Cachexia treatment

Abstract

The present application relates to cachexia treatment. Administration of an antibody that specifically binds IL-1a is useful for treating cachexia and increasing the lifespan of a subject with cachexia. The present application provides the use of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of an anti- interleukin-1a antibody (anti-IL-1a Ab) in the manufacture of a medicament for reversing lean body mass loss in a human subject with cancer and weight loss, increasing the lifespan of a subject with cancer and weight loss by at least 10% compared to the subject's projected lifespan, increasing caloric intake in a subject with cancer and weight loss, increasing appetite in a subject with cancer and weight loss, increasing the quality of life of a subject with cancer and noticeable weight loss, and the medicament is repeatedly administered to the subject.

Description

[0001] This application is a divisional of application 201280054593.9, filed September 21, 2012, entitled "Cachexia Treatment".

[0002] Cross Reference to Related Applications

[0003] This application claims priority to U.S. Provisional Patent Application No. 61 / 538,309, filed September 23, 2011. TECHNICAL FIELD

[0004] The present invention relates generally to the fields of medicine, oncology, metabolism, and immunology. More particularly, the present invention relates to the use of agents, such as antibodies (Abs) that specifically bind interleukin-1 alpha (IL-1 alpha), to treat one or more symptoms of cachexia.

[0005] BACKGROUND

[0006] Cachexia is a condition characterized by weight loss, muscle wasting, anorexia, fatigue, and weakness. It is commonly seen in patients with chronic progressive diseases such as AIDS, hormone deficiency, chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), tuberculosis (TB), and cancer. In cachexia, the decline in food intake related to energy expenditure leads to weight loss. Even with adequate nutritional support, abnormalities in the metabolism of carbohydrates, proteins, and fats result in persistent mobilization and ineffective satiation of host tissues. The physiological mechanisms that cause cachexia are poorly understood, although cachectins / TNF or other inflammatory cytokines have been implicated.

[0007] Nutritional support can help maintain weight in patients with cachexia, but does not prevent lean body mass loss. Glucocorticoids, particularly progestins, can increase appetite and reverse weight loss, although there is no evidence that it reverses the loss of muscle mass. In a clinical trial involving lung cancer patients, a humanized anti-IL-6 antibody was evaluated as a treatment for cachexia. The antibody was shown to be safe and well-tolerated, improved lung symptom scores, reversed fatigue, and reduced the rate of lean body mass loss. However, it did not reverse the process.

[0008] SUMMARY

[0009] The present application is based on the discovery that an agent that specifically targets IL-1a can ameliorate multiple symptoms of cachexia in a human patient, including reversing the decrease in lean body mass (or lean body tissue; LBT) and increasing survival of cancer patients having a decrease in lean body mass associated with cachexia. This is believed to be the first time that a cytokine-targeting agent has been shown to increase lean body mass in a human subject with cachexia and to increase survival of cancer patients having a decrease in lean body mass associated with cachexia.

[0010] Accordingly, the present application features a method of treating cachexia in a human subject by administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an amount of an IL-1a targeting agent effective to ameliorate a symptom of cachexia. Also within the present application is a method of increasing survival of a human subject with cachexia by administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an amount of an IL-1a targeting agent effective to increase survival of the subject.

[0011] The IL-1a targeting agent can be an anti-IL-1a Ab, such as an anti-IL-1a monoclonal Ab (mAb). The anti-IL-1a Ab can be designated MABpl (see U.S. Patent Application 13 / 225,029, filed September 2, 2011, for a description of this antibody) or a mAb comprising one or more complementarity determining regions (CDRs) of MABpl.

[0012] The pharmaceutical composition can be administered to the subject by subcutaneous, intravenous, or intramuscular injection. In the method, the dose administered to the patient can be at least 0.05 (e.g., at least 0.05, 0.10, 0.25, 0.5, 0.75., 1, 2, 3, 4, or 5) mg / kg of body weight.

[0013] The present application provides the following:

[0014] Item 1 : A method of treating cachexia in a human subject, the method comprising the step of administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an amount of an anti-IL-1a Ab effective to reduce at least one symptom of cachexia in the subject.

[0015] Item 2. The method of item 1, wherein the anti-IL-1a Ab is a mAb.

[0016] Item 3. The method of item 2, wherein the mAb is an IgGl.

[0017] Item 4. The method of item 2, wherein the mAb comprises a complementarity determining region of MABpl.

[0018] Item 5. The method of item 2, wherein the mAb is MABpl.

[0019] Item 6. The method of item 1, wherein the subject's lean body mass increases after administration of the pharmaceutical composition.

[0020] Item 7. The method of item 1, wherein the subject's body weight increases after administration of the pharmaceutical composition.

[0021] Item 8. The method of item 1, wherein the subject's appetite is improved after administration of the pharmaceutical composition.

[0022] Item 9. The method of item 1, wherein the subject has advanced cancer.

[0023] Item 10. The method of item 1, wherein the subject's muscle mass increases after administration of the pharmaceutical composition.

[0024] Item 11. The method of item 1, wherein the subject's lean body mass increases after administration of the pharmaceutical composition.

[0025] Item 12. A method of increasing the lifespan of a mammalian subject having cachexia, the method comprising the step of: administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an amount of an anti-IL-lα Ab effective to increase the subject's lifespan at least 10% as compared to the subject's predicted lifespan.

[0026] Item 13. The method of item 12, wherein the anti-IL-lα Ab is a mAb.

[0027] Item 14. The method of item 13, wherein the mAb is MABpl.

[0028] Item 15. The method of item 12, wherein the subject has advanced cancer.

[0029] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Definitions of common biologic terms can be found in Rieger et al., Glossary of Genetics: Classical and Molecular, Fifth Edition, Springer-Verlag: New York, 1991; and Lewin, Genes V, Oxford University Press: New York, 1994. Definitions of common medical terms can be found in Stedman's Medical Dictionary, Twenty-seventh Edition, Lippincott, Williams & Wilkins, 2000.

[0030] As used herein, an "Ab" or "Ab" is an immunoglobulin (Ig), a solution of identical or heterogeneous Igs, or a mixture of Igs. An "Ab" can also refer to fragments and engineered versions of Igs, such as Fab, Fab', and F(ab')2 fragments; and scFv, heteroconjugate Abs, and similar artificial molecules that utilize CDRs derived from Igs to confer antigen specificity. A "mAb" or "mAb" is an Ab expressed by a clonal B cell line or a population of Ab molecules that contains only the antigen binding site capable of immunoreacting with a specific epitope of a particular antigen. A "polyclonal Ab" or "polyclonal Ab" is a mixture of heterogeneous Abs. Typically, a polyclonal Ab will include a large number of different Ab molecules that bind a particular antigen, at least some of which immunoreact with different epitopes of the antigen. As used herein, a polyclonal Ab can be a mixture of two or more mAbs.

[0031] The "antigen binding portion" of an Ab is contained within the variable region of the Fab portion of the Ab and is the portion of the Ab that confers antigen specificity on 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. The "non-Fab portion" of an Ab is that portion of the Ab that is not within the Fab portion, e.g., the "Fc portion" or "Fc region." The "constant region" of an Ab is that portion of the Ab that is outside of the variable region. Typically included within the constant region is the "effector portion" of an Ab, which is the portion of an Ab responsible for binding other components of the immune system that assist in the immune response. Thus, for example, the site on an Ab that binds a complement component or an Fc receptor (other than via the antigen binding portion) is the effector portion of the Ab.

[0032] "purified" when referring to a protein molecule (e.g., an Ab) means separated from components that naturally accompany such a molecule. Typically, an Ab or protein is purified when it is at least about 10% (e.g., 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99%, 99.9%, and 100%) by weight relative to the non-Ab protein or other naturally occurring organic molecules with which it is naturally associated. Purity can be measured by any appropriate method, e.g., column chromatography, polyacrylamide gel electrophoresis, or HPLC analysis. A chemically synthesized protein or other recombinant protein produced in a cell type other than that in which the protein naturally occurs is "purified."

[0033] "binds" or "reacts with" means that a molecule recognizes and adheres to a particular second molecule in a sample, but does not substantially recognize or adhere to other molecules in the sample. Typically, an Ab that "specifically binds" another molecule has a K 5 , 10 6 , 10 7 , 10 8 , 10 9 , 10 10 , 10 11 , or 10 12 molar for the other molecule. d .

[0034] A "therapeutically effective amount" is an amount that is capable of producing a medically desirable effect in a treated animal or human, e.g., reducing or preventing a disease or symptoms of a disease, or extending survivability or lifespan.

[0035] Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including the definitions herein, will control. In addition, the particular examples discussed below are illustrative only and are not intended to be limiting. BRIEF DESCRIPTION OF DRAWINGS

[0036] Figure 1 is a Kaplan-Meier curve showing survival in patients with DEXA (n=18) according to LBT growth.

[0037] DETAILED DESCRIPTION

[0038] The present invention encompasses compositions and methods for alleviating one or more symptoms of cachexia in a subject and / or prolonging survival of a subject suffering from cachexia. The preferred embodiments described below illustrate adaptations of these compositions and methods. Nonetheless, other aspects of the invention can be accomplished and / or practiced based on the description provided below in light of the illustration of these embodiments.

[0039] General Methods

[0040] Methods involving conventional immunological and molecular biological techniques are described herein. Immunological methods (e.g., assays for detection and localization of antigen-Ab complexes, immunoprecipitation, immunoblotting, etc.) are generally known in the art and are described in methodological treatises, such as Current Protocols in Immunology, Coligan et al., eds., John Wiley & Sons, New York. Molecular biological techniques are described in detail in such treatises as Molecular Cloning: A Laboratory Manual, 2nd Ed., Vols. 1-3, Sambrook et al., eds., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 2001; and Current Protocols in Molecular Biology, Ausubel et al., eds., Greene Publishing and Wiley-Interscience, New York. Ab methods are described in Handbook of Therapeutic Abs, Dubel, S., ed., Wiley-VCH, 2007. General methods of medical treatment are described in McPhee and Papadakis, Current Medical Diagnosis and Treatment 2010, 49thEd., McGraw-Hill Medical, 2010; and Fauci et al., Harrison's Principles of Internal Medicine, 17thEd., McGraw-Hill Professional, 2008.

[0041] Treatment of cachexia

[0042] The compositions and methods described herein are useful for treating cachexia in a mammalian subject by administering to the subject a pharmaceutical composition comprising an amount of an IL-1 alpha targeting agent effective to ameliorate at least one characteristic of cachexia in the subject and / or to prolong survival of a mammalian subject having cachexia, particularly cancer-related cachexia. The mammalian subject can be any subject having cachexia, including humans, dogs, cats, horses, cows, sheep, goats, and pigs. The human subject can be a male, female, adult, child, or geriatric (65 years of age or older). The mammalian subject can be one having cancer (particularly metastatic cancer; solid tumor cancer; and Stage II, III, or IV cancer), HIV infection, TB, COPD, CHF, chronic renal failure, a hormonal disorder, severe trauma (e.g., burns), hypermetabolism (e.g., a sustained increase in heart rate of at least 6 bpm above normal for a given subject), excessive sympathetic nervous activity, a hyperinflammatory state (e.g., elevated CRP levels, increased IL-6 levels, increased TNF alpha levels, and / or increased IFN gamma levels), >5 lb weight loss in the preceding 2 months and / or <20 cal / kg estimated daily caloric intake. The subject having cancer can be one with less than 24, 18, 12, or 6 months life expectancy. The subject can also be one being treated or having been treated with steroids, nutritional supplements, and / or appetite stimulants.

[0043] Any symptom of cachexia that is susceptible to amelioration by administration of an IL-1 alpha targeting agent can be targeted. Examples of such symptoms include weakness, fatigue, gastrointestinal distress, sleep / wakefulness disturbances, pain, mental apathy, depression, restlessness, anorexia, weight loss, muscle atrophy, and loss of lean body mass. The improvement can be at least 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, or 90% if measurable on a percentage basis. Symptoms such as weakness, fatigue, pain, mental apathy, depression, and restlessness can be measured by techniques known in the art (e.g., using tests such as the EORTC- Quality of Life, Beck Depression Inventory, the Zung Self-rating Depression Scale, the Center for Epidemiologic Studies-Depression Scale, the Hamilton Rating Scale for Depression, and patient self-report). To assess anorexia, muscle mass, or lean body mass assessment, dual energy X-ray absorptiometry scans (DEXA), bioelectrical impedance analysis (BIA), indirect calorimetry, nutritional diaries, and similar known methods can be used.

[0044] The survival of a mammalian subject suffering from cachexia can be extended by at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, or 200% over the life expectancy of the subject. The life expectancy of a subject suffering from a particular disease associated with cachexia can be calculated by known methods, e.g., by averaging historical data. The expected survival time of a cancer patient can be determined by known methods, e.g., as described in Llobera et al., Eur. J. Cancer, 36:2036, 2000 and McCusker et al., J. Chron. Dis., 37:377, 1984.

[0045] Antibodies and other agents targeting IL-1 alpha

[0046] Any suitable type of Ab or other biologic agent (e.g., a fusion protein comprising an IL-1a binding component (e.g., an IL-1 receptor)) that specifically binds IL-1a and reduces one characteristic of cachexia in a subject and / or prolongs survival of a mammalian subject with cachexia can be used in the present application. For example, the anti-IL-1a Ab used can be a mAb (a polyclonal Ab), a mixture of multiple mAbs, or an Ab fragment or engineered Ab-like molecule, e.g., a scFv. The Ab preferably has a Ka of at least 1 x 10 9 M -1 or greater (e.g., greater than 9 x 10 10 M -1 , 8 x 10 10 M -1 , 7 x 10 10 M -1 , 6 x 10 10 M -1 , 5 x 10 10 M -1 , 4 x 10 10 M -1 , 3 x 10 10 M -1 , 2 x 10 10 M -1 , or 1 x 10 10 M -1 ). In a preferred embodiment, the present application utilizes a fully human mAb comprising (i) an antigen-binding variable region that exhibits very high binding affinity (e.g., at least nanomolar or picomolar) for human IL-1a and (ii) a constant region. The human Ab is preferably an IgGl, but it can also be a different isotype, such as IgM, IgA, or IgE, or a subclass, such as IgG2, IgG3, or IgG4. An example of a particularly useful mAb is MABpl, an IL-1a-specific IgGl mAb described in U.S. Patent Application Serial No. 12 / 455,458, filed June 1, 2009. Other useful mAbs are those comprising at least one but preferably all of the CDRs of MABpl. The CDRs can be determined according to known methods, e.g., the methods described in Ofran et al., J. Immunol., 181:6230, 2008; and Volume 2 of Antibody Engineering , Second Edition, Kontermann and Dubel (eds.), Springer, 2010.

[0047] Because B lymphocytes expressing Ig specific for human IL-1α occur naturally in humans, one current preferred method for increasing the mAb is to first isolate such a B lymphocyte from a subject and then immortalize it so that it can replicate indefinitely in culture. Subjects lacking a significant number of naturally occurring 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 made by immortalizing a human Ab-secreting cell (e.g., a human plasma cell). See, e.g., U.S. Patent No. 4,634,664.

[0048] In one exemplary method, one or more (e.g., 5, 10, 25, 50, 100, 1000 or more) human subjects are screened for the presence of such human IL-1α-specific Abs in their blood. Those 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 having B lymphocytes expressing human IL-1α-specific Abs. Such B lymphocytes are then isolated from the blood sample, e.g., by cell sorting (e.g., fluorescence-activated cell sorting, "FACS"; or magnetic bead cell sorting) to select for B lymphocytes expressing human IL-1α-specific Ig. These cells are then immortalized by viral transformation (e.g., using EBV) or by fusion with another immortalizing cell (such as a human myeloma cell), according to known techniques. B lymphocytes expressing Ig specific for human IL-1α within this population can then be isolated by limiting dilution (e.g., selecting cells positive for Ig specific to human IL-1α in wells of microtiter plates and subculturing, and repeating the process until a desired clonal line can be isolated). See, e.g., Goding, Monoclonal Antibodies: 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 cut, size exclusion, ion exchange separation, and affinity chromatography.

[0049] While immortalized B lymphocytes can be used for in vitro culturing to directly produce mAbs, in some cases it can be desirable to use a heterologous expression system to produce mAbs. See, e.g., the methods described in U.S. Patent Application No. 11 / 754,899. For example, the gene encoding one mAb specific for human IL-1 alpha can be cloned and introduced into an expression vector (e.g., a plasmid-based expression vector) for expression in a heterologous host cell (e.g., a CHO cell, a COS cell, a myeloma cell, and an E. coli cell). Because Ig comprises heavy (H) and light (L) chains (in an H2L2 configuration), the genes encoding each chain can be separately isolated and expressed in different vectors.

[0050] Although generally less preferred due to the greater likelihood that the subject will develop an anti-Ab response, chimeric mAbs (e.g., "humanized" mAbs) can still be used in the present application, which are antigen-binding molecules having different portions derived from different animal species (e.g., variable regions of mouse Ig fused to constant regions of human Ig). 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 having a desired binding specificity can be humanized by various vendors or as described in U.S. Patent Nos. 5,693,762; 5,530,101; or 5,585,089.

[0051] The mAbs described herein can be affinity matured by known methods to enhance or otherwise alter their binding specificity, such as VH and VL domain shuffling (Marks et al., Bio / Technology 10:779-783, 1992), random mutation of hypervariable region (HVR) and / or framework residues (Barbas et al., Proc. Natl. 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. In addition, modifications of the nucleic acid sequence encoding a mAb (e.g., without changing the amino acid sequence of the mAb) can be made for enhancing production of the mAb in certain expression systems (e.g., intron removal and / or codon optimization for a given expression system). The mAbs described herein can also be modified by conjugation to another protein (e.g., another mAb) or non-protein molecule. For example, a mAb can be conjugated to a water-soluble polymer (e.g., polyethylene glycol) or carbon nanotube (see, e.g., Kam et al., Proc. Natl. Acad. Sci. USA 102: 11600-11605, 2005). See, U.S. Patent Application No. 11 / 754,899.

[0052] Preferably, to ensure that high titer human IL-1 alpha specific mAbs can be administered to a subject with minimal side effects, the mAb compositions of the present application 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 or more percent pure by weight (free of any excipients). The mAb compositions of the present application can include only a single type of mAb (i.e., mAbs produced from a single clonal B lymphocyte line) or can include a mixture of two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) different types of mAbs.

[0053] While the IL-1 alpha specific Abs described above are preferred for use in the present application, in some cases other agents that specifically target IL-1 alpha can also be used, provided that their administration results in an improvement in one of the hallmarks of cachexia. These other agents can include small organic molecules, aptamers, peptides, and proteins (e.g., anakinra or rilonacept) that specifically bind to IL-1 alpha.

[0054] Pharmaceutical compositions and methods

[0055] The anti-IL-1 alpha Ab compositions can be administered to animals or humans in a pharmaceutically acceptable carrier (e.g., sterile saline), which is selected based on the mode and route of administration and standard pharmaceutical practice. Lists of pharmaceutically acceptable carriers, as well as formulations of drugs, can be found in standard texts of pharmaceutical science, such as Remington's Pharmaceutical Sciences, and in the USP / NF. Other materials can be added to these compositions, and other steps can be taken to stabilize and / or preserve these compositions, and / or to facilitate their administration to a subject.

[0056] For example, the Ab compositions can 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 stabilizing agents (e.g., albumin, dextrose, maltose, sucrose, sorbitol, polyethylene glycol, and glycine); filtered (e.g., using 0.45 and / or 0.2 micron filters); contacted with beta-propiolactone; and / or dissolved in a solution containing a microbiocidal agent (e.g., a detergent, an organic solvent, and a mixture of a detergent and an organic solvent).

[0057] The Ab compositions can be administered to animals or humans by any suitable technique. Typically, such administration will be parenteral (e.g., intravenous, subcutaneous, intramuscular, or intraperitoneal introduction). The compositions can also be administered directly to a target site, e.g., by injection. Other delivery methods, such as liposome delivery or diffusion from a device impregnated with the composition, are known in the art. The compositions can be administered as a single bolus injection, multiple injections, or by continuous infusion (e.g., intravenously or by peritoneal dialysis).

[0058] A therapeutically effective amount is an amount that is capable of producing a medically desirable result in the animal or human being treated. An effective amount of an anti-IL-1a Ab composition is an amount that shows clinical efficacy in a patient as measured by improvement in one or more cachectic features as described above. As is well known in the medical arts, dosages employed for any animal or human being depend on many factors, including the size, body surface area, age, specific composition to be administered, gender, time and route of administration, general health, and other drugs being administered concurrently. Preferred dosages are in the range of from about 0.2 to 20 (e.g., 0.05, 0.10, 0.15, 0.2, 0.3, 0.4, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or 40) mg / kg body weight. The dosage can be given repeatedly, such as hourly, daily, semi-weekly, weekly, bi-weekly, tri-weekly, or monthly. Preferably, 2 or more (e.g., 3, 4, 5, 6, 7, 8, 9, 10, or more) doses are given.

[0059] Example

[0060] Example 1 - Xilonix TM

[0061] Xilonix TM is a sterile, injectable, liquid formulation of MABpl at 15 mg / mL in a stable, isotonic buffer (pH 6.4). Each 10 mL Type I borosilicate glass serum vial contains 4, 5, or 10 mL of the formulation and is sealed with a 20 mm Daikyo Flurotec butyl rubber stopper and flip-off aluminum seal. The product is stored at 5 ± 3 °C, with an allowance for excursion to room temperature. The exact composition of the drug product is shown below:

[0062]

[0063] Method of Administration:

[0064] The calculated volume is withdrawn from the vial(s) containing the drug (mAb) using an appropriate syringe. The drug is then injected into a small IV bag containing 100 mL of normal saline (0.9% NaCl) and mixed by inversion. The diluted drug product can be stored at room temperature for 3 hours prior to administration and infused over a 1 hour period while monitoring the subject for signs of infusion reaction. The infusion is supplemented with a minimum of 30 mL of normal saline to deliver any product that can be trapped in the infusion set.

[0065] Example 2 - Improvement in body composition, nutritional intake, and quality of life in advanced cancer patients in a phase I study of MABpl, a fully human monoclonal antibody against IL-1a

[0066] Background: The pro-inflammatory cytokine IL-1α plays a crucial role in anorexia-cachexia syndrome, a complex metabolic disorder associated with muscle loss and pathological inflammatory responses. MABp1 is a first fully human monoclonal antibody with high affinity for IL-1α. The effects of MABp1 on body composition, nutrient uptake, and quality of life in age-matched patients with stage I disease were determined.

[0067] Methods: An open-label, first-in-human phase I trial of MABp1 was conducted in patients with refractory metastatic disease that had failed a median of five prior treatment regimens. Patients were defined as refractory after they had failed all standard-of-care treatments and had no treatment options expected to provide benefit. MABp1 was administered intravenously every three weeks at four dose levels (0.25, 0.75, 1.25, 3.75 mg / kg). To assess anorexia-cachexia, serial data were collected using dual-emission X-ray absorptiometry (DEXA), bioelectrical impedance analysis (BIA), indirect calorimetry, nutritional diaries, and the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC QLQ-C30). Body composition, nutritional intake, and quality of life were compared between baseline and cycle 3.

[0068] Early results: Baseline characteristics of the 36 enrolled patients were: mean age 60 years, 20 females (56%), 14 with colorectal malignancies (40%), median weight 61 kg (interquartile range 57–80 kg), and median body mass index 24 (21–29 kg / m²). 2 And 32 / 33 (97%) were metabolically hyperactive. Of these 24 restaging patients, an overall response rate of 37% (9 / 24) was achieved according to RECIST criteria (defined as stable or better condition lasting ≥3 months). Eighteen of these 24 patients were eligible for DEXA scanning at screening and at the 8-week follow-up assessment. Analysis of baseline and follow-up DEXA scans revealed noteworthy findings: the majority of patients experienced a reversal of their cachexia. At follow-up, 67% (12 / 18) of the patients had an objective increase in lean body mass (LBT). See Table 1 below. Responders showed a mean LBT increase of 1.57 ± 1.95 kg (p = 0.017) compared to their baseline values. On the other hand, the mean LBT change among the 6 non-responders was -0.82 ± 0.47 kg. For responders compared to nonresponders, the increase in LBT was 2.39 ± 1.7 kg (p = 0.001).

[0069] Table 1

[0070]

[0071]

[0072] Conclusion: It is unknown whether the reversal of the decrease in LBT occurs in patients with refractory metastatic disease. No agent has been reported in the literature that can help increase LBT in refractory metastatic disease. In the current study, the majority of patients enrolled in the study had a striking decrease in weight prior to enrollment. Nevertheless, several responders increased LBT sufficiently over the 8-week treatment period resulting in a higher weight than that observed 26 weeks prior to the start of the study.

[0073] Interestingly, these patients who gained LBT during treatment also had a mean decrease in fat mass of 0.4 kg. The concomitant lean tissue accrual with a decrease in fat mass strongly suggests a profound change in the control of metabolic energy use - from mobilizing muscle as an energy source to utilizing fat and synthesizing muscle tissue.

[0074] Other Results: 7 / 14 (50%) patients with BIA data also had an increase in muscle mass (median 1.4 kg, Q1-Q3 1.1-1.8 kg). The average daily caloric intake increased in a median of 362 kcal (Q1-Q3 234-922 kcal) in 8 / 13 (62%) patients. Between baseline and cycle 3, the EORTC-Appetite improved in 5 / 20 (25%) patients (median improvement 33 / 100, Q1-Q3 33-33) and remained the same in the remaining 15 / 20 (75%) patients. The EORTC-Overall Quality of Life improved in 7 / 20 (36%) (median improvement 20 / 100, Q1-Q3 8-25) and remained the same in 8 / 20 (40%) patients.

[0075] Example 3 - Age-matched cohort analysis of colorectal

[0076] The majority of patients enrolled and treated in the trial described in Example 2 had refractory metastatic colorectal cancer (14 of 42). Of the 18 subjects evaluated with DEXA, 7 had metastatic colorectal tumors and 5 of these 7 had an increase in LBT as a response. The mean increase in LBT for all 7 of these subjects was 3% and for those who responded, the mean increase was 4.6%. Subjects enrolled in this trial were also evaluated for tumor response using RECIST 1.1. As such, some subjects were discontinued for radiographic evidence of disease progression. Of the 14 subjects with colorectal tumors, the median time to survival was 129 days (4.3 months) and 4 of these data points have been censored. For 10 / 14 (71%) patients who received at least 3 doses of study drug, the median time to survival was 224 days (7.5 months). This median time to survival was also strongly correlated with increases in LBT. For the 5 (36%) patients with objective evidence of an increase in LBT from baseline to week 8, the median time to survival was 474 days (15.8 months). On the other hand, the 9 who showed no evidence of LBT increase showed a median survival of only 72 days (2.4 months). Based on studies performed in similar cohorts, the projected overall survival for refractory colorectal patients is approximately 4.6 months (Jonker, D. et al. Cetuximab for the Treatment of Colorectal Cancer. N Engl J Med 2006; 357:2040-8).

[0077] Example 4 - Summary of survival outcomes at late time points

[0078] Forty-two patients (57% female, median age 61 years) with advanced cancer refractory to a median of 5 systemic chemotherapy regimens were enrolled in the study described in Example 2. Colorectal tumors were the most common malignancy found, accounting for one-third of the total study population (14 / 42). Although 23 (55%) patients had complete 3 or more cycles, DEXA measurements with baseline and cycle 3 endpoints were available for 18 patients. A total of 18 / 42 (43%) deaths were reported at the date of analysis. The mean survival time was 278 ± 38 days and the median survival was 161 days.

[0079] Example 5 - Survival in responders versus non-responders

[0080] In the study described in Example 2, the total number of patients with valid DEXA measurements at screening and Day 15 of Cycle 3 was 18, of which 12 / 18 (67%) were responders (>0 kg LBT change). As shown in Table 1, overall survival among these responders was 377 ± 286 (median 339) days, and for non-responders was 313 ± 226 (median 277) days. In the responder group, 8 patients were censored and 4 deaths occurred. In the non-responders, 5 / 6 patients died (log-rank p = 0.143). Figure 1

[0081] Other Embodiments

[0082] It is to be understood that while the application has been described in conjunction with the detailed description thereof, the foregoing description is meant to illustrate and not limit the scope of the application. Other aspects, advantages and modifications are within the scope of the following claims.​

Claims

1. Use of a pharmaceutical composition in the manufacture of a medicament for reversing lean body mass loss in a human subject having cancer and weight loss, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier and an amount of an anti-interleukin-1 alpha antibody (anti-IL-1 alpha Ab) effective to reverse lean body mass loss in the subject, wherein the pharmaceutical composition is repeatedly administered to the subject until lean body mass loss in the subject is reversed, and wherein the anti-IL-1 alpha antibody is a monoclonal antibody that binds human IL-1 alpha with a Ka of at least 1 x 109 9 M -1 .

2. The use of claim 1, wherein the subject's body weight increases after administration of the pharmaceutical composition.

3. The use of claim 1, wherein the subject's appetite is improved after administration of the pharmaceutical composition.

4. The use of claim 1, wherein the subject has advanced cancer.

5. The use of claim 1, wherein the subject's muscle mass increases after administration of the pharmaceutical composition.

6. The use of claim 1, wherein the subject's life span is increased by at least 10% compared to the subject's projected life span.

7. Use of a pharmaceutical composition in the manufacture of a medicament for increasing the life span of a human subject having cancer and weight loss by at least 10% as compared to the life expectancy of the subject, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier and an anti-IL-1a Ab in an amount effective to increase the life span of the subject as compared to the life expectancy of the subject, wherein the pharmaceutical composition is repeatedly administered to the subject, and wherein the anti-IL-1a antibody is a monoclonal antibody that binds human IL-1a with a Ka of at least 1 x 109 9 M -1 .

8. The use of claim 7, wherein the subject has advanced cancer.

9. The use of claim 1, wherein the mAb is IgGl.

10. The use of claim 1, wherein the mAb comprises the complementarity determining regions of MABpl.

11. The use of claim 1, wherein the mAb is MABpl.

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