination therapy studies. The number of mice receiving each therapeutic regimen is listed above each bar.
DETAILED DESCRIPTION OF THE INVENTION [0020] A method is provided for treating patients having a tumor type known to express the Lewis Yantigen (Ley) by administration of an antibody-drug conjugate comprising an antibody reactive with Lewis Y antigen conjugated to doxorubicin, followed by a cytotoxic or cytostatic agent. The cytotoxic or cytostatic agent can be administered from about 4 hours to about 24 hours, to greater than 24 hours (i.e., at least 28 hours), to about 30 hours, to about 36 hours, to about 48 hours or to about 72 hours after administration of the antibody drug conjugate. Also provided is the use of the antibody drug conjugate in the manufacture of a medicament for the treatment of a tumor type known to express the Lewis Y antigen, wherein the antibody drug conjugate is administered to a subject having the tumor, followed by administration of a cytotoxic agent or cytostatic agent from about 4 hours to about 24 hours, to greater than 24 hours (i.e., at least 28 hours), to about 30 hours, to about 36 hours, to about 48 hours or to about 72 hours after administration of the antibody drug conjugate.
[0021] BR96-Dox is an immunoconjugate comprised of the chimeric anti-Lewis Y (Ley) mAb BR96, conjugated to doxorubicin by an acid cleavable linker. (Wahl et al, Int. J. Cancer 93:590-600 (2001)). Humanized anti-Le(y) antibody hu3 SI 93 is another antibody that can be conjugated to Dox. (Boghaert et al., Clin Cancer Res. 10(13):4538- 49 (2004); the disclosure of which is incorporated by reference herein.) The Ley antigen is a tetrasacharide found as a glycoprotein at the cell surface on over 75% of epithelial cancers, such as carcinomas of the breast, gastrointestinal (GI) tract (e.g., colorectal, esophageal or gastric), lung, prostate, pancreatic, ovarian, and kidney, head and neck, and other cancers. [0022] While BR96 is capable of inducing tumor regression in animal models in its native form, it is even more effective as a drug immunoconjugate. BR96-Dox induces its anti-tumor effect through binding to the cell surface Ley antigen. After binding to the cell surface antigen, the immunoconjugate is rapidly internalized with release of doxorubicin through acid hydrolysis inside the cell. This mechanism of targeted drug delivery allows for relative sparing of tissues normally affected by non-specific chemotherapy, and represents an attractive strategy for the treatment of Ley-expressing tumors. In a specific embodiment, the BR96-Dox is SGN-15 (an antibody drug conjugate composed of the BR96 mAb conjugated by a hydrazone linker to doxorubicin).
[0023] The majority of cytotoxic chemotherapeutics are cell cycle-dependent. As a result, rapidly dividing cells are more sensitive to the killing activity than resting cells. Since the cell surface expression of the Ley tumor antigen is invariant throughout the cell cycle, the rate of BR96-Dox-mediated intemalization and release of free doxorubicin into the cytosol is relatively constant. As BR96-Dox delivers doxorubicin, the anti-tumor activity of the targeted agent is cell cycle-specific and similar to that of free doxorubicin, as shown in Fig. 1. Cells in the S-phase are the most sensitive to BR96-Dox exposure with those in G2/Mitosis being least sensitive. Doxorubicin is a potent DNA intercalating agent and impairs normal DNA synthesis at several steps. Following exposure to doxorubicin, cells arrest in G2 as a consequence of inhibition of topoisomerase II activity. The G2 arrest can sensitize cells to subsequent treatment with a cytostatic or cytotoxic agent that can preferentially act in G2. hi contrast, when Taxol® precedes BR96-Dox an additive (or slightly antagonistic) effect is observed (Fig. 2A). When the two agents are applied together the result is antagonistic (Fig. 2B).
[0024] The cytostatic or cytotoxic agent can be, for example, a microtubule inhibitor, an agent that reduces (e.g., inhibits or interferes) with endocytosis, a DNA alkylating agent, DNA topoisomerase inhibitors, plant alkaloids, anti-metabolites, pyrimidine analogs, receptor antagonists, or retinoids/deltoids. Suitable cytostatic or cytotoxic agents include, but are not limited to, methotrexate, taxol, L-asparaginase, mercaptopurine, thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide, nitrosoureas, cisplatin, carboplatin, mitomycin, dacarbazine, procarbizine, topotecan, nitrogen mustards, cytoxan, etoposide, 5-fluorouracil, BCNU, irinotecan, camptothecms, bleomycin, doxorubicin, idarubicin, daunorubicin, dactinomycin, plicamycin, mitoxantrone, asparaginase, vinblastine, vincristine, vinorelbine, paclitaxel, and docetaxel. In one aspect, the cytostatic or cytotoxic agent includes, but is not limited to, a drug listed in the following Table 1.
TABLE 1
Figure imgf000008_0001
Figure imgf000009_0001
Figure imgf000010_0001
[0025] In some embodiments, the cytostatic or cytotoxic agent can be a taxane. For example, a taxane such as doxorubicin can act in G2 to arrest the cell cycle by causing ineffective spindle formation. In another example, a taxane such as paclitaxel (TAXOL®), which in contrast to doxorubicin is less effective in Gl, can also cause a block in G2/M. In combination, BR96-Dox and Taxol® are able to target complementary populations of growing cells. In other embodiments, cytostatic or cytotoxic agent is not a taxane. hi certain specific embodiments, the taxane is not paclitaxel or docetaxel.
[0026] In some embodiments, the therapeutic effect of administering the antibody-drug conjugate (comprising an antibody reactive with Lewis Y antigen conjugated to doxorubicin) followed by administration of a cytostatic or cytotoxic agent is additive. In other embodiments, the therapeutic effect of administering the antibody drug conjugate followed by administration of a cytostatic or cytostatic agent is synergistic. As used herein, "synergistic" means that the combined therapeutic effect of the antibody drug conjugate and the cytostatic or cytotoxic agent exceeds the sum of their individual effects.
[0027] The antibody drug cognate and cytostatic or cytotoxic agent are administered to a subject having an Ley-expressing cancer. The term "subject" as used herein means any mammalian patient to which the antibody drug conjugate can be admimstered, including, e.g., humans and non-human mammals, such as primates, rodents, and dogs. Subjects specifically intended for treatment using the methods described herein include humans. The antibody drug conjugate and cytostatic or cytotoxic agent can be administered for the treatment and/or prophylaxis of an Ley-expressing cancer. [0028] Various delivery systems are known and can be used to administer the antibody drug conjugate and cytostatic or cytotoxic agent. Methods of introduction include but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The antibody drug conjugate and cytostatic or cytotoxic agent can be administered, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, and the like).
[0029] In specific embodiments, each of the antibody drug conjugate and cytostatic or cytotoxic agent is administered by injection, by means of a catheter, by means of a suppository, or by means of an implant, the implant being of a porous, non-porous, or gelatinous material, including a membrane, such as a sialastic membrane, or a fiber. Typically, when administering the composition, materials to which the antibody drug conjugate or cytostatic or cytotoxic agent does not absorb are used.
[0030] In other embodiments, the antibody drug conjugate and/or cytostatic or cytotoxic agent is delivered in a controlled release system. In one embodiment, a pump maybe used (see, e.g., Langer, 1990, Science 249:1527-1533; Sefton, 1989, CRC Crit. Ref Biomed. Eng. 14:201; Buchwald et al, 1980, Surgery 88:507; Saudek et al, 1989, N. Engl. J. Med. 321:574). In another embodiment, polymeric materials can be used. See Medical Applications of Controlled Release (Langer & Wise eds., CRC Press, Boca Raton, Florida, 1974); Controlled Drug Bioavailability, Drug Product Design and Performance (Smolen & Ball eds., Wiley, New York, 1984); Ranger & Peppas, 1983, Macromol. Sci. Rev. Macromol. Chem. 23:61. See also Levy et al, 1985, Science 228:190; During et al., 1989, Ann. Neurol. 25:351; Howard et al, 1989, J Neurosurg. 71:105. Other controlled release systems are discussed, for example, in Langer, supra.
[0031] The antibody drug conjugate and/or cytostatic or cytotoxic agent can be administered as pharmaceutical compositions comprising a therapeutically effective amount of the antibody drug conjugate and/or cytostatic or cytotoxic agent and one or more pharmaceutically compatible ingredients. For example, the pharmaceutical composition typically includes one or more pharmaceutical carriers (e.g., sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like). Water is a typical carrier when the pharmaceutical composition is admimstered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin. Such compositions will contain a therapeutically effective amount of the antibody drug conjugate or the cytostatic or cytotoxic agent, typically in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulations correspond to the mode of administration.
[0032] In typical embodiments, each pharmaceutical composition (e.g., BR96-Dox or the cytostatic or cytotoxic agent) is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the pharmaceutical can also include a solubilizing agent and a local anesthetic such as lignocaine to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. Where the pharmaceutical is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the pharmaceutical is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.
[0033] Further, a pharmaceutical composition can be provided as a pharmaceutical kit comprising (a) a container containing the antibody drug conjugate (e.g., BR96-Dox) in lyophilized form, (b) a container containing a cytostatic or cytotoxic agent, (c) a container containing a pharmaceutically acceptable diluent (e.g., sterile water) for the antibody drug conjugate (e.g., BR96-Dox), and (d) a container containing a pharmaceutically acceptable diluent (e.g., sterile water) for the cytotoxic or cytostatic agent. The pharmaceutically acceptable diluent can be used for reconstitution or dilution of the antibody drug conjugate and/or cytostatic or cytotoxic agent. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
[0034] The amount of the antibody drug conjugate and cytostatic or cytotoxic agent that is effective in the treatment or prevention of an Ley-expressing cancer can be determined by standard clinical techniques. In addition, in vitro assays can optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the formulation will also depend on the route of administration, and the stage of the Ley- expressing cancer, and should be decided according to the judgment of the practitioner and each patient's circumstances. Effective doses may be extrapolated from dose- response curves derived from in vitro or animal model test systems.
[0035] For example, toxicity and therapeutic efficacy of the antibody drug conjugate and cytostatic or cytotoxic agent can be determined in cell cultures or experimental animals by standard pharmaceutical procedures for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50. Where the antibody drug conjugate and/or cytostatic or cytotoxic agent exhibits toxic side effects, a delivery system that targets the antibody drug conjugate and/or cytostatic or cytotoxic agent to the site of affected tissue can be used to minimize potential damage to reduce side effects.
[0036] The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of the antibody drug conjugate and/or cytostatic or cytotoxic agent typically lies within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For antibody drug conjugate and/or cytostatic or cytotoxic agent used in the method, the therapeutically effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound that achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma can be measured, for example, by high performance liquid chromatography.
[0037] Generally, the dosage of an antibody drug conjugate (e.g., BR96-Dox) and/or cytostatic or cytotoxic agent administered to a patient with an Ley-expressing cancer is typically 0.1 mg/kg to 100 mg/kg of the subject's body weight. More typically, the dosage administered to a subject is 0.1 mg/kg to 50 mg/kg of the subject's body weight, even more typically 1 mg/kg to 30 mg/kg, 1 mg/kg to 20 mg/kg, 1 mg/kg to 15 mg/kg, or 1 mg/kg to 10 mg/kg of the subject's body weight.
[0038] The invention is further described in the following examples, which are not intended to limit the scope of the invention. The following examples describe a method of treating patients having a tumor type known to express Lewis Y antigen or any tumor type in which the majority of patients with a tumor type express Lewis Y antigen.
EXAMPLE 1 [0039] BR96-Dox may be administered prior to the administration of a taxane, particularly docetaxel, paclitaxel or any other taxane. The BR96-Dox is administered prior to the TAXOTERE® to enable the BR96-Dox to circulate to the tumor site and reach the tumor cells. BR96-Dox is a large molecule and circulation to the tumor cell particularly through the tumor microvasculature may be slow because of high interstitial pressure, abnormal vasculature and sticking of the protein to the vessel wall. Sufficient time must be given for BR96-Dox to be internalized into the tumor cell through the process of endocytosis. About four hours, in some aspects about six hours, will be required to allow the circulation and intemalization of BR96-Dox. While the period of greater than 6 hours and less than 24 hours may also be suitable on pharmacological grounds, this would require the patient to be kept in hospital for a full day. If the patient was able to return the following day instead, thus giving the TAXOTERE® 24 hours following BR96-Dox administration, the TAXOTERE® is still administered during its pharmacological high point, yet conveniently for patient scheduling.
[0040] TAXOTERE® may be administered following BR96-Dox administration for about 4 days following or until the instability of the antibody drug conjugate would reduce the potential effectiveness of the combination.
[0041 ] The route of administration for both the BR96-Dox and the TAXOTERE® can be intravenous. However, in another embodiment, the monoclonal antibody portion may be given intraperitoneally. hitraperitoneal administration may be used, for example, in tumors with a tendency to peritoneal spread. One example of such tumors is ovarian tumors. The administration of the monoclonal antibody portion and/or the cytotoxic or cytostatic agent may also be accomplished orally if the compounds are formulated for oral administration.
[0042] TAXOTERE® can be administered at a dose of about 25-35 mg/m2/week and BR96-Dox can be administered at a dosage at about 200 mg/m to about 350 mg/m . A suboptimal dose of TAXOTERE® or the approved dose of TAXOTERE® according to the product label may be used. Additionally, any dose of TAXOTERE® which has been published in the literature as showing efficacy can be used for subsequent administration following BR96-Dox. A suboptimal dosage of BR96-Dox and/or a dosage close to the maximally tolerated dose (MTD) may be used.
[0043] The number of courses of treatment are determined by patient response, according to one of skill in the art, such as the patient's treating physician.
[0044] Patients receiving TAXOTERE® can receive pretreatment with dexamethasone or another steroid. They may also receive pretreatment with an antihistamine and/or an antinausea drug, such as but not limited to, 5HT antagonist.
[0045] One method of confirming the dosage interval that confers added efficacy will be by biomarker and PET Positron Emission Tomography (PET) analysis. Such a method can also be used to confirm the dosage interval of about 4 to about 72 hours. EXAMPLE 2
[0046] Mouse xenograft models of human non-small cell lung cancer demonstrate that the efficacy of the BR96-Dox and docetaxel when administered in combination is dependent of the schedule of administration. For example, administering BR96-Dox approximately 48 hours prior to docetaxel results in consistently greater efficacy than when the two agents are administered with a shorter interval or when docetaxel is administered first. The skilled artisan will appreciate that an interval in mouse can be equivalent to a different interval in humans, allowing for differences in body mass, tumor mass, increased peri-tumor fibrosis and differences in time to full distribution and tumor penetration.
[0047] Method and results: Human tumor xenografts were implanted subcutaneously in female athymic (nu/nu) mice using the non-small cell lung carcinoma line L2987 (Trail et al., Clinical Cancer Research 5:3632 (1999)). Tumor volumes were calculated using the formula (LxW2)/2. When tumor volumes averaged approximately 100 mm3 (range 40-144 mm3) study animals were randomly distributed into study groups. Study groups consisted of (1) untreated control, (2) BR96-Dox (also referred to as SGN-15) alone, (3) docetaxel alone, or a combination of BR96-Dox + docetaxel using the following schedules: (4) BR96-Dox + docetaxel administered on the same day; (5) BR96-Dox followed 24 hours later by docetaxel; (6) BR96-Dox followed 48 hours by docetaxel; (7) BR96-Dox followed 72 hours by docetaxel; (8) docetaxel followed 24 hours later by BR96-Dox; (9) docetaxel followed 48 hours later by BR96-Dox; and (10) docetaxel followed 72 hours later by BR96-Dox. For all groups therapy was administered every 7 days for 3 weeks. For single agent and combination therapies BR96-Dox was administered intraperitoneally at 15 mg/kg/dose and docetaxel was administered intravenously at 7.5 mg/kg/dose.
[0048] After initiation of therapy the tumors measured twice weekly. At the completion of the study each animal was scored for response or no-response. Response was defined as the tumor being of smaller volume at any measurement after the initiation of therapy relative to that tumor volume at the initiation of therapy. As shown in Figure 3, all of the combination groups showed enhanced response compared to either BR96- Dox or docetaxel alone. The highest response rate, 89%, was achieved when BR96-Dox was administered first with docetaxel administered 48 hours later. [0049] These results were confirmed through a series of additional experiments with BR96-Dox + docetaxel, summarized in Figure 4, as well as BR96-Dox + paclitaxel. In total these results demonstrate that the in vivo efficacy BR96-Dox + taxane is dependent on the sequence and timing of administration.
[0050] No license is expressly or implicitly granted to any patent or patent applications referred to or incorporated herein. The discussion above is descriptive, illustrative and exemplary and is not to be taken as limiting the scope defined by any appended claims.
[0051] Various references, including patent applications, patents, and scientific publications, are cited herein, the disclosures of each of which is incorporated herein by reference in its entirety.

Claims

1. A method of treating a patient having a tumor type known to express the Lewis Y antigen comprising: administering to the patient a therapeutically effective amount of an antibody-drug conjugate comprising an antibody reactive with Lewis Y antigen conjugated to doxorubicin, followed by administration of a therapeutically effective amount of a cytotoxic agent or cytostatic agent from about 4 hours to about 72 hours after administration of the BR96-Dox, with the proviso that if the cytotoxic agent or cytostatic agent is paclitaxel or docetaxel, the cytostatic agent or cytostatic agent is administered at least 30 hours after administration of BR96-Dox.
2. The method of claim 1, wherein the antibody-drug conjugate is BR96-Dox.
3. The method of claim 1, wherein the cytostatic agent or cytotoxic agent is a tubulin inhibitor, an agent that reduces endocytosis, a nitrogen mustards, a nitrosourea, an alkylsulphonates, a triazenes, a platinum containing compound, a vinca alkaloid, a taxoid, a DNA topoisomerase inhibitor, an epipodophyllin, a mitomycin, a DHFR inhibitor, an IMP dehydrogenase inhibitor, a ribonucleotide reductase inhibitor, a pyrimidine analog, a uracil analog, a cytosine analog, a purine analog, an anti-estrogen, an LHRH agonist, an anti-androgen, a Vitamin D3 analog, a photodynamic therapy, a cytokine, an isoprenylation inhibitor, a dopaminergic neurotoxin, a cell cycle inhibitor, an actinomycin, a bleomycin, an anthracycline, an MDR inhibitor, or a Ca + ATPase inhibitor.
4. The method of claim 1, wherein the tumor is an epithelial tumor.
5. The method of claim 4, wherein the epithelial tumor is selected from at least one of the group consisting of lung, colorectal, esophageal, gastric, and ovarian.
6. The method of claim 3, wherein the tubulin inhibitor is a taxane.
7. The method of claim 6, wherein the taxane is selected from at least one of the group consisting of paclitaxel and docetaxel.
8. The method of claim 7, wherein the taxane is docetaxel.
9. The method of claim 1 wherein the cytostatic or cytotoxic agent is administered about 24 hours following administration of BR96-Dox.
10. The method of claim 1, wherein the cytostatic or cytotoxic agent is administered about 48 hours following administration of BR96-Dox.
11. The method of claim 1 wherein the cytostatic or cytotoxic agent is administered about 72 hours following admimstration of BR96-Dox.
12. The use of an antibody-drug conjugate comprising an antibody reactive with Lewis Y antigen conjugated to doxorubicin in the manufacture of a medicament for the treatment of a tumor type known to express the Lewis Y antigen, wherein the BR96-Dox is administered to a subject having the tumor, followed by admimstration of a cytotoxic agent or cytostatic agent from about 4 hours to about 72 hours after administration of the BR96-Dox, with the proviso that if the cytotoxic agent or cytostatic agent is paclitaxel or docetaxel, the cytostatic agent or cytostatic agent is administered at least 20 hours after administration of BR96-Dox.
13. The use of claim 12, wherein the antibody drug conjugate is BR96-Dox.
14. The use of claim 12, wherein the cytostatic agent or cytotoxic agent is a tubulin inhibitor, an agent that reduces endocytosis, a nitrogen mustards, a nitrosourea, an alkylsulphonates, a triazenes, a platinum containing compound, a vinca alkaloid, a taxoid, a DNA topoisomerase inhibitor, an epipodophyllin, a mitomycin, a DHFR inhibitor, an IMP dehydrogenase inhibitor, a ribonucleotide reductase inhibitor, a pyrimidine analog, a uracil analog, a cytosine analog, a purine analog, an anti-estrogen, an LHRH agonist, an anti-androgen, a Vitamin D3 analog, a photodynamic therapy, a cytokine, an isoprenylation inhibitor, a dopaminergic neurotoxin, a cell cycle inhibitor, an actinomycin, a bleomycin, an anthracycline, an MDR inhibitor, or a Ca2+ ATPase inhibitor.
15. The use of claim 12, wherein the tumor is an epithelial tumor.
16. The use of claim 15, wherein the epithelial tumor is selected from at least one of the group consisting of lung, colorectal, esophageal, gastric, and ovarian.
17. The use of claim 14, wherein the tubulin inhibitor is a taxane.
18. The use of claim 17, wherein the taxane is selected from at least one of the group consisting of paclitaxel and docetaxel.
19. The use of claim 18, wherein the taxane is docetaxel.
20. The use of claim 12, wherein the cytostatic or cytotoxic agent is administered about 24 hours following admimstration of BR96-Dox.
21. The use of claim 12, wherein the cytostatic or cytotoxic agent is administered about 48 hours following administration of BR96-Dox.
22. The use of claim 12, wherein the cytostatic or cytotoxic agent is administered about 72 hours following administration of BR96-Dox.
PCT/US2005/002406 2004-01-23 2005-01-24 Drug immunoconjugate combination therapy WO2005070026A2 (en)

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US10918735B2 (en) 2012-12-04 2021-02-16 Massachusetts Institute Of Technology Substituted pyrazino[1′,2′:1,5]pyrrolo[2,3-b]indole-1,4-diones for cancer treatment
EP3204018A4 (en) * 2014-10-07 2018-05-23 Immunomedics, Inc. Neoadjuvant use of antibody-drug conjugates
EP3954373A1 (en) * 2014-10-07 2022-02-16 Immunomedics, Inc. Neoadjuvant use of antibody-drug conjugates
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US10640508B2 (en) 2017-10-13 2020-05-05 Massachusetts Institute Of Technology Diazene directed modular synthesis of compounds with quaternary carbon centers

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