Treatment for neoplastic diseases

Abstract

To provide a pharmaceutical agent for treating a tumor-associated disease in a human subject (for example, colorectal cancer having a KRAS mutation, EBV-associated cancers such as nasopharyngeal carcinoma or Burkitt lymphoma, non-small cell lung cancer (NSCLC), or a non-cancerous condition accompanied by a tumor such as Castleman disease).SOLUTION: Use of an antibody (Ab) that specifically binds to interleukin-1α (IL-1α) for treating a tumor-associated disease and other tumor-associated pathologies is provided. Administration of an mAb that specifically binds to IL-1α is useful for treating a tumor-associated disease in a human subject.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application Nos. 61 / 376,097, filed August 23, 2010, 61 / 406,759, filed October 26, 2010, 61 / 411,183, filed November 8, 2010, and 61 / 480,635, filed April 29, 2011, all of which are incorporated by reference in their entirety.

[0002] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT Not applicable.

[0003] The present invention relates generally to the fields of medicine, cancer, and immunology. In particular, the present invention relates to the use of antibodies (Abs) that specifically bind to interleukin-1α (IL-1α) to treat tumor-related diseases and other tumor-related conditions. [Background technology]

[0004] Despite significant advances, tumor-related diseases such as cancer remain one of the leading causes of death and illness in developed countries. Although much of the molecular mechanism of tumorigenesis is now understood, the standard treatments for the most aggressive tumors remain surgical resection, chemotherapy, and radiation therapy. While increasingly successful, each of these treatments still causes many undesirable side effects. For example, surgery results in pain, trauma to healthy tissue, and scarring. Radiation therapy and chemotherapy can cause nausea, immunosuppression, gastric ulcers, and secondary tumor formation.

[0005] Over the past few years, significant progress has been made in using biological agents such as Abs to treat cancerous tumors. Abs can directly target specific types of tumor cells to harness a patient's immune response to kill tumors. Alternatively, they can target cell growth factors to block tumor cell proliferation. As with traditional chemotherapy agents, not all anti-tumor Abs are useful for treating all types of neoplasms, and many initially effective antibodies subsequently lose their effectiveness. Therefore, new anti-tumor Abs are needed. Summary of the Invention

[0006] The present invention is based on the discovery that mAbs that specifically bind to IL-1α are useful for treating a variety of tumor-related diseases.

[0007] Accordingly, the present invention features agents and methods for treating neoplastic diseases (e.g., colorectal cancer, such as those with KRAS mutations; EBV-associated cancers, such as nasopharyngeal carcinoma or Burkitt's lymphoma; non-small cell lung cancer (NSCLC); or tumor-associated non-cancerous conditions, such as Castleman's disease) in a human subject. The methods can be carried out by administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an anti-IL-1α Ab in an amount effective to ameliorate symptoms of the tumor-associated condition and / or reduce tumor size by at least about 10% (e.g., at least 8, 9, 10, 15, 17, 20, 30, 40, 50, 60, 70, 80, 90, or 100%) in the subject. The agents can include an anti-IL-1α Ab. The anti-IL-1α Ab can be a mAb, such as IgG1. The anti-IL-1α Ab can be a mAb that is MABp1 or that includes one or more complementarity-determining regions (CDRs) of MABp1.

[0008] The pharmaceutical composition can be administered to a subject by subcutaneous, intravenous, intramuscular injection, or direct injection into a tumor. In this method, the dose can be at least 0.25 (e.g., at least 0.2, 0.5, 0.75, 1, 2, 3, 4, or 5) mg / mL.

[0009] Unless otherwise specified, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Commonly understood definitions of biological terms can be found in Rieger et al., Glossary of Genetics: Classical and Molecular, 5th edition, Springer-Verlag: New York, 1991; and Lewin, Genes V, Oxford University Press: New York, 1994. Commonly understood definitions of medical terms can be found in Stedman's Medical Dictionary, 27 th Edition, Lippincott, Williams & Wilkins, 2000.

[0010] As used herein, "Ab" or "Ab" refers to an immunoglobulin (Ig), a solution of homogeneous or heterogeneous Ig, or a mixture of Ig. "Ab" can also refer to fragments and variants of Ig, such as Fab, Fab', and F(ab')2 fragments; and scFv, heterozygous Abs, as well as similar artificial molecules that use Ig-derived CDRs to confer antigen specificity. "mAb" or "mAb" refers to an Ab expressed by a single clonal B cell line or a population of Ab molecules that contain only one type of antigen-binding site capable of immunoreacting with a specific epitope of a particular antigen. "Polyclonal Ab" or "polyclonal Ab" refers to a mixture of heterogeneous Abs. Generally, polyclonal Abs contain numerous different Ab molecules that bind to a specific antigen, with at least some of the different Abs immunoreacting with different epitopes of that antigen. As used herein, polyclonal Ab can be a mixture of two or more mAbs.

[0011] The "antigen-binding portion" of an Ab is the portion of the Ab that is contained within the variable region of the Fab portion and confers antigen specificity to the Ab (i.e., the three-dimensional pocket typically formed by the CDRs of the heavy and light chains of the Ab). A "Fab portion" or "Fab region" is a proteolytic fragment of a papain-digested Ig that contains the antigen-binding portion of that Ig. A "non-Fab portion" is a portion of an Ab that is not within the Fab portion, e.g., the "Fc portion" or "Fc region." The "constant region" of an Ab is the portion of the Ab outside the variable region. Generally encompassed within the constant region is the "effector portion" of the Ab, which is the portion of the Ab that is involved in binding to other immune system components to promote an immune response. Thus, for example, the site on an Ab that binds to complement components or Fc receptors (other than via its antigen-binding portion) is the effector portion of that Ab.

[0012] When referring to a protein molecule, such as an Ab, "purified" means separated from components that naturally accompany such a molecule. Generally, an Ab or protein is purified when it is at least about 10% by weight (e.g., 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99%, 99.9%, and 100%) free from non-Ab proteins or other naturally occurring organic molecules with which it is naturally associated. Purity can be measured by any suitable method, such as column chromatography, polyacrylamide gel electrophoresis, or HPLC analysis. Chemically synthesized proteins or other recombinant proteins produced in a cell type other than the cell type in which the protein naturally occurs are "purified."

[0013] "Bind," "binds," or "reacts with" means that a molecule recognizes and attaches to a specific second molecule in a sample, but does not substantially recognize or attach to other molecules in the sample. Generally, an Ab that "specifically binds" to another molecule has a specific binding affinity of about 10 to that other molecule. 5 , 10 6 , 107 , 10 8 , 10 9 , 10 10 , 10 11 or 10 12 K greater than L / mol d It has.

[0014] A "therapeutically effective amount" is an amount that is capable of producing a medically desired effect (eg, amelioration or prevention of a disease or symptoms of a disease) in the treated animal or human.

[0015] Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. Additionally, the specific embodiments discussed below are illustrative only and not limiting. DETAILED DESCRIPTION OF THE INVENTION

[0016] The present invention encompasses compositions and methods for ameliorating one or more symptoms of a tumor-related condition in a subject. The preferred embodiments described below illustrate the application of these compositions and methods. However, other aspects of the invention may arise and / or be practiced from the description of these embodiments based on the description provided below.

[0017] General Method Methods including conventional immunological and molecular biology techniques are described herein. Immunological methods (e.g., assays for the detection and localization of antigen-Ab complexes, immunoprecipitation, immunoblotting, etc.) are generally known in the art and are described in technical textbooks such as *Current Protocols in Immunology*, Coligan et al., ed., John Wiley & Sons, New York. Molecular biology techniques are described in detail in technical textbooks such as *Molecular Cloning: A Laboratory Manual*, 2nd ed., vols. 1-3, Sambrook et al., ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 2001; and *Current Protocols in Molecular Biology*, Ausubel et al., ed., Greene Publishing and Wiley-Interscience, New York. Ab-related methods are described in *Handbook of Therapeutic Abs*, Dubel, S., ed., Wiley-VCH, 2007. A common method of medical treatment is described by McPhee and Papadakis, Current Medical Diagnosis and Treatment 2010, 49 th Edition, McGraw-Hill Medical, 2010; and Fauci et al., Harrison's Principles of Internal Medicine, 17 th Edition, McGraw-Hill Professional, 2008.

[0018] Treatment of tumor-related diseases The compositions and methods described herein are useful for treating tumor-related diseases in mammalian subjects by administering to the subject a pharmaceutical composition containing an anti-IL-1α Ab in an amount effective to ameliorate at least one characteristic of the tumor-related disease in the subject. The mammalian subject may be any animal suffering from a tumor-related disease, including humans, dogs, cats, horses, cattle, sheep, goats, and pigs. Human subjects may be male, female, adult, pediatric, elderly (65 years or older), and those suffering from other diseases. Particularly preferred subjects are those whose disease has progressed after treatment with chemotherapy, radiation therapy, surgery, and / or biologic agents. Any type of tumor-related disease susceptible to treatment with anti-IL-1α Abs can be targeted. Administration of anti-IL-1α Abs is believed to be particularly effective for treating colorectal tumors (e.g., colorectal cancer with KRAS mutations), EBV-associated neoplasms such as nasopharyngeal carcinoma or Burkitt's lymphoma, NSCLC, and hematopoietic cancers such as those in Castleman's disease. Diseases involving tumors expressing IL-1α or tumors infiltrated with IL-1α inflammatory cells may also be targeted. Specific characteristics of the tumor-related disease to be ameliorated include tumor size (e.g., T0, Tis, or T1-4), metastatic status (e.g., M0, M1), number of tumors observed, lymph node involvement (e.g., N0, N1-4, Nx), grade (i.e., grade 1, 2, 3, or 4), stage (e.g., 0, I, II, III, or IV), the presence or concentration of certain markers in cells or body fluids (e.g., AFP, B2M, β-HCG, BTA, CA). The improvement may be an improvement in tumor volume or linear dimension (e.g., tumor size ...

[0019] Antibodies and other agents that target IL-1α Any suitable type of Ab or other biological agent (e.g., a fusion protein containing an IL-1α-binding component such as an IL-1 receptor) that specifically binds to IL-1α and alleviates tumor-related disease characteristics in a subject can be used in the present invention. For example, the anti-IL-1α Ab used can be a mAb, a polyclonal Ab, a mixture of mAbs, or a modified Ab-like molecule such as an Ab fragment or scFv. The Ka of the Ab is preferably at least 1×10 9 M -1 or more (e.g., 9×10 10 M -1 , 8×10 10 M -1 , 7×10 10 M -1 , 6×10 10 M -1 , 5×10 10 M -1 , 4×10 10 M -1 , 3×10 10 M -1 , 2 × 10 10 M -1 or 1 x 10 10 M -1 In a preferred embodiment, the present invention utilizes fully human mAbs comprising (i) an antigen-binding variable region that exhibits very high binding affinity (e.g., at least nano- or picomolar levels) for human IL-1α, and (ii) a constant region. The human Ab is preferably IgG1, but may be of various isotypes, such as IgM, IgA, or IgE, or subclasses, such as IgG2, IgG3, or IgG4. One particularly useful mAb is MABp1, an IL-1α-specific IgG1 mAb, described in U.S. Patent Application No. 12 / 455,458, filed June 1, 2009. Other useful mAbs include those that comprise at least one, but preferably all, CDRs of MABp1.

[0020] Because B lymphocytes expressing Ig specific for human IL-1α naturally occur in humans, the currently preferred method for generating mAbs is to first isolate such B lymphocytes from a subject and then immortalize them so that they can be continuously replicated in culture. Subjects who do not have large numbers of natural B lymphocytes expressing Ig specific for human IL-1α can be immunized with one or more human IL-1α antigens to increase the number of such B lymphocytes. Human mAbs are prepared by immortalizing human Ab-secreting cells (e.g., human plasma cells). See, e.g., U.S. Patent No. 4,634,664.

[0021] In a typical method, one or more (e.g., 5, 10, 25, 50, 100, 1000, or more) human subjects are screened for the presence or absence of such human IL-1α-specific Abs in their blood. Subjects expressing the desired Abs can then be used as B lymphocyte donors. In one possible method, peripheral blood is obtained from a human donor bearing B lymphocytes expressing Abs specific to human IL-1α. Such B lymphocytes are then isolated from the blood sample, for example, by cell sorting (e.g., fluorescence-activated cell sorting, "FACS"; or magnetic bead cell sorting), and B lymphocytes expressing Igs specific to human IL-1α are selected. These cells can then be immortalized by viral transformation (e.g., using EBV) or by fusion to another immortalized cell, such as a human myeloma, according to known techniques. B lymphocytes expressing Ig specific for human IL-1α can then be isolated from this population by limiting dilution (e.g., cells positive for Ig specific for human IL-1α in wells of a microtiter plate are selected, subcultured, and the process repeated until the desired clonal line is isolated). See, e.g., Goding, MAbs: Principles and Practice, pp. 59-103, Academic Press, 1986. Clonal cell lines expressing Ig with at least nanomolar or picomolar binding affinity for human IL-1α are preferred. MAbs secreted by these clonal cell lines can be purified from culture media or body fluids (e.g., ascites) by conventional Ig purification procedures such as salt cuts, size exclusion, ion exchange separation, and affinity chromatography.

[0022] Although immortalized B lymphocytes can be used in in vitro culture to directly produce MAbs, in some cases it may be desirable to use heterologous expression systems to produce mAbs. See, e.g., the methods described in U.S. Patent Application No. 11 / 754,899. For example, genes encoding mAbs specific for human IL-1α may be cloned and introduced into expression vectors (e.g., plasmid-based expression vectors) for expression in heterologous host cells (e.g., CHO cells, COS cells, myeloma cells, and Escherichia coli (E. coli) cells). Because Ig contains heavy (H) and light (L) chains in an H2L2 configuration, the genes encoding each can be isolated separately and expressed in different vectors.

[0023] Although generally less preferred due to a higher likelihood that the subject will develop an anti-Ab response, chimeric mAbs (e.g., "humanized" mAbs), which are antigen-binding molecules in which each portion is derived from a different animal species (e.g., a mouse Ig variable region fused to a human Ig constant region), may also be used in the present invention. Such chimeric Abs can be prepared by methods known in the art. See, e.g., Morrison et al., Proc. Nat'l. Acad. Sci. USA, 81:6851, 1984; Neuberger et al., Nature, 312:604, 1984; Takeda et al., Nature, 314:452, 1984. Similarly, Abs can be humanized by methods known in the art. For example, mAbs with a desired binding specificity can be humanized by various commercial suppliers or as described in US Pat. Nos. 5,693,762; 5,530,101; or 5,585,089.

[0024] The mAbs described herein may be affinity matured to enhance or alter their binding specificity by known methods, such as VH and VL domain shuffling (Marks et al. Bio / Technology 10:779-783, 1992), random mutagenesis of hypervariable region (HVR) and / or framework residues (Barbas et al. Proc Nat. Acad. Sci. USA 91:3809-3813, 1994; Schier et al. Gene 169:147-155, 1995; Yelton et al. J. Immunol. 155:1994-2004, 1995; Jackson et al. J. Immunol. 154(7):3310-9, 1995; and Hawkins et al. J. Mol. Biol. 226:889-896, 1992). Amino acid sequence variants of an Ab can be prepared by introducing appropriate changes into the nucleotide sequence encoding the Ab. Furthermore, modifications to the nucleic acid sequence encoding the mAb can be varied (e.g., intron deletion and / or codon optimization for a given expression system) to facilitate production of the mAb in certain expression systems (e.g., without changing the amino acid sequence of the mAb). The mAbs described herein can also be modified by conjugation to another protein (e.g., another mAb) or a non-protein molecule. For example, the mAb can be conjugated to a water-soluble polymer such as polyethylene glycol or carbon nanotubes (see, e.g., Kam et al., Proc. Natl. Acad. Sci. USA 102:11600-11605, 2005). See U.S. Patent Application No. 11 / 754,899.

[0025] Preferably, to ensure that high titers of human IL-1α-specific mAb can be administered to a subject with minimal adverse effects, the mAb compositions of the invention are at least 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 95, 96, 97, 98, 99, 99.9 percent pure by weight or more (excluding excipients). The mAb compositions of the invention may comprise only one mAb (i.e., produced from a single clonal B lymphocyte cell line) or may comprise a mixture of two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) different mAbs.

[0026] Human IL-1α mAbs may be conjugated to another molecule, such as a cytotoxin, to alter or enhance their function. Human IL-1α-specific mAbs may be conjugated to one or more cytotoxins to more effectively kill cells expressing IL-1α. A cytotoxin for use in the present invention can be any cytotoxic agent (e.g., a molecule capable of killing cells after contact with them) that can be conjugated to a human IL-1α-specific mAb. Examples of cytotoxins include radionuclides (e.g., 35 S, 14 C. 32 P, 125 I, 131 I, 90 Y, 89 Zr, 201 Tl, 186 Re, 188 Re, 57 Cu, 213 Bi and 211Further examples of cytotoxins include, but are not limited to, antimetabolites (e.g., 5-fluorouricil (5-FU), methotrexate (MTX), fludarabine, etc.), anti-microtubule agents (e.g., vincristine, vinblastine, colchicine, taxanes (e.g., paclitaxel and docetaxel), alkylating agents (e.g., cyclophasphamide, melphalan, bischloroethylnitrosurea (BCNU), etc.), platinum agents (e.g., cisplatin (also known as cDDP), carboplatin, oxaliplatin, JM-216, CI-973, etc.), anthracyclines (e.g., doxorubicin, daunorubicin, etc.), antibiotics (e.g., mitomycin-C), topoisomerase inhibitors (e.g., etoposide, tenoposide, and camptothecin), or other cytotoxic agents such as ricin, diphtheria toxin (DT), Pseudomonas aeruginosa exotoxin (PE) A, PE40, abrin, saporin, pokeweed virus protein, ethidium bromide, glucocorticoids, anthrax toxin, etc. See, e.g., U.S. Patent No. 5,932,188.

[0027] While the above-described IL-1α-specific Abs are preferred for use in the present invention, other agents that specifically target IL-1α may be used in some cases, so long as their administration results in amelioration of tumor-related disease characteristics. These other agents may include small organic molecules, aptamers, peptides, and proteins that specifically bind to IL-1α (e.g., anakinra or rilonacept).

[0028] Pharmaceutical Compositions and Methods The anti-IL-1α Ab compositions can be administered to animals or humans in a pharmaceutically acceptable carrier (e.g., sterile saline), selected based on the mode and route of administration and standard pharmaceutical practice. Lists of pharmaceutically acceptable carriers and pharmaceutical formulations can be found in Remington's Pharmaceutical Sciences and USP / NF, standard textbooks in this field. Other substances may be added to the compositions, and other steps taken to stabilize and / or preserve the compositions and / or to facilitate their administration to subjects.

[0029] For example, the Ab composition may be lyophilized (see Draber et al., J. Immunol. Methods. 181:37, 1995; and PCT / US90 / 01383); dissolved in a solution containing sodium and chloride ions; dissolved in a solution containing one or more stabilizers, such as albumin, glucose, maltose, sucrose, sorbitol, polyethylene glycol, and glycine; filtered (e.g., using a 0.45 and / or 0.2 micron filter); contacted with β-propiolactone; and / or dissolved in a solution containing a disinfectant (e.g., a surfactant, an organic solvent, and a mixture of a surfactant and an organic solvent).

[0030] The Ab compositions may be administered to animals or humans by any suitable technique. Generally, such administration is parenteral (e.g., intravenous, subcutaneous, intramuscular, or intraperitoneal introduction). The compositions may also be administered directly to the target site (e.g., intratumorally), for example, by injection. Other delivery methods are known in the art, such as liposomal delivery or diffusion from a device impregnated with the composition. The compositions may be administered in a single bolus, multiple injections, or by continuous infusion (e.g., intravenously or by peritoneal dialysis).

[0031] A therapeutically effective amount is an amount capable of producing a medically desirable result in the treated animal or human. An effective amount of an anti-IL-1α Ab composition is an amount that shows a clinical benefit in the patient as assessed by improvement in one or more of the above-mentioned characteristics of the tumor-related disease. As is well known in the medical arts, the dosage for any single animal or human depends on many factors, including the subject's size, body surface area, age, the particular composition to be administered, sex, time and route of administration, general health, and other drugs administered concomitantly. A preferred dosage ranges from about 0.2 to 20 (e.g., 0.15, 0.2, 0.3, 0.4, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 50, or 100) mg / kg body weight. This dosage can be given repeatedly, e.g., hourly, daily, twice weekly, weekly, once every two weeks, once every three weeks, or monthly. [Example]

[0032] Example 1 - Xilonix™ Xilonix™ is a sterile injectable formulation of 15 mg / mL MAbp1 in a stabilized isotonic buffer (pH 6.4). Each 10 mL Type I borosilicate glass serum vial contains 5 mL of this formulation and is sealed with a 20 mm Daikyo Seiko Flurotec butyl rubber stopper and flip-off aluminum seal. The product is stored at 5±3°C and may be taken to room temperature. The exact composition of this formulation is shown below. TIFF2025166117000001.tif84153

[0033] Administration method: Using an appropriate syringe, the calculated volume is withdrawn from the drug (mAb)-containing vial. The drug is then injected into a small IV bag containing 100 mL of saline (0.9% NaCl) and mixed by inversion. The diluted formulation can be stored at room temperature for 3 hours before administration and infused over 1 hour, monitoring the subject for signs of infusion reactions. A minimum of 30 mL of saline flush is performed to deliver all of the product that can be held in the infusion set.

[0034] Example 2 - Treatment of colorectal cancer with IL-1α-specific MAb (Xilonix™) The human subject was a 63-year-old woman diagnosed with metastatic colorectal cancer (KRAS mutation-positive). Prior to treatment with Xilonix™, the subject underwent a right hemicolectomy and was reportedly staged as T3N1MX. The subject then underwent adjuvant chemotherapy with FOLFOX for a total of 12 cycles over approximately 6 months. A PET-CT scan performed approximately 2 months after completing FOLFOX treatment revealed a mass in the subject's pelvis. The subject was hospitalized for placement of a ureteral stent due to obstructive hydronephrosis, apparently of tumor origin. The subject was immediately initiated on FOLFIRI and Avastin and received 8 cycles of treatment. The subject then underwent re-staging with a PET-CT scan, which confirmed disease in the pelvis and also revealed intrapulmonary nodules consistent with metastatic disease. A CT scan of the chest, abdomen, and pelvis revealed a 12-cm pelvic mass, a 2-cm omental mass, and right-sided hydronephrosis with a ureteral stent. The subject received two additional cycles of FOLFIRI and Avastin. Subsequent PET / CT scans showed progression of bilateral pulmonary nodules. The subject then began irinotecan and Erbitux® (cetuximab) therapy. Follow-up PET / CT scans revealed disease progression in the lungs.

[0035] The subject began a Phase 1 trial with Doxil® (liposomal doxorubicin), Velcade® (bortezomib), and Gemzar® (gemcitabine), but unfortunately, initial restaging indicated disease progression. The subject also completed another Phase 1 trial with oxaliplatin in combination with azacitidineone, completing two cycles without disease progression. Upon completion of the subject's participation in this final Phase 1 clinical trial, the subject was enrolled in this clinical trial.

[0036] The subject was enrolled in the first dose cohort (0.25 mg / mL) and completed a 5-21 day cycle in the protocol, thus receiving a total of five infusions of MABp1 (0.25 mg / kg) every 21 days. The subject's dose was increased to 0.75 mg / kg on day 1 of cycle 6. The initial PET CT scan revealed a reduction in the sum of the patient's tumor diameters during follow-up by approximately 17%. After further administration of MABp1, the patient's sum of the follow-up tumor diameters was observed to decrease by more than 30%. A chest CT scan showed that the paratracheal lymph node had shrunk from a previous measurement of 3.5 cm to 2.9 cm at the end of cycle 6. The left lung metastasis shrank from 2.2 cm to 1.9 cm, and the explanted metastatic tissue from the left rectus muscle shrank from 3.2 cm to 2.7 cm. The baseline CEA tumor marker was 81, which decreased to 69.2 at the end of cycle 3 and was 27.9 on day 1 of cycle 7. The patient has remained on treatment for over 71 weeks with stable disease.

[0037] Example 3 - Treatment of Nasopharyngeal Carcinoma with IL-1α-Specific MAb (Xilonix™) The subject was a 47-year-old Chinese man with EBV+ (Epstein-Barr virus) nasopharyngeal carcinoma with the histological subtype lymphoepithelioma (old term) or nonkeratinizing carcinoma. The subject had previously received treatment with cisplatin, 5-FU, radiation therapy, Taxotere® (docetaxel), Gemzar® (gemcitabine), Xeloda® (capecitabine), EBV-directed T cell transfer, and Cymevene® (ganciclovir) in combination with Gemzar® (gemcitabine). Prior to treatment, the patient experienced fatigue, fever, and sweats and frequently underwent paracentesis for the treatment of ascites.

[0038] The subject began MABp1 therapy at 1.25 mg / kg IV every 2 weeks on day 0. By days 3 and 4, the subject noted a significant reduction in fatigue, fever, and sweating. Ascites also resolved. An abdominal CT scan showed that one of the masses, a metastatic liver tumor, had reduced in size from 50.4 mm on day 1 to 35.8 mm by day 36 (nearly 30%). Several other liver lesions had reduced in size, and the bone lesions were considered stable.

[0039] Example 4 - Treatment of Castleman's disease with IL-1α-specific MAb (Xilonix™) The subject was a 55-year-old woman with Castleman's disease (a variant known as the POEMS syndrome). Her symptoms included fatigue, edema, and nerve pain. Previous treatment with Rituxan® (rituximab) and an investigational anti-IL-6 therapy had failed. The subject received an infusion of MABp1 (0.75 mg / kg) every 21 days for a total of four doses. In the next cycle, the subject's dose was increased to 1.25 mg / kg.

[0040] The subject's disease remained stable through two re-stagings and was treated for over four months. Approximately two weeks after each injection, the subject's symptoms of fatigue, edema, and neuralgia improved significantly, then gradually recurred until the next injection. The subject's RECIST staging criteria showed a 2% increase in lymph node size from baseline at the first re-staging and a 4% increase in lymph node size from baseline at the second re-staging.

[0041] After completing seven cycles, the subject withdrew consent to treatment in order to try another experimental treatment. Eight weeks after being removed from the clinical trial, the subject's physician requested that the subject be allowed to resume treatment with MABp1 due to "rapid disease progression." Since resuming treatment, the subject's disease has stabilized, and the subject has remained in the study for over 58 weeks.

[0042] Example 5 - Treatment of NSCLC with IL-1α-specific MAb (Xilonix™) The subject was an 84-year-old woman with a history of metastatic non-small cell lung cancer diagnosed by fine-needle aspiration. Three months after diagnosis, the subject began treatment with Tarceva® (erlotinib) for eight months, at which point disease progression was noted. The subject was then treated with Alimta® (Permetrexed) for 11 cycles for eight months, at which point treatment was discontinued due to the development of renal failure of unknown etiology. Six months later, progressive disease was noted, and the patient was again treated with Tarceva® (erlotinib) for three months. At that time, the patient's CAT scan showed further progressive disease in the lungs, with an increasing size of the right upper lobe mass, intrapulmonary nodules consistent with metastasis, and increasing intrathoracic lymphadenopathy.

[0043] The subject was then enrolled in a clinical trial using Xilonix™. MABp1 (3.75 mg / kg) was administered intravenously every 21 days for nine cycles. After treatment, stable disease was noted for approximately 30 weeks, and at the most recent restaging, the right lung lesion appeared to have cavitated.

[0044] Example 6 - Treatment of non-small cell lung cancer with IL-1α specific MAb (Xilonix™) The subject was a 52-year-old woman diagnosed with KRAS-positive non-small cell lung cancer (adenocarcinoma) on day 0. A PET / CT scan from day 14 revealed a 4x3.5cm left upper lobe mass, with disease metastases to the lung, hilar node, right inguinal lymph node, right adrenal gland, right fourth rib, and sacroiliac joint. The subject began treatment with carboplatin, paclitaxel, and bevacizumab several weeks after the scan. The subject's initial response was good, and after completing five cycles, progression occurred approximately five months after initial treatment. Over the next six months, the subject was treated with three cycles of docetaxel and one cycle of carboplatin plus pemetrexed. Despite this treatment, the subject continued to progress.

[0045] The subject subsequently began treatment with MABp1. After just four days, the subject began experiencing worsening headaches. These were initially attributed to sinusitis, but an MRI revealed brain metastases. Although the investigator believed these were likely present before treatment began, the subject discontinued the study after only one dose of MABp1 to undergo gamma knife radiotherapy. Twenty days after the first dose of MABp1, the subject was observed at follow-up and reported subjective improvement, with a reduction in chest pain. Consequently, the investigator reviewed a chest x-ray, which showed a "clear reduction in the size of the subject's lung lesions" after just one dose. A study exemption was issued, and the subject resumed treatment. Forty-six days after the first dose of MABp1, the subject was restaged and graded according to RECIST, revealing a 6% reduction in the sum of all lesion diameters.

[0046] Other embodiments While the present invention has been described in conjunction with the detailed description herein, it is to be understood that the foregoing description is illustrative and does not limit the scope of the invention, which is defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

1. A pharmaceutical composition for reducing the size of a metastatic tumor in a human patient, wherein the human patient has metastatic cancer that has progressed after treatment with chemotherapy and is characterized by a tumor expressing human IL-1α or a tumor infiltrated by human IL-1α expressing inflammatory cells, The pharmaceutical composition comprises a human monoclonal anti-IL-1α antibody, characterized in that the human monoclonal anti-IL-1α antibody is bound to human IL-1α at a Ka value similar to or identical to that of MABp1.

2. The pharmaceutical composition according to Claim 1, characterized in that the metastatic cancer is colorectal cancer.

3. The pharmaceutical composition according to Claim 1, characterized in that the metastatic cancer is non-small cell lung cancer (NSCLC).

4. The pharmaceutical composition according to claim 2, characterized in that the pharmaceutical composition is administered repeatedly to the human patient until the level of the CEA tumor marker decreases.

5. The pharmaceutical composition according to Claim 2, characterized in that the cancer is KRAS mutation positive.

6. The pharmaceutical composition according to claim 3, characterized in that the cancer is KRAS mutation positive.

7. The pharmaceutical composition according to Claim 1, characterized in that the metastatic cancer is EBV-related.

8. The pharmaceutical composition according to claim 7, characterized in that the EBV-related cancer is EBV-related nasopharyngeal cancer.

9. The pharmaceutical composition according to claim 8, characterized in that the pharmaceutical composition is repeatedly administered to the human patient until at least the ascites has subsided.

10. The pharmaceutical composition according to claim 8, characterized in that the pharmaceutical composition is administered repeatedly to the human patient until at least fatigue, fever, and sweating improve.

11. A pharmaceutical composition according to Claim 1, characterized in that the pharmaceutical composition is for administering the anti-IL-1α antibody in a dose of about 0.2 to 20 mg / kg human patient body weight.