Uses of myostatin antagonists, combinations containing them, and uses thereof

Abstract

To provide combinations for the treatment of cancer cachexia.SOLUTION: Bimagrumab, a myostatin antagonist, was found to be beneficial in the treatment of cancer cachexia by reducing body weight loss. The present invention provides combinations of a myostatin antagonist and an mTOR inhibitor for treating cancer cachexia by reducing, maintaining or increasing body weight loss or for use in treating age-related conditions.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This disclosure relates to the treatment of cancer cachexia using myostatin or activin antagonists. , in particular, regarding the use of activin type II (ActRII) receptor inhibitors.

[0002] More specifically, the present invention relates to the treatment of cancer cachexia, and to simultaneous, individual, or sequential treatments. For use, (a) activin type II receptor (ActRII) inhibitor and (b) Combinations containing chemotherapeutic agents or pharmaceutically acceptable salts thereof, their use, or their Regarding the method of use and treatment.

[0003] This disclosure relates to a combination of a myostatin antagonist and an mTOR inhibitor and This also concerns use. Such combined use is used in cancer cachexia and aging. This is for continuous use. [Background technology]

[0004] Cachexia affects the majority of patients with advanced cancer, leading to poor outcomes and poor treatment tolerance. Below, it relates to response to treatment, quality of life, and survival. Skeletal muscle loss is associated with cancer cachexia. This appears to be the most important issue, and conventional nutritional support cannot completely reverse it. It is not possible [Fearon et al 2011, Tan et al 2009]. Recently, the macules of ectopic lung and colon cancer In the Uss model, direct myostatin inhibition and solubilization are performed using monoclonal antibodies. Indirect inhibition using ActRIIB-Fc protects against muscle wasting, and furthermore... It has been shown that survival is extended [Benny Klimek et al 2010, Busquets et al 2012, Mu rphy et al 2011, Zhou et al 2010].

[0005] A transylamine containing myostatin, activin A, and growth differentiation factor 11 (GDF-11) Some members of the forming growth factor beta (TGF-β) superfamily This involves negatively regulating skeletal muscle mass in animals and humans throughout their life cycle. It is known that the mechanism of myostatin signaling involves the activation of several downstream pathways. Therefore, it is complicated [Elkina et al 2011]. Myostatin, activin and GDF-1 1 binds to the activin type II receptor (ActRII) and aggregates with the activin type I receptor. It induces synthesis. In the absence of myostatin in animal and human development, muscle fibers This results in a hypermuscular phenotype with increased number and size [Lee and McPherron 2001]. [Schuelke et al 2004]. Similarly, inhibition of myostatin activity in adult animals Muscle mass increased, suggesting that myostatin also suppresses skeletal muscle mass in adults. [Whittemore et al 2003, Lee et al 2005, Nakatani et al 2008]. In contrast, High levels of myostatin or activin A promote cachexia and subsequent muscle wasting. This has been reported [Zimmers et al, 2002; Chen et al, 2014].

[0006] International Publication No. 07 / 067616 describes the treatment of 5-fluorouracil In normal mice, administration of myostatin binders such as peptide-bonded myostatin was performed This indicates that weight loss is reduced. However, International Publication No. 07 / 067616 pamphlet As demonstrated by this disclosure, the procedure does not involve the use of anticancer drugs, or does not involve the use of anticancer drugs. In either of the following cases, in tumor-carrying mouse models such as CT-26, peptide-bonded mice It has not been shown whether Ostatin reduces weight loss or increases weight.

[0007] Bimaglumab has a higher affinity for myostatin, a natural ligand, than activin A. This is a human monoclonal antibody developed to competitively bind to ActRII. In mice, glumab induced skeletal muscle hypertrophy, while dexamethasone-induced atrophy. Protects against contracture [Lach-Trifilieff et al 2014], does not cause serious adverse events, sporadic It has been shown to improve the disease status of patients with inclusion body myositis [Amato et al 2020]. 14]. By pharmacological blockade of the ActRII pathway using soluble receptor antagonists. In mice, it has been shown that they are protected from cancer-induced cachexia. [ts et al 2012, Zhou et al 2010] states that patients with cachexia and advanced cancer should not be treated as standard treatment. They will likely receive anticancer drugs for specific cancer types, and ActRII inhibitors are anti It remains unclear whether or not it will remain effective when combined with cancer drugs.

[0008] According to the present invention, in mice, the risk of immunogenicity is reduced, and long-term profiling is performed. While enabling research, it preserves the binding, selectivity, and potency profile of bimaglumab. The efficacy of a chimeric mouse version of bimaglumab has been demonstrated in CT-26 mice. We evaluated the interaction between bimaglumab and chemotherapy in a colon cancer cachexia model and clarified it. Furthermore, intervention at the activin type II receptor level through the use of bimagrumab, a neutralizing Ab is effective in protecting against cancer-induced cachexia, as previously reported through blockade of circulating ligands (anti-myostatin Ab or soluble ActRIIB- Fc).

[0009] Platinum-based drugs, such as cisplatin, are cytotoxic intercalating agents that interfere with DNA replication in a very non-specific manner and are typically used as first-line therapy. Unfortunately, cisplatin has been shown to accelerate weight and muscle mass loss as a side effect. Therefore, the inventors first aimed to evaluate the potential of bimagrumab to counteract the cisplatin-mediated effects on muscle wasting. Subsequently, in a follow-up study, the effects of more frequent administration of bimagrumab and everolimus, new generation, less cytotoxic, molecularly targeted agents that inhibit the mammalian target of rapamycin (mTOR) in cancer cachexia were evaluated. Furthermore, when muscle mass decreases and, concomitantly, total body water content decreases (as part of the pathophysiology of cachexia), the volume of distribution of chemotherapeutic agents becomes smaller [Parsons 2012]. This, in turn, causes these cytotoxic agents to reach higher concentrations (Cmax and AUC) and results in more adverse events and poor chemotherapy tolerance in cancer patients with cachexia compared to those without cachexia [Sjoblom 2015, Better chemotherapy tolerance, more effective anticancer treatment, and better outcomes (progression-free survival and This means that it can result in overall survival.

[0011] Currently, there is no standard treatment for cancer cachexia. [Overview of the Initiative] [Problems that the invention aims to solve]

[0012] Therefore, whether or not chemotherapy is used, in particular, mTOR inhibitor Using bitters to reduce, prevent, or further reduce weight loss in the context of cancer Drug therapy that can increase weight is strongly desired for this condition.

[0013] Furthermore, myostatin or activin antagonists and mTOR inhibitors as disclosed herein Bitter combinations also have the potential to treat age-related conditions. [Means for solving the problem]

[0014] Therefore, the first subject of this disclosure is ActRII receptors for treating cancer cachexia. This concerns combinations of inhibitors and chemotherapeutic agents.

[0015] Therefore, another subject of this disclosure is myostatin-binding molecules or ActRII-binding molecules. A method for treating cancer cachexia or myostatin or activator may be used. Regarding the use of compositions containing an antagonist.

[0016] According to this disclosure, in mice, the risk of immunogenicity is reduced and long-term profiling is achieved. While enabling research, it preserves the binding, selectivity, and potency profile of bimaglumab. The efficacy of a chimeric mouse version of bimaglumab has been demonstrated in CT-26 mice. We evaluated the interaction between bimaglumab and chemotherapy in a colon cancer cachexia model and clarified it. Furthermore, at the activin type II receptor level via the use of the neutralizing agent bimaglumab. The intervention involves blocking the circulating ligand (anti-myostatin Ab or soluble ActRII B- As previously reported through Fc), to protect against cancer-induced cachexia It is effective.

[0017] Platinum-based drugs, such as cisplatin, interfere with DNA replication in a highly nonspecific manner. It is a cytotoxic interstitial agent that is typically used as a first-line therapy. The problem is... Cisplatin has been shown to accelerate weight and muscle mass loss as a side effect. First, when counteracting the cisplatin-mediated effects on muscle wasting, bimaglumab's potential... The aim was to evaluate the force. Subsequently, a follow-up study was conducted on cancer cachexia. A new generation of low-cytotoxicity drugs that inhibit the mammalian target (mTOR) of rapamycin. The effects of more frequent administration of the target agents bimaglumab and everolimus were evaluated. .

[0018] Muscle regulation and ActRII receptors Transylamine containing myostatin, activin A, and growth differentiation factor 11 (GDF11) Some members of the Forming Growth Factor Beta (TGF-β) superfamily are Throughout the life cycle, it negatively regulates skeletal muscle mass in animals and humans. Signaling occurs via type II activin receptors (ActRIIA and B) Both, as well as the Smad2 / 3 pathway, are involved in muscle protein synthesis and muscle cell differentiation. It inhibits proliferation. In animal and human development, none of these ligands are present. This results in a hypermuscular phenotype with an increase in the number and size of muscle fibers. When myostatin levels decrease, the size of existing muscle fibers increases, resulting in skeletal muscle Hypertrophy occurs (Lee et al 2005; Lee et al 2010; Trendelenburg et al 2012). However By disrupting this signaling pathway at the receptor level, muscle growth can be modulated. The ability to do so was previously recognized through a direct anti-myostatin approach. It's also quite large.

[0019] When used herein, "myostatin antagonist" refers to the function of myostatin. Antagonizing expression and / or signaling (e.g., reducing, inhibiting, decreasing) This refers to molecules that can delay or accelerate (for example, myostatin receptors of myostatin). (i.e., by blocking the binding to ActRIIB). Unrestricted example of an antagonist. As such, myostatin-binding molecules and ActRII (ActRIIA, ActRIIB) Examples include ActRIIA / B receptor-binding molecules. The methods, regimens, and kits disclosed herein are also available. In some embodiments of the process, use, and composition, a myostatin antagonist is used. It is used.

[0020] A "myostatin-binding molecule" is a molecule that, alone or in association with other molecules, binds to human myostatin. This refers to any molecule that can bind to an antigen. A binding reaction is, for example, the binding of a molecule to a receptor. Binding assays, competition assays, or bioassays to determine inhibition of ostatin binding While specificity is not relevant, ideally, antibodies of the same isotype, for example, anti-C1 Standard protocols including any type of binding assay based on a negative control test using D25 antibody This may be demonstrated by a method (qualitative assay). As an example of a non-limiting myostatin-binding molecule, Myostatin is a small molecule produced by B cells or hybridomas that binds to myostatin. Statin receptor decoys and antibodies, as well as chimeric, CDR grafts, or human antibodies or any fragment thereof, e.g., F(ab')2 and Fab fragments, as well as single strands or Examples include single-domain antibodies. Preferably, the myostatin-binding molecule is a myostatin-binding molecule. Antagonizing function, expression, and / or signaling (e.g., reducing, inhibiting, decreasing) (To reduce, to delay). Methods, regimens, kits, processes, uses and compositions disclosed herein. In some embodiments of the material, myostatin-binding molecules are used.

[0021] "ActRII receptor inhibitors" are substances that, alone or in association with other molecules, inhibit human A It binds to the ctRII receptor (ActRIIA and / or ActRIIB) and the receptor This refers to any molecule that can inhibit signal transduction. Binding and inhibitory reactions are examples. For example, a binding assay to determine the inhibition of ActRII receptor binding to myostatin, Competitive assays or bioassays, or specificity, are not relevant, but ideally the same Any negative control test using an isotype antibody, for example, an anti-CD25 antibody, as a reference. This may be demonstrated by standard methods (qualitative assays) including various types of binding assays. ActR Non-limiting examples of II receptor inhibitors include those produced by B cells or hybridomas. Small molecules, myostatin decoys, and antibodies against the ActRII receptor, as well as Chimeras, CDR grafts, or human antibodies or any fragment thereof, e.g., F(ab')2 Examples include Fab fragments, as well as single-chain or single-domain antibodies. Preferably, ActRII receptor-binding molecules affect the function, expression, and / or function of myostatin / activin. It antagonizes signal transduction (e.g., reduces, inhibits, decreases, or delays it). In some embodiments of the combinations, uses, methods, and compositions of the present disclosure, ActRII receptor Inhibitors are used.

[0022] Bimagrumab Bimaglumab, a pharmaceutically active compound used in accordance with the present invention, promotes muscle mass growth. Activin has a higher affinity than natural ligands that restrict it (including myostatin and activin). A fully human monochromosome developed to competitively bind to the vin receptor type II (ActRII). This is a non-alcoholic antibody (modified IgG1, 234-235-Ala-Ala, λ2). Maglumab cross-reactive with human and mouse ActRIIA and ActRIIB. Yes, it is effective for human, cynomolgus monkey, mouse, and rat skeletal muscle cells. Glumab has extremely high affinity (KD 1.7±0.3pM) for human ActRIIB, It binds to human ActRIIA with relatively low affinity (KD 434±25pM).

[0023] This invention relates to the receptor ActRII (ActRIIB and / or ActRIIA). Sufficient blockage of myostatin binding inhibits skeletal muscle growth that acts on the receptor. The activity of tin and other ligands is significantly reduced, while some of these ligands are secondary. A therapeutic approach that allows other physiological functions to be performed via specific receptors (Upton et al 2009) It is based on . Other approaches to reduce myostatin activity include, namely, soluble receptor Competitively soluble ActRII, which causes a reaction sink, has activity at other receptors. It may deplete the ActRII ligands of the receptor, such as bimaglumab. Using tagagonist antibodies may pose a greater safety risk.

[0024] Another approach involves myostats such as LY2495655 (Eli Lilly). One approach is the use of antibodies that bind to the ActRII receptor, which then transmit the signal via the ActRII receptor. This will inhibit or reduce signal transmission.

[0025] As a potent inhibitor of ActRII, bimaglumab is used in conjunction with myostatin and activating The effects of γ-A, GDF11, and possibly other ligands that act through this receptor. Block it.

[0026] Therefore, the present invention is particularly for use in the treatment of cancer cachexia, myosta Zin antagonist or activin (e.g., activin A, activin B or activin) Tibin AB) antagonist, preferably a myostatin-binding molecule or antibody, more preferably or inhibitor or more preferably anti-ActRII receptor antibody, most preferably bimethyl We offer glumab.

[0027] The present invention is described in detail below with reference to the attached drawings: [Brief explanation of the drawing]

[0028] [Figure 1]This graph shows the effects of cisplatin alone or in combination with CDD866 on body weight (A, B, C), tumor volume (D), and weight (E) in CT-26 mice with colon cancer-induced cachexia. Values ​​are expressed as mean ± SEM (n=10). Percentage change in body weight was calculated compared to the start of treatment on day 0; *: P<0.05, **: P<0.01 vs. non-tumor control; &&: P<0.01 vs. CT-26 control; ++: P<0.01 vs. non-tumor cisplatin; ##: P<0.01 vs. CT-26 cisplatin (Sidak multiple comparison test after ANOVA). [Figure 2] This graph shows the effects of cisplatin alone or in combination with CDD866 on muscle mass and progression-free survival in CT-26 mice with colon cancer-induced cachexia. Values ​​are expressed as mean ± SEM (n=10). The percentage change in muscle mass normalized to initial body weight on day 0 was calculated compared to non-tumor controls (A, B, C); *: P<0.05, **: P<0.01 vs non-tumor control; &: P<0.05, &&: P<0.01 vs CT-26 control; ++: P<0.01 vs non-tumor cisplatin; xx: P<0.01 vs non-tumor CDD866; ##: P<0.01 vs CT-26 cisplatin; $: P<0.05, $$: P<0.01 vs CT-26 CDD866 (Sidak multiple comparison test after ANOVA). The progression-free interval was expressed as a percentage event defined by the discontinuation criteria (D); the median number of days elapsed before reaching the discontinuation criteria was represented by a box with a minimum to maximum range (n=10) (E); and P<0.05 and P<0.01 were compared to CT-26 control (vehicle 1 / vehicle 2) (by Dunn multiple comparison test after ANOVA). [Figure 3]This graph shows the effects of everolimus alone or in combination with CDD866 on body weight (A, B, C), tumor volume (D), and weight (E) in CT-26 mice with colon cancer-induced cachexia. Values ​​are expressed as mean ± SEM (n=10). Percentage change in body weight was calculated compared to the start of treatment on day 0; *: P<0.05, **: P<0.01 vs. non-tumor control; &&: P<0.01 vs. CT-26 control; ++: P<0.01 vs. non-tumor everolimus; ##: P<0.01 vs. CT-26 everolimus (Sidak multiple comparison test after ANOVA). [Figure 4] This graph shows the effects of everolimus alone or in combination with CDD866 on muscle mass and progression-free survival in CT-26 mice with colon cancer-induced cachexia. Values ​​are expressed as mean ± SEM (n=10). Percentage change in muscle mass normalized to initial body weight on day 0 was calculated compared to non-tumor controls (A, B, C); *: P<0.05, **: P<0.01 vs non-tumor control; &: P<0.05, &&: P<0.01 vs CT-26 control; ++: P<0.01 vs non-tumor everolimus; xx: P<0.01 vs non-tumor CDD866; ##: P<0.01 vs CT-26 everolimus; $: P<0.05, $$: P<0.01 vs CT-26 CDD866 (Sidak multiple comparison test after ANOVA). The progression-free interval was expressed as a percentage event defined by the discontinuation criteria (D); the median number of days elapsed before reaching the discontinuation criteria was represented by a box with a minimum to maximum range (n=10) (E); and P<0.05 and P<0.01 were compared to CT-26 control (vehicle 1 / vehicle 2) (by Dunn multiple comparison test after ANOVA). [Figure 5] This figure shows that mTOR is overexpressed in the muscles of aged versus young rats. 1. mTOR is hyperactive in the skeletal muscle of aged versus young rats. 2. In the skeletal muscle of aged versus young rats, mTOR is not adequately downregulated after fasting. [Modes for carrying out the invention]

[0029] Detailed description of the present invention The present invention relates to (a) activin receptor type II receptor for the treatment of target cancer cachexia. A combination comprising (b) an inhibitor and (b) a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, and relating to its use for simultaneous, individual, or consecutive uses.

[0030] The present invention relates to (a) myostatin or activin for treating age-related conditions. This also concerns combinations of taggers and (b)mTOR inhibitors.

[0031] This combination may or may not be fixed, and is preferably not fixed.

[0032] Unless otherwise explicitly stated, the following definitions apply to the general terms used herein. It will be done.

[0033] The terms "comprising" and "including" are different. Unless otherwise noted, the terms used herein are used in an open-ended and non-restrictive sense. ru.

[0034] Terms "a", "an", and "the" and similar terms The reference is made in the context of describing the present invention (in particular, in the context of the following claims). ), unless otherwise shown herein or explicitly denied by the context. Therefore, it should be interpreted as encompassing both singular and plural forms. When used in relation to salts, it is thought to refer to a single compound, such as a salt.

[0035] The term "combination" or "combination drug" refers to a fixed combination of a single unit dosage form. Combinations that are not used, or activin type II receptor (ActRII) antagonists Alternatively, a blocking agent and a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, in combination. A time interval in which partners can demonstrate collaborative, for example, additive or synergistic effects. Within the body, the following can be administered simultaneously, individually, or sequentially, independently: Defined herein to refer to any of the parts.

[0036] The term "fixed combination" refers to a combination in which the active ingredient or therapeutic agent is in the form of a single entity or dosage form. This means that the medications are administered to patients simultaneously.

[0037] The term "unfixed combination" refers to a combination of active ingredients or therapeutic agents, both of which are fixed over time. Without restriction, simultaneously, concurrently, or sequentially, as individual entities or dosage forms, for patients It is administered to the target that needs it, for example, mammals or humans. This means delivering three compounds to the body at therapeutically effective levels.

[0038] Preferably, in this specification, the terms “combination” or “combination drug” are not fixed. It is a combination that does not exist.

[0039] The term "pharmaceutical composition" refers to a specific disease affecting a subject, such as a mammal or a human. Or, to treat a condition, it contains at least one therapeutic agent to be administered to the subject. As defined herein, this refers to a mixture or solution.

[0040] The term "pharmaceutically acceptable" means, within the bounds of sound medical judgment, for example, a feeding animal. Suitable for contact with objects or human tissues, and does not cause excessive toxicity, irritation, allergic reactions, or other issues. It does not have problematic complications and offers a reasonable benefit / risk ratio, and the compound is viable. In this specification, it is defined to mean a physical agent, material, composition and / or dosage form. .

[0041] The term "combined administration," as used herein, refers to a single subject, for example, a mammal or Defined to encompass the administration of selected therapeutic agents to humans, and that therapeutic agent is administered via the same administration method. This is intended to include treatment regimens that are not necessarily administered on the road or simultaneously.

[0042] The terms “to treat” or “treatment” as used herein refer to a small number of cases in the subject matter. To reduce, lessen, or alleviate at least one symptom, or to alleviate a disease, condition, and / Or, treatments that slow the progression of the disability. For example, treatments that address one or more of the disabilities. This may result in a temporary reduction of symptoms or complete eradication of the disorder. In the sense of the present invention, the term "treatment" "To prevent" means to stop or delay the onset of the disease (i.e., the period before the clinical symptoms of the disease appear), and It also indicates a reduced risk of developing or worsening of the disease.

[0043] The term "progression-free survival," as used herein, refers to the survival of a patient with a disease, such as cancer. The patient is alive but not deteriorating, including the length of time during and after treatment for the disease. Clinical trial In trials, measuring progression-free survival is used to determine whether the new treatment is working effectively. This is one method. Progression-free survival is also called PFS.

[0044] The term "overall survival," as used herein, means that a person is diagnosed with a disease, such as cancer. The patient is still alive, including the length of time since the date of diagnosis or the start of treatment for the disease. In clinical trials, measuring overall survival is used to determine whether a new treatment is working effectively. This is one way to achieve overall survival. Overall survival is also called OS.

[0045] The term "pharmaceutically effective dose" or "therapeutic effective dose" for combinations of therapeutic agents is used in relation to the disease. This results in observable improvement over baseline in clinically observable signs and symptoms. That is a sufficient amount.

[0046] When used herein, the term "synergistic effect" means, in the context of, producing an effect, for example For example, to promote and / or enhance the immune response, e.g., (a), and (b), The effect of two drugs, such as their pharmaceutically acceptable salts, is the effect of each administered drug. It refers to an effect greater than the simple sum of the effects themselves. A synergistic effect is achieved through appropriate methods, for example, Si gmoid-Emax formula (Holford, NHG and Scheiner, LB, Clin. Pharmacokin et. 6: 429-453 (1981), Loewe's arithmetic addition (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol. 114: 313-326 (1926)) and median-effect formula (the me dian-effect equation)(Chou, TC and Talalay, P., Adv. En It can be calculated using methods such as Zyme Regul. 22: 27-55 (1984). Apply each formula to the experimental data, create corresponding graphs, and evaluate the effects of drug combinations. This can be helpful. The corresponding graphs related to the formulas mentioned above are, These are concentration-effect curves, isobologram curves, and combined exponential curves.

[0047] The terms “subject” or “patient” as used herein refer to promoting and / or promoting an immune response. This includes animals that may be enhanced or / or have age-related conditions. For example, mammals such as humans, dogs, cows, horses, pigs, sheep, goats, cats, and ma Examples include crickets, rabbits, rats, and transgenic non-human animals. Preferred implementation Morphologically, the subjects are humans, for example, those suffering from cancer cachexia or age-related conditions. A person who is at risk of developing a disease or is potentially at risk of developing one.

[0048] The terms "about" or "approximately" mean within 10%, more preferably 5%, of a given value or range. It means "within a percent".

[0049] The present invention will be described and illustrated in more detail below.

[0050] The present invention is provided in the following embodiments: 1. A combination comprising (a) an ActRII receptor inhibitor and b) a chemotherapeutic agent.

[0051] 2. Combinations of the items described in Embodiment 1 for simultaneous, individual, or consecutive use.

[0052] 3. a) ActRII receptor inhibitors and b) chemotherapeutic agents are separate forms. , the combination described in embodiment 1 or 2.

[0053] 4.a) The combination according to Embodiments 1 to 3, wherein the anti-ActRII receptor antibody.

[0054] 5. The combination according to embodiments 1 to 4, wherein the anti-ActRII antibody is bimaglumab.

[0055] 6.b) The combination according to embodiments 1 to 5, wherein the platinum-containing anticancer agent is 6.b.

[0056] 7. A combination of any of the above embodiments for use as a pharmaceutical product.

[0057] 8. (a) ActRII receptor inhibitors for use in the treatment of cancer cachexia (b) A combination according to embodiment 1 to 6, comprising a chemotherapeutic agent.

[0058] 9. A combination of the embodiments described in 1 to 6, wherein the treatment for cancer cachexia is the reduction of weight loss.

[0059] 10. ActRII receptor inhibitors for use in the treatment of cancer cachexia.

[0060] 11. For use as described in aspect 11, where cancer cachexia is caused by treatment with chemotherapy agents. ActRII receptor inhibitor.

[0061] 12. Treating cancer cachexia is to reduce weight loss, any aspect 10~ ActRII receptor inhibitor for use as described in 12.

[0062] 13. In delaying the progression-free period of cancer in patients, use as described in aspects 10-12 ActRII receptor inhibitor.

[0063] 14. A for use in the delay of progression-free survival in cancer cachexia, as described in embodiments 10-12. ctRII receptor inhibitor.

[0064] 15. ActRII reception for use according to embodiments 10-12 in extending cancer survival Body inhibitor.

[0065] 16. The ActRII receptor inhibitor is an anti-ActRII receptor antibody, embodiment 10~ ActRII receptor inhibitor for use as described in 15.

[0066] 17. The anti-ActRII receptor antibody is bimaglumab, for use according to embodiment 16. ActRII receptor inhibitor.

[0067] 18. Ac for use according to embodiments 11-17, wherein the chemotherapy agent is a platinum-containing anticancer agent. tRII receptor inhibitor.

[0068] 19. A combination of a) a myostatin antagonist and b) an mTOR inhibitor.

[0069] 20. A myostatin antagonist is an ActRII receptor inhibitor, embodiment 19 The combinations described above.

[0070] 21. The ActRII receptor inhibitor is an anti-ActRII receptor antibody, in embodiment 20. The combinations listed.

[0071] 22. The combination according to embodiment 21, wherein the anti-ActRII receptor antibody is bimaglumab.

[0072] 23. The combination according to embodiments 19 to 22, wherein the mTOR inhibitor is everolimus.

[0073] 24. Combinations of the substances described in embodiments 19 to 23 for use as pharmaceuticals.

[0074] 25. Combinations according to embodiments 19 to 23 for use in the treatment of cancer cachexia.

[0075] 26. Treating cancer cachexia prevents weight loss, as described in aspects 19-23. A combination of items.

[0076] 27. Maintaining body weight is a treatment for cancer cachexia, as described in aspects 19-23. A combination of items.

[0077] 28. Treating cancer cachexia involves increasing body weight, as described in aspects 19-23. A combination of these.

[0078] 29. The combination or state according to Embodiments 1 to 9, wherein the therapeutic agent is present in the individual pharmaceutical composition. A combination of items for use as described in items 19-28.

[0079] 30. For use in the treatment of age-related conditions, as described in any one of the embodiments 19 to 23. A combination of items.

[0080] 31. Age-related conditions include sarcopenia, cutaneous atrophy, muscle wasting, cerebral atrophy, and atherosclerotic artery disease. Sclerosis, arteriosclerosis, emphysema, osteoporosis, osteoarthritis, hypertension, erectile dysfunction, dementia, Han Chinton's disease, Alzheimer's disease, cataracts, age-related macular degeneration, prostate cancer, stroke, average life expectancy Reduced life expectancy, renal impairment, and age-related hearing loss, age-related mobility impairment (e.g., frailty), cognitive impairment. Intellectual decline, age-related dementia, memory impairment, tendon stiffness, cardiac hypertrophy, and systolic dysfunction and dilation. Choose from a group consisting of cardiac dysfunction such as impaired heart function, immunosenescence, cancer, obesity, and diabetes. The combination described in embodiment 30.

[0081] 32. Myosta for use in delaying the progression-free survival period of cancer in patients treated with chemotherapy agents. A chin antagonist.

[0082] 33. The chemotherapeutic agent is a platinum-containing anticancer drug such as cisplatin or carboplatin. , or an mTOR inhibitor such as everolimus, for use as described in Embodiment 30 It is a myostatin antagonist.

[0083] 34. Embodiments in which the myostatin antagonist is an ActRII receptor inhibitor. Myostatin antagonists for use as described in sections 32-33.

[0084] 35. Embodiment 3, in which the ActRII receptor inhibitor is an anti-ActRII receptor antibody. A myostatin antagonist for use as described in 4.

[0085] 36. The use described in embodiment 35, wherein the anti-ActRII receptor antibody is bimaglumab. A myostatin antagonist.

[0086] 37. A method for treating a subject having cancer cachexia, which is effective against said cancer cachexia. A method comprising administering an ActRII receptor inhibitor to the subject in a certain amount.

[0087] 38. The method according to embodiment 37, wherein cancer cachexia is caused by treatment using a chemotherapeutic agent.

[0088] 39. The method according to embodiment 38, wherein the chemotherapeutic agent is a platinum-containing anticancer agent.

[0089] 40. Treating cancer cachexia is to reduce weight loss, any aspect 37~ The method described in 39.

[0090] 41. A method for delaying the progression-free period of cancer in a subject with cancer, wherein the cancer Administer an ActRII receptor inhibitor to the subject in a dose effective in delaying the exacerbation period. A method that includes the act of doing so.

[0091] 42. A method for delaying the progression-free period of cancer in a subject with cancer cachexia, ActRII receptor inhibitors are administered in an amount effective in delaying the progression-free period of cachexia. A method that includes administering the substance to an elephant.

[0092] 43. A method for extending the survival of a target cancer, wherein the amount is effective in extending cancer survival. A method comprising administering an RII receptor inhibitor to the subject.

[0093] 44. The ActRII receptor inhibitor is an anti-ActRII receptor antibody, as described in Embodiment 37~ Method 44.

[0094] 45. The method according to embodiment 44, wherein the anti-ActRII receptor antibody is bimaglumab.

[0095] 46. ​​A method for treating a subject with cancer cachexia, comprising a myostatin antagonist A method comprising administering an mTOR inhibitor to the subject.

[0096] 47. A method for treating subjects with age-related conditions, comprising a myostatin antagonist A method comprising administering an mTOR inhibitor to the subject.

[0097] 48. A myostatin antagonist is an ActRII receptor inhibitor, aspect 46 Methods ~47.

[0098] 49. The ActRII receptor inhibitor is an anti-ActRII receptor antibody, in embodiment 48. Method of description.

[0099] 50. The method according to embodiment 49, wherein the anti-ActRII receptor antibody is bimaglumab.

[0100] 51. The method according to embodiments 46 to 50, wherein the mTOR inhibitor is everolimus.

[0101] 52. Age-related conditions include sarcopenia, cutaneous atrophy, muscle wasting, cerebral atrophy, and atherosclerotic artery disease. Sclerosis, arteriosclerosis, emphysema, osteoporosis, osteoarthritis, hypertension, erectile dysfunction, dementia, Han Chinton's disease, Alzheimer's disease, cataracts, age-related macular degeneration, prostate cancer, stroke, average life expectancy Reduced life expectancy, renal impairment, and age-related hearing loss, age-related mobility impairment (e.g., frailty), cognitive impairment. Intellectual decline, age-related dementia, memory impairment, tendon stiffness, cardiac hypertrophy, and systolic dysfunction and dilation. Choose from a group consisting of cardiac dysfunction such as impaired heart function, immunosenescence, cancer, obesity, and diabetes. The method according to embodiments 46-50.

[0102] 53. Methods of treatment in accordance with either of the above uses or combinations.

[0103] A preferred combination and its use involves bimaglumab and platinum-containing antibiotics such as cisplatin. It is a drug.

[0104] Another preferred combination and its use is mTOR such as bimaglumab and everolimus. It is an inhibitor.

[0105] Further embodiments include: a) ActRII receptor inhibitors such as bimaglumab, and b) PI3K inhibitors - A combination that includes -.

[0106] ActRII receptor inhibitors such as bimaglumab, and b) VEGF receptor inhibitors A combination according to any of the above embodiments, including a tar.

[0107] Further specific examples include a) bimaglumab, etc., for use in improving progression-free survival. This is a combination of an ActRII receptor inhibitor and (b) a chemotherapeutic agent.

[0108] Another further specific embodiment is a) bimaglumab, etc., for use in improving overall survival. This is a combination of an ActRII receptor inhibitor and (b) a chemotherapeutic agent.

[0109] All embodiments can be combined with one another within the scope of the present invention.

[0110] In a further embodiment, the present invention relates to the treatment of cancer cachexia, and the amounts of both which are therapeutically effective. A pharmaceutical composition containing, individually, the use thereof, or delaying the progression-free period of cancer / cancer cachexia. Therefore, in order to prolong cancer survival, to improve progression-free survival or overall survival, and to add To treat age-related conditions, they may be administered separately, in parallel, or sequentially. Such a pharmaceutical composition consisting of the given combination partner (a) and combination partner (b) This invention provides a method for treating cancer cachexia using a substance.

[0111] Bimagrumab The manufacturing of bimaglumab is described in International Publication No. 2010 / 125003. It is listed.

[0112] Bimaglumab has a hypervariable region in its sequence, CDR1 of SEQ ID NO: 1, and C of SEQ ID NO: 2. At least one immunoglobulin heavy chain variable DR2 and CDR3 of SEQ ID NO: 3 Main (V H It contains an antigen-binding site that includes ).

[0113] One of the sequences of CDR1, CDR2, and / or CDR3 of the heavy chain has been altered. The use of antibodies having two or three residues is also within the scope of the present invention.

[0114] Bimaglumab has a hypervariable region in its sequence, CDR1 of SEQ ID NO: 4, and C of SEQ ID NO: 5. At least one license including DR2 and CDR3 or its CDR equivalent of Sequence ID No. 6 Epidemic globulin light chain variable domain (V L This also includes antigen-binding sites, including those listed above.

[0115] One of the light chain CDR1, CDR2, and / or CDR3 sequences has been altered. The use of antibodies having two or three residues is also within the scope of the present invention.

[0116] Bimaglumab also includes the light chain of SEQ ID NO: 7 or SEQ ID NO: 8 and the heavy chain of SEQ ID NO: 9.

[0117] According to the present invention, the use of an antibody having 95% identity with the light chain and / or heavy chain is also included. It can be done.

[0118] Bimaglumab sequence listing

[0119] [ka]

[0120] [ka]

[0121] [ka]

[0122] [ka]

[0123] [ka]

[0124] [ka]

[0125] [ka]

[0126] [ka]

[0127] [ka]

[0128] [ka]

[0129] [ka]

[0130] [ka]

[0131] Cachexia or wasting syndrome is a condition in which weight loss occurs in individuals who are not actively trying to lose weight. It is characterized by a decrease in blood volume, muscle atrophy, fatigue, weakness, and a marked loss of appetite. The formal definition of cachexia is that it is caused by Even if affected patients consume more calories, they cannot recover nutritionally. This indicates a loss of fat mass and a decrease in body mass (weight), suggesting that the primary pathology is appropriate.

[0132] Cachexia is associated with cancer, AIDS, chronic obstructive pulmonary disease, multiple sclerosis, congestive heart failure, and tuberculosis. Familial amyloid polyneuropathy, gadolinium poisoning, mercury poisoning (acrospinal pain syndrome) It is also seen in patients with hormone deficiencies.

[0133] Cachexia is a positive risk factor for death; that is, if a patient has cachexia, the underlying condition The chances of death increase dramatically from this state. Cachexia is a sign of various underlying disorders. It is possible; when a patient presents with cachexia, the doctor generally considers cancer, metabolic acidosis ( (Due to decreased protein synthesis and increased protein catabolism), certain infectious diseases (e.g., tuberculosis) AIDS, chronic pancreatitis, and some autoimmune disorders, or amphetamine addiction. Consider the possibility of cachexia, ranging from loss of appetite, asthenia, and anemia to complete immobility. Cachexia is a part of the pathology that weakens patients physically and usually results in poor response to standard treatments. Sarcopenia is included as one example.

[0134] Cancer cachexia: Cancer cachexia cannot be completely reversed with conventional nutritional support and leads to progressive functional impairment. This results in a progressive decrease in skeletal muscle mass (which may or may not include a decrease in fat mass). It is a multifactorial syndrome defined by ( ).

[0135] Chemotherapy agents: As chemotherapy agents, platinum-containing anticancer drugs (e.g., cisplatin, carboplatin), P I3K / mTOR inhibitor, everolimus, PI3K inhibitor and VEGFR Inhibitors are one example.

[0136] In a broader sense, when referring to "chemotherapy," alkylating agents (e.g.) are used as chemotherapy. For example, cyclophosphamide, temozolomide), platinum-containing drugs, antimetabolites (e.g., 5-f Luoruracil, methotrexate, hydroxyurea, cytarabine, gemcitabine) Topoisomerase inhibitors (e.g., doxorubicin, irinotecan), microtubule polymerization Agents / depolymerizing agents (e.g., vinblastine, vincristine, paclitaxel, docetaxel) (Lu), endocrine agents (e.g., bicalutamide, leuprorelin, tamoxifen, letrozole) Examples include (and more recent molecularly targeted agents) such as kinase inhibitors and antibodies. It can be done.

[0137] mTOR inhibitor: As used herein, the term “mTOR inhibitor” refers to the cellular mTOR kinase This refers to a compound or ligand that inhibits [a certain substance], or a pharmaceutically acceptable salt thereof. In this case, the mTOR inhibitor is an allosteric inhibitor. In one embodiment, mTOR inhibitors are catalytic inhibitors.

[0138] As an allosteric mTOR inhibitor, rapamycin, a neutral tricyclic compound, ( Sirolimus), for example, rapamycin derivatives, rapamycin analogs (also called rapalogs) A compound that has structural and functional similarities to rapamycin, including ( ). Examples include isin-related compounds and other macrolide compounds that inhibit mTOR activity. .

[0139] Rapamycin is a compound of Streptomyces hygroscopicus (St), which has the structure shown in formula A. It is a known macrolide antibiotic produced by Reptomyces hygroscopicus.

[0140] [ka] For example, McAlpine, JB, et al., J. Antibiotics (1991) 44: 688; Schreiber, SL, et al., J. Am. Chem. Soc. (1991) 113: 7433; US Pat. No. 3,929,992 See also. Various numbering schemes have been proposed for rapamycin. To avoid confusion, when naming specific rapamycin analogs in this specification, The names are assigned based on rapamycin, which uses the numbering scheme of formula A.

[0141] A useful rapamycin analog in the present invention is, for example, cyclohexyl rapamycin. The hydroxyl group of the ring is OR1 (wherein R1 is hydroxyalkyl, hydroxyalkoxy) It is a cyalkyl, acylaminoalkyl, or aminoalkyl; for example, its contents are Incorporated by reference U.S. Patent No. 5,665,772 and International Publication No. 94 / RAD, also known as Everolimus, is listed in pamphlet No. 09010. It is an O-substituted analog that is replaced by (there is 001). Other suitable Rapamay Syn analogs include those substituted at positions 26 or 28. (e.g., rapamycin) The analogues are epimers of the aforementioned analogues, in particular analogues substituted at positions 40, 28, or 26. It may also be an epimer, and in some cases, for example, its contents may be incorporated by reference. U.S. Patent No. 6,015,815, International Publication No. 95 / 14023 As described in International Open Brochure No. 99 / 15530, further hydrogenation It may also be, for example, ABT578, also known as Zotarolimus, or The contents of U.S. Patent No. 7,091,213 and International Publication No. 98 are incorporated by reference. As described in pamphlet No. / 02441 and international release pamphlet No. 01 / 14387 Rapamycin analogs, such as AP23, also known as ridafololimus, are being used. 573 is also acceptable.

[0142] A suitable rap for use in the present invention from U.S. Patent No. 5,665,772 Examples of mycin analogs, though not limited to these, include 40-O-benzylrapamycin. , 40-O-(4'-hydroxymethyl)benzylrapamycin, 40-O-[4' -(1,2-dihydroxyethyl)]benzylrapamycin, 40-O-allyl-rapamycin Mycin, 40-O-[3'-(2,2-dimethyl-1,3-dioxolane-4(S)- (Il)-propa-2'-en-1'-yl]-rapamycin, (2'E,4'S)-40 -O-(4',5'-dihydroxypenta-2'-en-1'-yl)-rapamycin, 40-O-(2-hydroxy)ethoxycarbonylmethyl-rapamycin, 40-O-( 2-Hydroxy)ethyl-rapamycin, 40-O-(3-Hydroxy)propyl-rapamycin Mycin, 40-O-(6-hydroxy)hexyl-rapamycin, 40-O-[2-( 2-Hydroxy)ethoxy]ethyl-rapamycin, 40-O-[(3S)-2,2-di [methyldioxolan-3-yl]methylrapamycin, 40-O-[(2S)-2,3 -Dihydroxypropane-1-yl]-rapamycin, 40-O-(2-acetoxy)eth ru-rapamycin, 40-O-(2-nicotinoyloxy)ethyl-rapamycin, 40 -O-[2-(N-morpholino)acetoxy]ethyl-rapamycin, 40-O-(2- N-imidazolylacetoxy)ethyl-rapamycin, 40-O-[2-(N-methyl- N'-piperazinyl)acetoxy]ethyl-rapamycin, 39-O-desmethyl-39 ,40-O,O-ethylene-rapamycin, (26R)-26-dihydro-40-O-( 2-Hydroxy)ethyl-rapamycin, 40-O-(2-aminoethyl)-rapamycin 40-O-(2-acetaminoethyl)-rapamycin, 40-O-(2-nicotine (Amidoethyl)-rapamycin, 40-O-(2-(N-methyl-imidazo-2'-yl Carbesoxamide)ethyl)-rapamycin, 40-O-(2-ethoxycarbonylamide) (noethyl)-rapamycin, 40-O-(2-tolylsulfonamidoethyl)-rapamycin Syn and 40-O-[2-(4',5'-dicarboethoxy-1',2',3'-tri A azole-1'-yl)-ethyl]-rapamycin is one example.

[0143] Other rapamycin analogs useful in the present invention are those of the cyclohexyl ring of rapamycin. The hydroxyl group and / or the hydroxyl group at position 28 are replaced by a hydroxyester group. An analogue that has been found is, for example, rapamycin, which is found in US RE44,768. An analogue, such as *Temsirolimus*, is known.

[0144] In the present invention, other rapamycin analogs that are useful include those in which the methoxy group at position 16 is located in a different position. Substituting group, preferably (optionally hydroxy-substituted) alkynyloxy, benzyl, or Substituted with tomechobenzyl or chlorobenzyl, and / or 39 The methoxy group at position 39 disappears along with the 39th carbon, thus cyclofeeding rapamycin. One example is a cyclopentyl ring in which the xyl ring lacks the methoxy group at position 39. For example, the contents of which are incorporated by reference in the pamphlet International Publication No. 95 / 16691 As stated in the brochure and International Publication No. 96 / 41807. The body can be further modified such that the hydroxy at position 40 of rapamycin is alkylated and / or the 32-carbonyl is reduced.

[0145] As rapamycin analogs from WO 95 / 16691, these include, but are not limited to, 16-demethoxy-16-(penta-2-ynyl)oxy-rapamy cin, 16-demethoxy-16-(buta-2-ynyl)oxy-rapamycin, 16-demethoxy-16-(propargyl)oxy-rapamycin, 16-demethoxy-16-(4-hydroxy-but-2-ynyl)oxy-rapamycin, 16-demethoxy-16-benzyloxy-40-O-(2-hydroxyethyl)-rapamycin, 16-demethoxy-16-benzyloxy-rapamycin, 16-demethoxy-16-ortho-methoxybenzyl-rapamycin, 16-demethoxy-40-O-(2-methoxyethyl)-16-(penta-2-ynyl)oxy-rapamycin, 39-demethoxy-40-desoxy-39-formyl-42-nor-rapamycin, 39-demethoxy-40-desoxy-39-hydroxymethyl-42-nor-rapamycin, 39-demethoxy-40-desoxy-39-carboxy-42-nor-rapamycin, 39-demethoxy-40-desoxy-39-(4-methyl-piperazin-1-yl)carbonyl-42-nor-rapamycin, 39-demethoxy-40-desoxy-39-(morpholin-4-yl)carbonyl-42-nor-rapamycin, 39-demethoxy-40-desoxy-39-[N-methyl,N-(2-pyridin-2-yl-ethyl)]carbamoyl-42-nor-rapamycin [[ID=二十九]] / / ​​​​​​​​​​​​​and 39-demethoxy-40-deoxy-39-(p-toluenesulfonylhydra zonemethyl)-42-nor-rapamycin can be mentioned.

[0146] As rapamycin analogs from WO 96 / 41807 pamphlet, these are not limited to, but include 32-deoxo-rapamycin, 16-O-penta-2-ynyl-3 2-deoxo-rapamycin, 16-O-penta-2-ynyl-32-deoxo-40- O-(2-hydroxy-ethyl)-rapamycin, 16-O-penta-2-ynyl-32 -(S)-dihydro-40-O-(2-hydroxyethyl)-rapamycin, 32(S) -dihydro-40-O-(2-methoxy)ethyl-rapamycin and 32(S)-dih dro-40-O-(2-hydroxyethyl)-rapamycin can be mentioned.

[0147] Another suitable rapamycin analog is everolimus described in U.S. Patent Application Publication No. 2005 / 0101624, the content of which is incorporated by reference.

[0148] In mammalian cells, the target of rapamycin (mTOR) kinase exists as a multi-protein complex described as the mTORC1 complex or the mTORC2 complex (which senses the availability of nutrients and energy and integrates inputs from growth factors and stress signaling). The mTORC1 complex is sensitive to allosteric mTOR inhibitors such as rapamycin and is composed of mTOR, GβL, and the regulatory associated protein of mTOR (raptor), and binds to the peptidyl-prolyl isomerase FKBP12 protein (FK506-binding protein 1A, 12 kDa). In contrast ​ Furthermore, the mTORC2 complex is rapamycin-insensitive to mTOR, GβL, and mTOR. Composed of companion proteins (rictors), FKBP1 in vitro 2. Does not bind to proteins.

[0149] mTO acts as a growth factor and a nutrient-sensitive apparatus for regulating growth and proliferation. The RC1 complex has been shown to be involved in the regulation of protein translation. 1 regulates protein translation via two important downstream substrates: P70S6 kinase This then phosphorylates the ribosomal protein P70 S6, which is a translation initiation factor in eukaryotes. A certain 4E-binding protein 1 (4EBP1) is eIF4E-regulated cap-dependent translation It plays a crucial role in modulating the cellular energy and It regulates cell growth in response to nutrient homeostasis, and the deregulation of mTORC1 is multifaceted. This is common to various human cancers. The function of mTORC2 is mediated by Akt phosphorylation. This includes the regulation of cell survival and the modulation of actin cytoskeleton dynamics.

[0150] The mTORC1 complex forms an intracellular complex with FKBP12 and the FKB of mTOR The action of rapamycin, primarily involving binding to the P12-rapamycin binding (FRB) domain. This method is effective against allosteric mTOR inhibitors such as rapamycin and its derivatives. It is receptive. This alters and weakens its interaction with its scaffold protein, raptor. In order, substrates such as P70 S6K1 access mTOR and are prevented from being phosphorylated. It is thought to cause conformational changes in mTORC1. Rapamycin and everolimus, such as RAD001, has clinical relevance by inhibiting the hyperactivation of mTOR associated with both benign and malignant

[0151] growth disorders. In addition, RAD001, known as everolimus (Afinitor®), has the chemical name (1R,9S,12S,15R,16E,18R,19R,21R,23S, 24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12- {(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-meth oxycyclohexyl]-1-methylethyl}-19,30-dimethoxy-15,17,2 1,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo [30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-

[0152]

Chemical Structure

[0153] Everolimus is an FDA-approved drug for the treatment of advanced renal cancer and is being investigated in several other Phase III clinical trials in oncology. Preclinical studies have shown that everolimus can inhibit the growth of a variety of tumor cell lines both in vitro and in vivo, probably through the inhibition of rapamycin-sensitive mTORC1 function. Everolimus, as a It is a very powerful allosteric mTOR inhibitor in 0 S6. Allosteric mTOR inhibitors such as Limus (and other rapamycin analogs) This involves inhibition of the mTORC2 pathway, or the resulting activation of its Akt signaling pathway. It has only a slight effect or no effect at all. Allosteric Further examples of mTOR inhibitors include sirolimus (rapamycin, AY-2298) 9), 40-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate [T]-rapamycin (also known as temsirolimus or CCI-779) and ridaf One example is the olorimus (AP-23573 / MK-8669). Allosteric mTO Other examples of R inhibitors include Zotarolimus (ABT578) and Umilolimus. It is possible.

[0154] Alternatively, or even better, a catalytic, ATP-competitive mTOR inhibitor is mTORquine It is possible to directly target the zedomain and target both mTORC1 and mTORC2. These were also released. These also show rapamycin-resistant mTORC1 output, e.g., 4E To modulate BP1-T37 / 46 phosphorylation and cap-dependent translation, rapa A more complete mTORC1 inhibitor than allosteric mTOR inhibitors such as mycin. It is an inhibitor.

[0155] The combination of bimaglumab and mTOR inhibitors such as everolimus is bimaglumab Because it increases muscle mass and everolimus improves muscle quality, it is a treatment for age-related muscle dysfunction. It may be particularly effective against [unclear]. Bimaglumab is a myostatin / activin drug. It improves muscle mass by inhibiting pathways. Everolimus is overactive in aging muscles. By inhibiting a certain mTOR pathway, muscle function can be improved (by adding the present inventors). (Previously unpublished internal data obtained). Inhibition of mTOR enhances mitochondrial function and inflammation. In some cases, muscle function can be improved by reducing [a certain factor] and increasing autophagy. Combining bimaglumab with mTOR inhibitors such as everolimus increases muscle mass and Improving muscle function may have therapeutic benefits in sarcopenia and heart failure. Yes. Furthermore, improving muscle mass and muscle function is related to glucose uptake in the muscles. Increasing mTO may have therapeutic benefits in diabetes mellitus. Increased R activity was observed in healthy older subjects (6) compared to healthy younger subjects (18-40 years old). This was demonstrated in muscle biopsies obtained from individuals aged 0-84 years (Markofski M et al., Exp Geront, 2015). ).

[0156] [Examples] The present invention will be described in more detail below, particularly with reference to examples, but this is the present invention. This is not intended to limit anything.

[0157] material and method material Bimaglumab is a human IgG1 Leu234Ala / Le targeting ActRII. This is a u235Ala monoclonal antibody. The Fc region of the human antibody is the same as that of mouse Fc.CD. CDD866, the mouse version of bimaglumab, was replaced by D866. CH of Novartis Pharma AG (Basel, Switzerland) It was produced in O cells. Cisplatin (cis-diaminedichloro-platinum(II)) was converted to Si I purchased it from GMA Aldrich (catalog number 479306). Everolimus is Synthesized at Novartis Pharma AG.

[0158] Animal experiments Adult male Balb / cJRj mice, 11 to 12 weeks old, were sent to Janvier Laboratories. I bought it from atories (Le Genest St Isle, France). Mice were acclimated to the facility for 7 days. Animals were kept in groups of 5 or fewer at 25°C in a 12:1 ratio. The animals were housed in a 2-hour light-dark cycle. The animals were given 18.2% protein and 3.0% fat. Contains standard experimental food (energy content of 15.8 MJ / kg) (NAFAG 3890) They were given Kliba, Basel, and Switzerland. Food and water were provided freely. did.

[0159] Mouse colon cancer cell line CT-26 was inactivated with 10% heat in fetal bovine serum and antibiotics. Substance-Antifungal drug solution was added to RPMI 1640 medium at 37°C with 5% CO2. The cells were cultured in Accutase® (PAA Laboratories). The process is carried out using tories GmbH (Pasching, Austria). Take 50% PBS and 50% BD Matrigel (without phenol red). (Trademark) Matrix (Catalog number 356237, BD Biosciences, Be Suspended in a solution containing (dford, MA, USA). 3 × 10 5 Contains individual cells A 0.1 mL cell suspension was subcutaneously inoculated into the left flank of the mouse. If a tumor could be palpated... , mice bearing tumors of acceptable morphology and size were randomized, and the size of the tumor was determined. Balanced groups were generated in terms of mean and range of weight. Treatment was performed on the day of randomization. It started on [date].

[0160] We will conduct therapeutic intervention studies to evaluate the effects of CDD866, either alone or in combination with anticancer drugs. CDD866 was administered once or twice a week at a dose of 5 mL / kg, with a dose of 20 mg / kg s. It was administered at .c. Cisplatin was administered twice a week at 1 mg / kg ip. Verolimus was administered once daily at a dose of 5 mg / kg po. In the combination group, cisplatin was used. Chin or everolimus treatment, with subcutaneous administration of CDD866 once or twice a week, Each was combined. Body weight and tumor volume were measured two to three times a week. At the end of the experiment... The mice were euthanized with CO2, and tumors, the tibialis anterior muscle, the gastrocnemius-soleus-plantar muscle complex, four Head muscle tissue was collected and weighed.

[0161] A combination of CDD866 and cisplatin or everolimus has resulted in a weight loss of up to 20%. Small or 1,500mm 3 Cancer cachexia, which is defined as a tumor volume exceeding a certain threshold for discontinuation. As a follow-up to evaluate whether the progression of the disease was slowed, a progression-free study was conducted. The treatment regimen was the same as that used in the therapeutic intervention study. Body weight and tumor volume For the first two weeks, measurements were taken two to three times a week, and then daily until the end of the experiment. Approaching 0%, or the tumor volume reaches 1,500 mm³. 3 If it exceeds that, the mouse will be cooled with CO2. They put him to death.

[0162] Protein analysis 1% protease inhibitor cocktail (Calbiochem # 539131) and extraction reagent supplemented with 0.2% SDS (Phosphosafe; Novagen A lysis buffer consisting of Prec Inc. (Madison, WI, USA) was added. ellys Homogenates(FastPrep-Machine FP20) The components were separated by centrifugation at 4°C for 20 minutes (14,000 rpm). The supernatant was then rotated. The protein content is collected and measured using a commercially available protein determination kit (BCA Kit; Th The measurements were taken using ermo Scientific. The sample was then processed using SDS-PAGE. Diluted in crevasse and denatured at 70°C for 10 minutes. Equivalent amounts of protein were added, ranging from 4 to 12% and 8% polyacrylamide gel (NuPAGE Bis-Tris gel; Invit Loading against the lane of rogen Corp., Carlsbad, CA, USA The samples were separated by electrophoresis and then transferred to a nitrocellulose membrane. Blocked in TBS containing % Tween and 5% w / v nonfat milk powder. Primary antibody Phospho-SMAD3 (Millipore #04 1042 1:1000 is rare) (Analysis) and α-tubulin (diluted with Sigma T6199 1:5000) in a 0.1% solution In TBS containing Tween20 and 5% w / v nonfat milk powder, secondary antibodies were found in 0.1% Tw Incubate in TBS containing een20, 0.05% SDS, and 5% nonfat milk. It activated immune activity with SuperSignal West Femto Maximum S In ensitivity Substrate (Thermo Scientific) Detected and exposed to film or acquired by FusionSpectra. The quantitative determination of mTOR and IL-6 is performed according to the manufacturer's instructions using MesoScale D. Using the discovery reader from MesoScale Discovery The procedure was carried out using a Ssei kit.

[0163] statistical analysis Values ​​are expressed as mean ± SEM. Statistical analysis was performed on the control group (non-tumor) in the treatment intervention study. (Sore-bearing and tumor-bearing), anticancer drug alone (cisplatin or everolimus) or CD Sidak multiple comparison test after ANOVA to compare D866 alone with treatment groups. Dunn's multiple comparison test was used for progression-free study studies. Probability values ​​<0.0 A value of 5 was considered statistically significant. Statistical analysis was performed using GraphPad Prism. GraphPad Software, Inc., La Jolla, CA, USA) Therefore, the procedure was carried out. Body weight was expressed as a percentage change from day 0, which was the start of the treatment. cubic m The tumor volume m is given by the formula (length × width) 2 Calculated according to ) / 2. Muscle weight is measured on the day of cell inoculation. The results were normalized to body weight (initial weight) and then expressed as a percentage change from the non-tumor control group. [Examples]

[0164] Bimaglumab inhibits cisplatin-induced weight loss. Extensive weight loss has been identified as a significant determinant of cancer-related mortality. Then, long-term weight growth was monitored (Figures 1A and B). Ten days after the start of treatment, Tumor-carrying animals receiving cisplatin as monotherapy lost 20% of their initial body weight (Figure 1). B and C). In contrast, vehicle-treated, tumor-bearing animals experienced a 10% weight loss. However, animals treated with CDD866 alone or in combination with cisplatin showed different results. They showed only moderate weight loss of 3% and 5% (Figures 1B and C). In healthy control animals... Cisplatin does not affect body weight, and CDD866 administration is effective when cisplatin is not present. Whether present or not, significant weight gain occurred (Figures 1A and C). These data are valid. In animals with cachexia, cisplatin at an antitumor dose (see Figure 1E) actually caused weight loss. By accelerating the process, CDD866 has been demonstrated to significantly reduce chemotherapy-induced waste. ru.

[0165] The primary focus of this research is the effectiveness of chemotherapy in promoting tumor growth and CDD. The issue concerned potential drug-drug interactions that could reduce the effects of 866. At the start of the procedure, the average tumor volume was ≥260 mm². 3 (Figure 1D). CDD866 was a tumor It did not accelerate tumor progression (Figures 1D and E), nor did it impair the antitumor effect of cisplatin. (Figures 1D and E). Therefore, CDD866 interferes with the antitumor effect of cisplatin. However, it is effective in reducing chemotherapy-mediated weight loss in cancer cachexia. [Examples]

[0166] Bimaglumab counteracts cisplatin-induced muscle wasting. Taking into account the positive effect of CDD866 on body weight, the inventors then considered the individual The effects of various interventions on skeletal muscle were determined. In the gastrocnemius muscle, cisplatin reduced 25% of muscle mass. It induced a decrease in weight. The CDD866 treatment tended to reduce muscle weight loss by up to 13%. Yes, and this protective effect was maintained even in the presence of cisplatin (12%) (Figure 2B). A level of protection was observed in the quadriceps (Figure 2C). The tibialis anterior muscle underwent CDD866 treatment. The greatest benefit was obtained from this. In the tibialis anterior muscle, animals treated with cisplatin showed 34% muscle wasting. In our experience, co-administration with CDD866 significantly reduced muscle loss to 16% (Figure 2A). . [Examples]

[0167] Bimaglumab combined with cisplatin delays the progression-free survival period in cancer cachexia. Extensive tumor growth and subsequent weight loss are important predictors of mortality in cancer patients. Therefore, the inventors believe that the combination of CDD866 and cisplatin affects the length of survival. We wanted to evaluate whether or not it had it. For ethical reasons, the inventors decided against using conventional life Existence research was avoided. Instead, each mouse was subjected to a weight loss of more than 20% of its initial body weight, or 1 ,500mm 3 If the tumor reaches any of the following levels, it is euthanized individually and does not progress. The period was decided.

[0168] On average, animals receiving vehicle or cisplatin treatment last 12 days and 12 days, respectively. They had to be slaughtered (Figures 2D and E). Animals treated with CDD866 were 1 Although it had to be euthanized after 6 days, this was because the CDD866 treatment reduced weight loss. This supports previous findings that it lowered the tumor but did not promote tumor growth. CDD The combination treatment of 866 and cisplatin was superior to any of the other interventions tested. In fact, the combination treatment extended the progression-free interval to 21 days (Figure 2E). Monitoring was 35% of the animals in the combination group that had not yet met one of the defined discontinuation criteria, It stopped after 9 days (Figure 2D).

[0169] In combination with cisplatin Despite substantial tumor growth inhibition, cisplatin exacerbated weight loss in cachectic animals, which may be due to the high toxicity of the anticancer agent. CDD866 fully prevented cisplatin-mediated weight loss and demonstrated that ActRII inhibition remained effective in the presence of cisplatin. Cisplatin treatment alone or in combination with CDD866 decreased CT-26 tumor weight to similar levels, highlighting that the anticancer effect of cisplatin was not negatively affected by CDD866.

[0170] Consistently, cisplatin treatment did not improve CT-26 tumor-induced skeletal muscle wasting but rather tended to exacerbate muscle loss. In contrast, administration of CDD866 alone or in combination with cisplatin protected against skeletal muscle weight loss compared to animals receiving only cisplatin, further supporting that ActRII inhibition remains fully effective under cisplatin treatment. Thus, these results demonstrate that CDD866 in combination with cisplatin counteracts muscle wasting in cachectic animals compared to cisplatin treatment alone. Notably, CDD866 was administered only once a week and mice received only two injections throughout the study (except for survival studies). Release of activin by cancer tissue may potentially compete with CDD866-mediated ActRII inhibition, and higher doses or frequencies of CDD866 administration may be required to elicit more pronounced or maximal responses in cancer cachexia. Indeed, 17 ​​​​​​​​​​​​​​In addition, avoiding greater muscle wasting is possible in combination with everolimus under more frequent dosing regimens. In this study, CDD866 alone was found to be effective.

[0171] Cancer patients with low muscle mass have an increased risk of chemotherapy-related treatment-related toxicity, overall This indicates an increase in the mortality rate. 18 Without contradiction, CDD866 significantly increases muscle mass. By adding this, disease progression is significantly delayed. The progression-free period for cancer cachexia is CDD. The simultaneous therapy of 866 and cisplatin further delays tumor growth, while simultaneously combating muscle wasting. It inhibited growth. [Examples]

[0172] Bimaglumab and everolimus prevent cancer cachexia additively. In the next step, it is known that mTOR plays a central role in cell growth and proliferation. Therefore, rapamycin is a molecular targeted agent for mammalian targets (mTOR), and evero Lims was selected as the combination partner. Furthermore, the treatment frequency for CDD866 was Increase the dosage to twice a week to ensure a significant anti-cachexic effect when administered as a monotherapy, and to ensure the effectiveness of everoli. The combination of Mus and CDD866 was evaluated in non-tumor mice and tumor-bearing cachexia mice.

[0173] In the non-tumor-bearing group, weight gain was not significantly affected by everolimus treatment. In contrast, as expected, the CDD866 treatment resulted in a significant increase in weight gain (Figures 3A and C). ). Weight gain was slightly slower in the combined group (Figures 3A and C), but with everolimus alone, weight gain was slower. It is still quite different from Germany, and until the end of day 14, CDD866 alone is not very... There was no difference. In the CT-26 group, body weight was the same on day 14 compared to the non-tumor control group. Body weight induced by CT-26 was significantly reduced in the tumor-bearing control group (Figures 3B and C). The decrease is due to everolimus, CDD866, and combinations of everolimus and CDD866. This was completely thwarted. The effect of CDD866 on body weight was maintained in the presence of everolimus. It was done.

[0174] Everolimus slows CT-26 tumor growth and maintains its antitumor effect in the presence of CDD866. (Figure 3D). CT-26 tumor weight was measured by Eve alone or in combination with CDD866. Lolimus treatment significantly reduced tumor weight. CDD866 treatment significantly reduced CT-26 tumor weight. There was no effect.

[0175] In the non-tumor-bearing group, the weights of the tibialis anterior, gastrocnemius-soleus-plantar complex, and quadriceps were , unaffected by everolimus treatment, but significantly increased by CDD866 treatment. Figures 4A-C). The effect of CDD866 on muscle mass was maintained in the presence of everolimus. The CT-26 tumor showed improved muscle function in the tibialis anterior, gastrocnemius-soleus-foot muscles compared to the non-tumor-bearing control group. It induced a significant decrease in the weight of the plantar muscle complex and quadriceps (Figure 4A-C). CT-26 The resulting decrease in muscle mass is significantly reduced by everolimus or CDD866 treatment. Interestingly, the combination of everolimus and CDD866 additively stimulated skeletal muscle The weight loss appears to be reversed, and the effect of the combination treatment is significantly different from that of everolimus treatment alone. It had become that way. [Examples]

[0176] Bimaglumab combined with everolimus delays the progression-free survival period in cancer cachexia. The effects of everolimus and CDD866 on CT-26-induced cachexia in therapeutic intervention studies. In addition to beneficial effects, the effects of these treatments on the progression of cancer and associated cachexia are considered by the The same criteria used in the splatin combination study were applied for evaluation. CT-26 control group Therefore, the median number of days elapsed until the discontinuation criterion (progression-free interval) is 1 day from randomization and treatment initiation. This was 7.5 days later (Figures 4D and E). Everolimus treatment was mainly due to its antitumor effect. However, the progression-free interval was significantly extended to 23 days, but the extension trend shown by CDD866 was 2 It was not significant until the 1st. The lack of significance of CDD866 regarding progression-free survival is This treatment is very effective in preventing weight loss, but the second discontinuation criterion is tumor formation. This is explained by the fact that it did not inhibit growth. Importantly, everolimus and CD The combination of D866 appears to further delay the progression-free interval to 28.5 days, and this effect The results were significantly better compared to the CT-26 control group.

[0177] combination with everolimus mTOR is known to play a central role in cell growth and proliferation, so Lolimus-mediated mTOR inhibition was as expected, both in the absence and presence of CDD866. It showed a remarkable antitumor effect. This result indicates that the anticancer effect of everolimus is similar to that of CDD866. This clearly demonstrates that it is not negatively affected by ActRII inhibition. -26 In line with the weight loss caused by tumors, skeletal muscle mass is consistent with CT-2 In the control group, the levels were significantly reduced. Everolimus or CDD866 treatment alone was used in conjunction with CT-26. Tumor-bearing mice were significantly protected from skeletal muscle weight loss caused by tumors. Interestingly, CDD866-mediated inhibition of ActRII is effective in the presence of everolimus. Not only does it remain that way, but despite the fact that mTOR is necessary for normal muscle growth Furthermore, it showed a less significant tendency towards an additive effect of reversing skeletal muscle weight loss. Similarly, non-tumor In mice carrying sores, everolimus treatment had no effect on body weight, but CDD866 showed It caused a significant increase in body weight. The effect of CDD866 on body weight was maintained even in the presence of everolimus. It was clearly demonstrated that mTOR inhibition did not alter the effect of CDD866 on body weight. This was shown. Muscle anabolic activity observed in non-tumor-bearing mice upon CDD866 treatment. The response was remarkable and unaffected by mTOR inhibition at doses that were clearly effective against the tumor. .

[0178] Everolimus treatment alone extends progression-free survival as an alternative to survival and CDD8 66 also showed a tendency towards extension. Importantly, the combination of everolimus and CDD866 was It appeared to further delay the progression-free period. Each treatment was supplemented to produce a beneficial effect. They acted specifically, with everolimus inhibiting tumor growth and CDD866 preventing cachexia. The tendency toward additive anticachetic effects observed with the combination of D866 and everolimus is A How ctRII blockade and mTOR inhibition positively affect skeletal muscle under the progression of cachexia Further explanation is needed regarding how they interact.

[0179] mTORC1 has been reported to be activated in denervated skeletal muscle atrophy. However, the anti-atrophic effect of mTOR inhibition by rapamycin treatment was not conclusive. OR activation suggests that mTOR inhibition may be beneficial in aging, obesity, and insulin resistance. It has also been reported in other pathological conditions such as diabetes. In this study, in tumor-bearing mice... Phosphorylation and the total amount of mTOR increase significantly. Therefore, CT-26 induces colon cancer. Such abnormal activation of mTOR in cachexia is also caused by cells. It contributes to quality, and therefore, mTOR inhibition, when combined with ActRII blockade, is even more effective. They probably demonstrated the benefits. [Examples]

[0180] The combination of mTOR inhibitors and myostatin antagonists in aging The combination of bimaglumab and mTOR inhibitors such as everolimus is bimaglumab Because it increases muscle mass and everolimus improves muscle quality, it is a treatment for age-related muscle dysfunction. It may be particularly effective against [unclear]. Bimaglumab is a myostatin / activin drug. It improves muscle mass by inhibiting pathways. Everolimus is overactive in aging muscles. Muscle function is improved by inhibiting a certain mTOR pathway. Inhibition of mTOR is mitochondrial By enhancing the function of ndria, reducing inflammation, and increasing autophagy... It may improve muscle function. Bimaglumab and mTOR inhibitors such as everolimus Combining these methods to improve muscle mass and function can help with sarcopenia and heart failure. It may have therapeutic benefits. Furthermore, improving muscle mass and muscle function can lead to muscle By increasing glucose uptake in meat, therapeutic benefits in diabetes mellitus are obtained. There are cases where it is beneficial.

[0181] The data in Figure 5 shows the relationship between mTOR inhibitors and the myostatin / activin pathway in aging. Supporting the rationale for the beneficial use of antagonists (e.g., bimaglumab) This indicates the following: 1. mTOR is hyperactive in the skeletal muscle of aged rats compared to juvenile rats. 2. mTOR was appropriately degraded in the skeletal muscle of aged rats after fasting compared to young rats. It is not restricted.

[0182] References The following references, in particular the definitions and descriptions therein, are referred to herein by reference. It will be incorporated into it. ·Fearon, K. et al. Definition and classification of cancer cachexia : an international consensus. Lancet Uncool. 12, 489-495 (2011). ·Tan, BH, Birdsell, LA., Martin, L., Baracos, VE & Fearon, KC Sarcopenia in an overweight or obese patient is an adverse prognostic f Actor in pancreatic cancer. Clin. Cancer Res. 15,: 6973-6979 (2009). ·Benny Klimek, ME et al. Acute inhibition of myostatin-family pro teins preserves skeletal muscle in mouse models of cancer cachexia. Biochem Biophys. Res. Commun. 391, 1548-1554 (2010). ·Busquets, S. et al. Myostatin blockage using actRIIB antagonism in mice bearing the Lewis lung carcinoma results in the improvement of muscle wasting and physical performance. J. Cachexia Sarcopenia Muscle. 3, 37-43 (2012 ). ·Murphy, K. T. et al. Antibody-directed myostatin inhibition enhances mu scle mass and function in tumor-bearing mice. Am. J. Physiol. Regul. Integr. Com p. 301, R716-R726 (2011). ·Zhou, X. et al. Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival. Cell. 142, 531-543 (2010). ·Elkina, Y., von Haehling, S., Anker, S. D. & Springer, J. The role of myostatin in muscle wasting: an overview. J. Cachexia Sarcopenia Muscle. 2, 143-151 (2011). ·Lee, S. J. & McPherron, A. C. Regulation of myostatin activity and musc le growth. Proc. Natl. Acad. Sci. U.S.A. 98, 9306-9311 (2011). ·Schuelke, M. et al. Myostatin mutation associated with gross muscl e hypertrophy in a child. N. Engl. J. Med. 350, 2682-2688 (2004). ·Whittemore, L. A. et al. Inhibition of myostatin in adult mice inc reases skeletal muscle mass and strength. Biochem. Biophys. Res. Commun. 300, 96 5-971 (2003). ·Lee, S. J. et al. Regulation of muscle growth by multiple ligands signaling through activin type II receptors. Proc. Natl. Acad. Sci. U.S.A. 102, 18117-18122 (2005). ·Nakatani, M. et al. Transgenic expression of a myostatin inhibitor derived from follistatin increases skeletal muscle mass and ameliorates dy strophic pathology in mdx mice. FASEB J. 22, 477-487 (2007). ·Zimmers, T. A. et al. Induction of cachexia in mice by systemically adm inistered myostatin. Science. 296, 1486-1488 (2002). ·Chen, J. L. et al. Elevated expression of activins promotes muscle wast ing and cachexia. FASEB J. 28, 1711-1723 (2014). ·Lach-Trifilieff, E. et al. An antibody blocking activin type II rec eptors induces strong skeletal muscle hypertrophy and protects from atrophy . Mol. Cell. Bio. 34, 606-618 (2014). ·Amato, A. A. et al. Treatment of sporadic inclusion body myositis with bimagrumab. Neurology. 83, 2239-2246 (2014). ·Arrieta O. et al. Nutritional Status, Body Surface, and Low Lean Body Ma ss / Body Mass Index Are Related to Dose Reduction and Severe Gastrointestina l Toxicity Induced by Afatinib inPatients With Non-SmallCell LungCancer, Th e Oncologist 20, 967-974 (2015). ·Sjoblom et al. Low muscle mass is associated with chemotherapy-induced haematological toxicity in advanced non-small cell lung cancer. Lung Cancer 90 8 5-91 (2015) ·Parsons HA, Tsimberidou AM, Fu S, Hong D, Wen S, Baracos VE, Kurzrock R . Evaluation of the clinical relevance of body composition parameters in patients with cancer metastatic to the liver treated with hepatic arterial infusion chemotherapy. Nutr Cancer; 64: 206-17 (2012). ·Reis, F. M. et al. Serum and tissue expression of activin a in postmeno pausal women with breast cancer. J. Clin. Endocrinol. Metab. 87, 2277-2282 (2002 ). ·Tsai, S. Importance of lean body mass in the oncologic patient. Nutr. C lin. Pract. 27, 593-598 (2012). ·Bentzinger, C. F. et al. Skeletal muscle-specific ablation of rapt or, but not of rictor, causes metabolic changes and results in muscle dystr ophy. Cell Metab. 8, 411-424 (2008). ·Risson, V. et al. Muscle inactivation of mTOR causes metabolic and dystrophin defects leading to severe myopathy. J. Cell Biol. 187, 859-874 (2009 ). ·Argadine, H. M., Mantilla, C. B., Zhan, W. Z. & Sieck, G. C. Intracellu lar signaling pathways regulating net protein balance following diaphragm muscle denervation. Am. J. Physiol. Cell Physiol. 300, C318-327 (2 011). ·Machida, M. et al. Reduction of ribosome biogenesis with activatio n of the mTOR pathway in denervated atrophic muscle. J. Cell Physiol. 227, 1569-1576 (2012). ·MacDonald, E. M. et al. Denervation atrophy is independent from Akt and mTOR activation and is not rescued by myostatin inhibition. Dis. Model. Me ch. 7, 471-481 (2014). ·Tang, H. et al. mTORC1 promotes denervation-induced muscle atrophy through a mechanism involving the activation of FoxO and E3 ubiquitin liga ses. Sci. Signal. 7, ra18 (2014). ·Nacarelli, T., Azar, A. & Sell, C. Aberrant mTOR activation in senescen ce and aging: A mitochondrial stress response? Exp. Gerontol. 68, 66-70 (2015). ·Khamzina, L., Veilleux, A., Bergeron, S. & Marette, A. Increased activa tion of the mammalian target of rapamycin pathway in liver and skeletal mus cle of obese rats: possible involvement in obesity-linked insulin resistanc e. Endocrinology. 146, 1473-1481 (2005). ·Drake, J. C., Always, S. E., Hollander, J. M. & Williamson, D. L. AICAR treatment for 14 days normalizes obesity-induced dysregulation of TORC1 signaling and translational capacity in fasted skeletal muscle. Am. J. Physio l. Regul. Integr. Comp. Physiol. 299, R1546-1554 (2010). ·Markofski M. et al. Effect of age on basal muscle protein synthesis an d mTORC1 signaling in a large cohort of young and older men and women. Exp. Geront. 65, 1-7. 2015

Claims

[Claim 1] The invention described in the present specification.

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