ACTRII antibody fixed unit dose therapy

Abstract

Provided herein are compositions and methods for subcutaneously administering a fixed unit dose of an ActRII antibody for disease treatment, wherein the treatment is administered across a range of subject weights. As provided herein, the fixed unit dose of an ActRII antibody may include from about 25 mg to about 600 mg, e.g., about 150 mg, of an ActRII antibody, for example in a volume of about 1 ml.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 373,684, filed on August 26, 2022, and U.S. Provisional Patent Application No. 63 / 378,128, filed on October 3, 2022, the contents of which are incorporated herein by reference in their entirety.

[0003] Sequence Listing Incorporated by Reference

[0004] The contents of the electronic sequence listing (VRNS_010_02WO_SeqList_ST26.xml; size: 4,428,735 bytes; and creation date: August 25, 2023) are incorporated herein by reference in their entirety.

[0005] background

[0006] Therapeutic antibodies are often administered based on the subject's weight. However, such customization especially requires a medical professional to plan and administer the dosage. An attractive alternative is to administer a fixed dose, which can be administered to subjects across a range of body weights. There is another advantage in that a fixed dose can even be administered by the subject, for example, at home using a handheld hypodermic syringe. However, for therapeutic antibodies, fixed administration requires pharmacokinetics (PK) and pharmacodynamics (PD) optimization to achieve the required exposure range, while taking into account antigen affinity, antigen density, phagocytic clearance, IgG recycling, errors associated with erroneous ego-administration, and the consequences of missed doses. Such PK / PD optimized shortages result in ineffective administration and interfere with the efficacy of otherwise life-saving treatments.

[0007] Treatment with ActRII antibodies can be used for a variety of diseases, such as metabolic diseases, muscle wasting diseases, heart disease, and liver disease. Current clinical applications of such antibodies do not include fixed dosing regimens. Therefore, there is a need for PK / PD-optimized fixed unit doses of ActRII antibodies that are applicable across a range of body weights and can be used for self-administration, and are provided herein accordingly.

[0008] Overview

[0009] Provided herein are compositions and methods for subcutaneously administering a fixed unit dose of an ActRII antibody that may be used to treat a variety of diseases, wherein the fixed unit dose is administered to subjects across a range of body weights. In exemplary embodiments, the pharmaceutical composition in the form of a fixed unit dose comprises a dose of about 25 mg to about 600 mg of an ActRII antibody. In some exemplary embodiments, the pharmaceutical composition in the form of a fixed unit dose comprises a dose of about 100 to about 400 mg of an ActRII antibody. In some exemplary embodiments, the fixed unit dose comprises a dose of about 150 mg of an ActRII antibody. In some exemplary embodiments, the fixed unit dose comprises a dose of about 300 mg of an ActRII antibody.

[0010] In some embodiments, the ActRII antibody comprises the CDR amino acid sequences of SEQ ID NOs: 1-6. In some embodiments, the ActRII antibody comprises the VH amino acid sequence of SEQ ID NO: 7, or a sequence having at least 80% sequence identity thereto, and the VL amino acid sequence of SEQ ID NO: 8, or a sequence having at least 80% sequence identity thereto.

[0011] In some embodiments, the ActRII antibody comprises the amino acid sequence of SEQ ID NO:9, or a sequence with at least 80% sequence identity thereto, and the amino acid sequence of SEQ ID NO:10, or a sequence with at least 80% sequence identity thereto.

[0012] In some embodiments, the ActRII antibody comprises one or more of the CDR amino acid sequences of SEQ ID NOs: 11-75. In some embodiments, the ActRII antibody comprises one or more of the CDR amino acid sequences of SEQ ID NOs: 76-81. In some embodiments, the ActRII antibody comprises one or more of the CDR amino acid sequences of SEQ ID NOs: 82-5049.

[0013] In some embodiments, the ActRII antibody is specific for ActRIIA and / or ActRIIB.

[0014] In some embodiments, the ActRII antibody is present in the fixed unit dose at a concentration of about 25 mg / ml, about 50 mg / ml, about 75 mg / ml, about 100 mg / ml, about 125 mg / ml, about 150 mg / ml, about 175 mg / ml, about 200 mg / ml, about 225 mg / ml, about 250 mg / ml, about 275 mg / ml, about 300 mg / ml, about 325 mg / ml, about 350 mg / ml, about 375 mg / ml, about 400 mg / ml, about 425 mg / ml, about 450 mg / ml, about 475 mg / ml, about 500 mg / ml, about 525 mg / ml, about 550 mg / ml, about 575 mg / ml, or about 600 mg / ml. In some embodiments, the ActRII antibody is present in the fixed unit dose at a concentration of about 150 mg / ml.

[0015] In some embodiments, the fixed unit dose is a volume of about 0.25 ml, about 0.5 ml, about 0.75 ml, about 1.0 ml, about 1.24 ml, about 1.5 ml, about 1.75 ml, about 2.0 ml, about 2.25 ml, about 2.5 ml, about 2.75 ml, about 3.0 ml, about 3.25 ml, about 3.5 ml, about 3.75 ml, about 4.0 ml, about 4.25 ml, about 4.5 ml, about 4.75 ml, or about 5.0 ml. In some embodiments, the fixed unit dose is a volume of about 1 ml. In some embodiments, the fixed unit dose is a volume of about 2 ml. In some embodiments, the composition is contained in a syringe. In some embodiments, the syringe is a needle or syringe.

[0016] In some embodiments, the pharmaceutical composition comprises a hormone agonist and an ActRII antibody. In some embodiments, the hormone agonist is an incretin agonist. In some embodiments, the incretin agonist is selected from exenatide, exenatide extended release, dulaglutide, liraglutide, lixisenatide, semaglutide, telpotide, cotidulide, noiiglutide, oxyntomodulin, retaglutide, albiglutide, benaglutide, PEG-loxenatide, pegvitide, and danuglipron.

[0017] In some embodiments, the hormone agonist is selected from a long-acting amylin receptor agonist, a dual amylin calcitonin receptor agonist (DACRA), and a peptide YY agonist.

[0018] In some embodiments, provided herein are methods of treating a disease in a subject in need thereof, comprising subcutaneously administering to the subject a fixed unit dose of an ActRII antibody. In some embodiments, the ActRII antibody is present at about 25 mg to about 600 mg per fixed unit dose. In some embodiments, the ActRII antibody is present at about 100 mg to about 400 mg per fixed unit dose. In some embodiments, the ActRII antibody is present at about 150 mg per fixed unit dose. In some embodiments, the ActRII antibody is present at about 300 mg per fixed unit dose.

[0019] In some embodiments, a fixed unit dose of an ActRII antibody is administered to a subject about daily, about six times a week, about five times a week, about four times a week, about three times a week, about twice a week, about once a week, about once every two weeks, about once every three weeks, about once every four weeks, about once every five weeks, about once every six weeks, about once every seven weeks, or about once every eight weeks. In some embodiments, a fixed unit dose of an ActRII antibody is administered to a subject about once a week.

[0020] In some embodiments, administration of an ActRII antibody loading dose precedes administration of an ActRII antibody fixed unit dose. In some embodiments, the ActRII antibody loading dose is administered intravenously at about 3 mg / kg to about 50 mg / kg.

[0021] In some embodiments, the ActRII antibody loading dose is administered intravenously at about 10 mg / kg. In some embodiments, the ActRII antibody loading dose is administered intravenously at about 30 mg / kg.

[0022] In some embodiments, the ActRII antibody loading dose is administered at a dose of about 150 mg to about 4500 mg. In some embodiments, the ActRII antibody loading dose is administered at a dose of about 210 mg. In some embodiments, the ActRII antibody loading dose is administered at a dose of about 700 mg.

[0023] In some embodiments, the ActRII antibody loading dose is administered at a dose of about 25 mg to about 600 mg. In some embodiments, the ActRII antibody loading dose is administered at a dose of about 100 mg to about 400 mg. In some embodiments, the ActRII antibody loading dose is administered at a dose of about 150 mg. In some embodiments, the ActRII antibody loading dose is administered at a dose of about 300 mg. In some embodiments, the ActRII antibody loading dose is administered intravenously. In other embodiments, the ActRII antibody loading dose is administered subcutaneously.

[0024] In some embodiments, the ActRII antibody loading dose is administered about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, or about 5 weeks prior to administration of the ActRII antibody fixed unit dose.

[0025] In some embodiments, the subject's disease is a metabolic disease. In some embodiments, the metabolic disease is selected from the group consisting of obesity, diabetes, metabolic syndrome, antipsychotic-associated obesity, glucocorticoid-induced obesity, hypothalamic obesity associated with craniopharyngioma, and monogenic disorders associated with obesity.

[0026] In some embodiments, the monogenic disorder associated with obesity is Bardet-Biedl syndrome, or one of the obesity resulting from mutations in one or more genes comprising ADCY3, ALMS1, ARL6, BBS1, BBS2, BBS4, BBS5, BBS7, BBS9, BBS10, BBS12, BDNF, CCDC28B, CEP290, CREBBP, EP300, GNAS, IER3IP1, MKKS, MKS1, MRAP2, NTRK2, PCSK1, PHF6, POMC, SH2B1, SIM1, TMEM67, TRIM32, TTC8, and VPS13B.

[0027] In some embodiments, the metabolic disease is Prader-Willi syndrome.

[0028] In some embodiments, the subject's disease is amyotrophy or sarcopenia. In some embodiments, the subject's disease is aging-related muscle dysfunction. In some embodiments, the subject's disease is heart disease. In some embodiments, the subject's disease is liver disease.

[0029] In some embodiments, the subject has a body mass index (BMI) of 30 or greater. The method according to any one of claims 20-43, wherein the subject has a body mass index (BMI) of 27 or greater and has one or more obesity-related conditions. In some embodiments, the subject weighs about 200 kg or less. In some embodiments, the subject weighs greater than about 200 kg.

[0030] In some embodiments, the ActRII antibody used in the treatment methods comprises the CDR amino acid sequences of SEQ ID NOs: 1-6. In some embodiments, the ActRII antibody comprises the VH amino acid sequence of SEQ ID NO: 7, or a sequence with at least 80% sequence identity thereto, and the VL amino acid sequence of SEQ ID NO: 8, or a sequence with at least 80% sequence identity thereto. In some embodiments, the ActRII antibody comprises the HC amino acid sequence of SEQ ID NO: 9, or a sequence with at least 80% sequence identity thereto, and the LC amino acid sequence of SEQ ID NO: 10, or a sequence with at least 80% sequence identity thereto.

[0031] In some embodiments, the ActRII antibody used in the treatment method comprises a CDR amino acid sequence of one or more of SEQ ID NOs: 11-75. In some embodiments, the ActRII antibody used in the treatment method comprises a CDR amino acid sequence of one or more of SEQ ID NOs: 76-81. In some embodiments, the ActRII antibody used in the treatment method comprises a CDR amino acid sequence of one or more of SEQ ID NOs: 82-5049.

[0032] In some embodiments, the ActRII antibody is specific for ActRIIA and / or ActRIIB.

[0033] In some embodiments, the ActRII antibody is present in the fixed unit dose at a concentration of about 25 mg / ml, about 50 mg / ml, about 75 mg / ml, about 100 mg / ml, about 125 mg / ml, about 150 mg / ml, about 175 mg / ml, about 200 mg / ml, about 225 mg / ml, about 250 mg / ml, about 275 mg / ml, about 300 mg / ml, about 325 mg / ml, about 350 mg / ml, about 375 mg / ml, about 400 mg / ml, about 425 mg / ml, about 450 mg / ml, about 475 mg / ml, about 500 mg / ml, about 525 mg / ml, about 550 mg / ml, about 575 mg / ml, or about 600 mg / ml.

[0034] In some embodiments, the fixed unit dose is a volume of about 0.25 ml, about 0.5 ml, about 0.75 ml, about 1.0 ml, about 1.24 ml, about 1.5 ml, about 1.75 ml, about 2.0 ml, about 2.25 ml, about 2.5 ml, about 2.75 ml, about 3.0 ml, about 3.25 ml, about 3.5 ml, about 3.75 ml, about 4.0 ml, about 4.25 ml, about 4.5 ml, about 4.75 ml, or about 5.0 ml.

[0035] In some embodiments, the fixed unit dose is contained in a syringe configured for subcutaneous administration. In some embodiments, the syringe is a needle or syringe. In some embodiments, the fixed unit dose is designed to be self-administered.

[0036] In some embodiments, a hormone agonist is administered as part of a combination therapy with an ActRII antibody of the disclosure.

[0037] In some embodiments, the hormone agonist is an incretin agonist. In some embodiments, the incretin agonist is selected from exenatide, exenatide extended release, dulaglutide, liraglutide, lixisenatide, semaglutide, telpotide, cotidol, noriglutide, oxyntomodulin, retaglutide, albiglutide, benaglutide, PEG-loxenatide, pegvitide, and danglitazone. In some embodiments, the hormone agonist is selected from a long-acting amylin receptor agonist, a dual amylin calcitonin receptor agonist (DACRA), and a peptide YY agonist.

[0038] In some embodiments, the hormone agonist is administered prior to the ActRII antibody. In some embodiments, the ActRII antibody is administered prior to the hormone agonist. In some embodiments, the ActRII antibody and hormone agonist are co-formulated for administration as a combination therapy. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 is a schematic diagram of an exemplary clinical study design conducted to evaluate the pharmacodynamics and pharmacokinetics of subcutaneous administration of an ActRII antibody (BYM338, also known as bimagrumab).

[0041] Figure 2 It's about Figure 1 The demographics of the subjects in the clinical studies are shown in the table.

[0042] Figure 3 It's at the beginning Figure 1 The physical characteristics of the subjects before the study are shown in the table.

[0043] Figure 4 Is from Figure 1 The summarized PK parameters Cmax and Cmin of the studies are shown in the table.

[0044] Figure 5 It is a summary from Figure 1 The PK parameters of the studies including Tmax and AUC are shown in the table.

[0045] Figure 6 Is from Figure 1 Semi-logarithmic plots of model-fitted mean serum concentration curves for the study shown in FIG, for intravenous administration of bimalumab at concentrations of 210 mg and 700 mg.

[0046] Figure 7 Is from Figure 1 Semi-logarithmic plots of model-fitted mean serum concentration curves for the study shown in Figure 2 for bimalumab administered by subcutaneous infusion at concentrations of 1500 mg and 525 mg.

[0047] Figure 8 Is from Figure 1 Semi-logarithmic plots of model-fitted mean serum concentration curves for the study shown in , for subcutaneous bolus administration of bimalumab at concentrations of 150 mg, 300 mg, and 52.5 mg.

[0048] Figure 9 It is a summary from Figure 1 The table shows the lean body mass and fat body mass results of the studies.

[0049] Figure 10 Is from Figure 1 Line graph of lean body mass results for intravenous infusion of the study shown in .

[0050] Figure 11 Is from Figure 1 Line graph of limb lean body mass results for the intravenous infusion of the study shown in .

[0051] Figure 12 Is from Figure 1 Line graph of lean body mass results for subcutaneous infusions of the studies shown in .

[0052] Figure 13 Is from Figure 1 Line graph of limb lean body mass results for subcutaneous infusions of the study shown in .

[0053] Figure 14 Is from Figure 1 Line graph of lean body mass results for subcutaneous bolus administration of the study shown in .

[0054] Figure 15 Is from Figure 1Line graph of limb lean body mass results for subcutaneous bolus administration of the study shown in .

[0055] Figure 16 Is from Figure 1 Line graph of fat mass results for the intravenous infusion of the study shown in .

[0056] Figure 17 Is from Figure 1 Line graph showing the fat body mass results of subcutaneous infusions for the study.

[0057] Figure 18 Is from Figure 1 Line graph of fat body mass results for subcutaneous bolus administration of the study shown in .

[0058] Figure 19 is a line graph of model-predicted bimalumab receptor occupancy (RO) and the associated dosing effects on fat body mass (FBM) loss and lean body mass (LBM) gain.

[0059] Figure 20 The following is a line graph and table showing the model-predicted time to reach various bimalumab concentrations in a population of 2500 subjects, each weighing 100 kg, with 300 mg of bimalumab administered weekly and subcutaneously. The threshold levels of 5 μg / ml and 10 μg / ml are indicated in the figure and table below.

[0060] Figure 21

[00145] The following table shows the model-predicted time to reach various bimalumab concentrations in a population of 2500 subjects weighing 60 to 140 kg, with 300 mg of bimalumab administered weekly and subcutaneously. The time to threshold levels of 5 μg / ml and 10 μg / ml is indicated in the table below.

[0061] Figure 22 is a line graph of model-predicted bimalumab concentrations over time in a subject population weighing 50 to 200 kg, with 300 mg of bimalumab administered weekly and subcutaneously without a loading dose on Day 1.

[0062] Figure 23 is a line graph of model-predicted changes in total fat body mass over time in a population of subjects weighing 50 to 200 kg with weekly and subcutaneous administration of 300 mg of bimalumab without a loading dose on Day 1.

[0063] Figure 24 is a line graph of model-predicted bimalumab concentrations over time in a subject population weighing 50 to 200 kg, with 300 mg bimalumab administered weekly and subcutaneously, with two doses of 300 mg bimalumab administered subcutaneously on day 1.

[0064] Figure 25 is a line graph of model-predicted changes in total fat body mass over time in a population of subjects weighing 50 to 200 kg with weekly and subcutaneous administration of 300 mg of bimalumab, with two doses of 300 mg of bimalumab administered subcutaneously on day 1.

[0065] Figure 26 is a line graph of model-predicted bimalumab concentrations over time in a population of subjects weighing 50 to 200 kg, with 300 mg bimalumab administered weekly and subcutaneously, with three doses of 300 mg bimalumab administered subcutaneously on day 1.

[0066] Figure 27 is a line graph of model-predicted changes in total fat body mass over time in a population of subjects weighing 50 to 200 kg with weekly and subcutaneous administration of 300 mg of bimalumab, with three doses of 300 mg of bimalumab administered subcutaneously on day 1.

[0067] Figure 28 is a line graph comparing the effects of model-predicted loading doses (0, 1, or 2 loading doses) on bimalumab concentrations over time in a population of subjects weighing 100 kg, where 300 mg of bimalumab was administered weekly and subcutaneously.

[0068] Figure 29 is a line graph comparing the effects of model-predicted loading doses (0, 1, or 2 loading doses) on total fat body mass change over time for a population of subjects weighing 100 kg, in which 300 mg of bimalumab was administered weekly and subcutaneously.

[0069] Figure 30 is a line graph of model-predicted bimalumab concentrations over time in a population of subjects weighing 50 to 200 kg, with 600 mg of bimalumab administered weekly and subcutaneously without a loading dose on Day 1.

[0070] Figure 31 is a line graph of model-predicted changes in total fat body mass over time in a population of subjects weighing 50 to 200 kg with weekly and subcutaneous administration of 600 mg of bimalumab without a loading dose on Day 1.

[0071] Figure 32 is a line graph of the model-predicted effects of bimalumab concentration on fat mass and lean mass in a population of subjects with individual response variability.

[0072] Figure 33is a line graph of model-predicted bimalumab concentrations over time in a population of subjects with individual response variability. Subjects ranged in weight from 50 to 200 kg and were administered 300 mg of bimalumab subcutaneously weekly without a loading dose on day 1.

[0073] Details

[0074] I. Definition

[0075] Unless otherwise defined herein, the scientific and technical terms used herein shall have the meanings commonly understood by those of ordinary skill in the art. Generally, the nomenclature used in connection with chemistry, molecular biology, cell biology, immunology, pharmacology and protein chemistry and the techniques thereof described herein are those well known and commonly used in the art.

[0076] It must be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" refers to one or a mixture of such agents, and reference to "a method" includes reference to equivalent steps and methods known to those skilled in the art, and so forth.

[0077] As used herein, when applied to one or more values of interest, the term "approximately" or "about" refers to a value that is similar in magnitude to the reference value and / or within a range similar to the reference value. In certain embodiments, the term "approximately" or "about" refers to a range of values that fall within 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less in either direction (greater than or less than) of the reference value, unless otherwise indicated or otherwise apparent from the context (unless such number exceeds 100% of the possible values).

[0078] As used herein, the terms "polypeptide," "peptide," and "protein" refer to amino acid polymers of any length. These terms also include amino acid polymers that have been modified; for example, to include disulfide bond formation, glycosylation, lipidation, phosphorylation, or conjugation with a labeling component.

[0079] As used herein, when referring to the comparison of two sequences, the terms "identity" and "identical" refer to the percentage of exact matching residues in an alignment of a sequence as provided herein with a reference sequence, such as an alignment generated by the BLAST algorithm or other alignment algorithms known in the art. Identity may be calculated based on an alignment of the full-length sequence as provided herein with the full-length reference sequence. If the reference sequence is longer than the sequence provided herein, identity may also be calculated based on a partial alignment of the sequence as provided herein with the reference sequence. If the reference sequence is shorter than the sequence provided herein, identity may also be calculated based on a partial alignment of the sequence as provided herein with the reference sequence. Thus, when two sequences are aligned, according to the above, a query sequence "shares at least x% identity with the subject sequence" if, in the alignment of the two sequences, at least x% (rounded down) of the residues in the subject sequence are aligned as exact matches with the corresponding residues in the query sequence, where the numerator is the number of exact matches and the denominator is the length of the query sequence. In some embodiments, the denominator may alternatively be the length of the query sequence minus any gaps between two or more unmatched residues. When the subject sequence has variable positions (eg, residues denoted as X), alignment with any residue in the query sequence is counted as a match.

[0080] As used herein, "antibody" includes reference to immunoglobulin molecules that immunologically react with specific antigens, including both polyclonal antibodies and monoclonal antibodies. The term includes humanized antibodies, chimeric antibodies (e.g., mouse variable regions with human constant regions) and conjugated antibodies. The term "antibody" also includes antigen-binding forms of antibodies, including fragments that retain antigen-binding ability (e.g., Fab', F(ab')2, Fab, single-chain variable fragments (scFv) and single-chain antibody fragments (scAb) containing VH and VL sequences linked together in one chain. The term antibody also includes bivalent or bispecific molecules, diabodies, triabodies and tetrabodies.

[0081] The terms "treatment", "treating" and the like are generally used herein to mean obtaining a desired pharmacological and / or physiological effect with a therapeutic agent. The effect may be preventive in terms of completely or partially preventing a disease or its symptoms, for example, reducing the likelihood of the disease or its symptoms occurring in a subject, and / or may be therapeutic in terms of completely or partially alleviating symptoms, or partially or completely curing the disease and / or the adverse effects attributable to the disease. As used herein, "treatment" encompasses any treatment of a disease in a mammal, and includes: (a) preventing the disease from occurring in a subject who may be susceptible to the disease but has not yet been diagnosed with the disease; (b) inhibiting or slowing the onset or development of the disease; or (c) alleviating the disease, for example, causing the disease or symptoms associated with the disease to subside. The therapeutic agent may be administered before, during, or after the onset of the disease. The treatment of persistent diseases in which the treatment stabilizes or alleviates the patient's undesirable clinical symptoms may be of particular interest. In some embodiments, the treatment is performed before the complete loss of function in the affected tissue. In some embodiments, the subject's treatment will be administered during the symptomatic phase of the disease, and in some embodiments, after the symptomatic phase of the disease.

[0082] The terms "disease" and "disorder" may be used interchangeably to describe any affliction affecting a subject and for which one or more symptoms are present.

[0083] As used herein, the term "dose" refers to the amount of a therapeutic agent administered to a subject to achieve a therapeutic goal.

[0084] As used herein, the term "fixed dose" refers to a dose that is not individualized for a particular subject. A fixed dose may be suitable for a population of subjects with a range of weights.

[0085] The term "loading dose" refers to one or more doses of a therapeutic agent administered in addition to a treatment comprising periodic administration of a fixed unit dose. As used herein, a "loading dose" may refer to one or more doses of a therapeutic agent at the same concentration, a lower concentration, or a higher concentration than the fixed unit dose. In some embodiments, the loading dose is administered prior to the start of a treatment comprising periodic administration of a fixed unit dose. In some embodiments, the loading dose is administered concurrently with the start of a treatment comprising periodic administration of a fixed unit dose.

[0086] The terms "individual," "subject," and "patient" are used interchangeably herein and refer to any subject for whom treatment is desired. The subject may be a mammalian subject. Mammalian subjects include, for example, humans, non-human primates, rodents (e.g., rats, mice), lagomorphs (e.g., rabbits), ungulates (e.g., cattle, sheep, pigs, horses, goats, etc.), and the like. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human primate, such as a cynomolgus monkey. In some embodiments, the subject is a companion animal (e.g., a cat, a dog).

[0087] II. ActRII Antibodies

[0088] The present disclosure provides compositions and methods for subcutaneously administering an ActRII antibody in a fixed unit dose, which may be used to treat a range of diseases, and wherein the fixed unit dose is administered to subjects having a range of body weights. In exemplary embodiments, the ActRII antibody fixed unit dose comprises from about 25 mg to about 600 mg of subcutaneously administered ActRII antibody. In some exemplary embodiments, the ActRII antibody fixed unit dose comprises from about 100 mg to about 400 mg of subcutaneously administered ActRII antibody. In some exemplary embodiments, the ActRII antibody fixed unit dose comprises about 300 mg of subcutaneously administered ActRII antibody. In some exemplary embodiments, the ActRII antibody fixed unit dose comprises about 150 mg of subcutaneously administered ActRII antibody. As provided herein, treatments comprising regular administration of fixed unit doses of ActRII antibodies may be used to treat diseases including, but not limited to, metabolic diseases, muscular dystrophy, heart disease, and liver disease.

[0089] The fixed unit doses provided herein comprise an ActRII antibody that binds to the activin receptors ActRIIA and / or ActRIIB. Administration of ActRII antibodies has previously been shown in clinical studies to increase lean muscle mass, reduce fat mass, and improve glycemic control (WO2010125003A1, WO2018116201A1, and WO2021044287A1, the contents of which are incorporated herein by reference in their entirety, and Heymsfield et al. 2021; 4(1):e2033457, JAMA).

[0090] Exemplary antibodies

[0091] In some embodiments, exemplary antibodies of the present disclosure comprise the sequence of bimalumab (BYM338). The following table provides the relevant complementary determining regions (CDRs), variable heavy chains (VH), variable light chains (VL), heavy chains (HC), and light chains (LC) amino acid sequences for bimalumab. In some embodiments, exemplary antibodies of the present disclosure comprise sequences related to bimalumab (BYM338).

[0092]

[0093] In some embodiments, exemplary ActRII antibodies of the present disclosure comprise a variable heavy chain comprising the CDR amino acid sequences of SEQ ID NO: 1 (CDRH1), SEQ ID NO: 2 (CDRH2), and SEQ ID NO: 3 (CDRH3).

[0094] In some embodiments, exemplary ActRII antibodies of the present disclosure comprise a variable light chain comprising the CDR amino acid sequences of SEQ ID NO:4 (CDRL1), SEQ ID NO:5 (CDRL2), and SEQ ID NO:6 (CDRL3).

[0095] In some embodiments, exemplary ActRII antibodies of the present disclosure comprise a variable heavy chain comprising the CDR amino acid sequences of SEQ ID NO: 1 (CDRH1), SEQ ID NO: 2 (CDRH2), and SEQ ID NO: 3 (CDRH3); and a variable light chain comprising the CDR amino acid sequences of SEQ ID NO: 4 (CDRL1), SEQ ID NO: 5 (CDRL2), and SEQ ID NO: 6 (CDRL3).

[0096] In some embodiments, exemplary ActRII antibodies of the present disclosure comprise a variable heavy chain (VH) comprising the amino acid sequence of SEQ ID NO: 7, or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or a variable light chain (VL) comprising the amino acid sequence of SEQ ID NO: 8, or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; NO:8, or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto.

[0097] In some embodiments, exemplary ActRII antibodies of the present disclosure comprise a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO:9, or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or a light chain (LC) comprising the amino acid sequence of SEQ ID NO:10, or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0098] In some embodiments, the ActRII antibody binds to ActRIIB with a KD of 100 nM or less, 10 nM or less, or 1 nM or less. Preferably, the ActRII antibody binds to ActRIIB with an affinity of 100 pM or less (e.g., 100 pM, 50 pM, 10 pM, 1 pM or less). In some embodiments, the ActRII antibody binds to ActRIIB with an affinity between 10 and 20 pM.

[0099] In some embodiments, the ActRII antibody binds to ActRIIB with an affinity that is 5-fold greater than that of ActRIIA, more preferably 10-fold greater, even more preferably 50-fold greater, and even more preferably 100-fold greater. In some embodiments, the ActRII antibody binds to ActRIIA with an affinity of 100 pM or greater (i.e., 250 pM, 500 pM, 1 nM, 5 nM, or greater).

[0100] In some embodiments, the ActRII antibodies of the present disclosure comprise one or more CDRs of SEQ ID NOs: 11-75, as provided in WO2017156488, the contents of which are incorporated herein by reference in their entirety. It should be noted that the CDR sequences of SEQ ID NOs: 11-75 include combinations of the six CDRs described in WO2017156488, wherein the ActRII antibody is, for example, any antibody of the AH lineage as provided in Table 1 of WO2017156488.

[0101] In some embodiments, the ActRII antibodies of the present disclosure comprise one or more CDRs of SEQ ID NOs: 76-81, as provided in WO2012064771, the contents of which are incorporated herein by reference in their entirety. It should be noted that the six CDR sequences of SEQ ID NOs: 76-81 correspond to the CDR sequences of SEQ ID NOs: 4-9 of WO2012064771, respectively, wherein the antibody is Ab-14E1.

[0102] In some embodiments, the ActRII antibodies of the present disclosure comprise one or more CDRs of SEQ ID NOs: 82-5049, as provided in WO2018183376, the contents of which are incorporated herein by reference in their entirety. It should be noted that the CDR sequences of SEQ ID NOs: 82-5049 include a combination of the six CDRs described in WO2018183376, wherein the antibody is, for example, any ActRII antibody of the AH lineage as provided in Tables 3A-3F of WO2018183376.

[0103] III. ActRII Antibody Fixed Unit Dose

[0104] The compositions and methods provided herein include fixed unit doses of ActRII antibodies configured for subcutaneous administration. In exemplary embodiments, the fixed unit dose of an ActRII antibody of the present disclosure comprises from about 25 mg to about 600 mg of an ActRII antibody per fixed unit dose. In some exemplary embodiments, the fixed unit dose of an ActRII antibody of the present disclosure comprises from about 100 mg to about 400 mg of an ActRII antibody per fixed unit dose. In some exemplary embodiments, the fixed unit dose of an ActRII antibody comprises from about 300 mg of an ActRII antibody per fixed unit dose. In some exemplary embodiments, the fixed unit dose of an ActRII antibody comprises from about 150 mg of an ActRII antibody per fixed unit dose.

[0105] In other embodiments, the fixed unit dose of an ActRII antibody of the present disclosure comprises about 100 mg to about 400 mg of an ActRII antibody. In some embodiments, the fixed unit dose of an ActRII antibody of the present disclosure comprises about 100 mg to about 400 mg of an ActRII antibody administered weekly and subcutaneously.

[0106] In an exemplary embodiment, the ActRII antibody fixed unit dose comprises about 300 mg of the ActRII antibody. In some exemplary embodiments, the composition comprises a fixed unit dose of about 300 mg of the ActRII antibody administered weekly and subcutaneously.

[0107] In an exemplary embodiment, the ActRII antibody fixed unit dose comprises about 150 mg of the ActRII antibody. In some exemplary embodiments, the composition comprises a fixed unit dose of about 150 mg of the ActRII antibody administered weekly and subcutaneously.

[0108] In some embodiments, an ActRII antibody may be present in an ActRII antibody fixed unit dose at about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, or about 600 mg per fixed unit dose. In some exemplary embodiments, an ActRII antibody is present at about 100 mg to about 400 mg per fixed unit dose. In exemplary embodiments, an ActRII antibody is present at about 300 mg per fixed unit dose. In other exemplary embodiments, an ActRII antibody is present at about 150 mg per fixed unit dose.

[0109] In some embodiments, the ActRII antibody is present in the ActRII antibody fixed unit dose at a concentration of about 25 mg / ml, about 50 mg / ml, about 75 mg / ml, about 100 mg / ml, about 125 mg / ml, about 150 mg / ml, about 175 mg / ml, about 200 mg / ml, about 225 mg / ml, about 250 mg / ml, about 275 mg / ml, about 300 mg / ml, about 325 mg / ml, about 350 mg / ml, about 375 mg / ml, about 400 mg / ml, about 425 mg / ml, about 450 mg / ml, about 475 mg / ml, about 500 mg / ml, about 525 mg / ml, about 550 mg / ml, about 575 mg / ml, or about 600 mg / ml. In some embodiments, the ActRII antibody is present in the ActRII antibody fixed unit dose at a concentration of about 150 mg / ml.

[0110] In some embodiments, the ActRII antibody fixed unit dose comprises a volume of about 0.25 ml, about 0.5 ml, about 0.75 ml, about 1.0 ml, about 1.24 ml, about 1.5 ml, about 1.75 ml, about 2.0 ml, about 2.25 ml, about 2.5 ml, about 2.75 ml, about 3.0 ml, about 3.25 ml, about 3.5 ml, about 3.75 ml, about 4.0 ml, about 4.25 ml, about 4.5 ml, about 4.75 ml, or about 5.0 ml. In some embodiments, the ActRII antibody fixed unit dose comprises a volume of about 1 ml. In some embodiments, the ActRII antibody fixed unit dose comprises a volume of about 2 ml. In some embodiments, the ActRII antibody fixed unit dose comprises any of the above concentrations in any of the above volumes.

[0111] In some embodiments, an ActRII antibody fixed unit dose is administered periodically to a subject weighing 200 kg or less. In some embodiments, an ActRII antibody fixed unit dose is administered periodically to a subject weighing 300 kg or less. In some embodiments, an ActRII antibody fixed unit dose is administered periodically as two fixed unit doses to a subject weighing 200 kg or more. In some embodiments, an ActRII antibody fixed unit dose is administered periodically as two fixed unit doses to a subject weighing 300 kg or more. In some embodiments, the number of ActRII antibody fixed unit doses administered periodically increases stepwise with the subject's weight. In some embodiments, the number of fixed unit doses is increased for approximately every 50 kg, approximately every 75 kg, approximately every 100 kg, approximately every 150 kg, approximately every 200 kg, or approximately every 300 kg increase in the subject's weight.

[0112] In some embodiments, a fixed unit dose of an ActRII antibody is administered to a subject daily, about six times a week, about five times a week, about four times a week, about three times a week, about twice a week, about once a week, or about once every two weeks. In some embodiments, a fixed unit dose of an ActRII antibody is administered to a subject about once every three weeks, about once every four weeks, about once every five weeks, about once every six weeks, about once every seven weeks, or about once every eight weeks. In an exemplary embodiment, a fixed unit dose of an ActRII antibody is administered to a subject about once a week.

[0113] In some embodiments, an ActRII antibody fixed unit dose is administered to a subject for about one month, about two months, about three months, about six months, about one year, about two years, about five years, or indefinitely.

[0114] loading dose

[0115] In some embodiments, administration of an ActRII antibody loading dose precedes administration of an ActRII fixed unit dose. Without being bound by theory or mechanism, it is believed that administration of a loading dose reduces the time required to achieve the desired serum concentration for an ActRII fixed unit dose treatment. Accordingly, in some embodiments, provided herein is the inclusion of one or more loading doses.

[0116] The loading dose may be administered by any route of administration, including, but not limited to, subcutaneous or intravenous administration, independent of the subsequent subcutaneous administration of a fixed unit dose.

[0117] In some embodiments, one or more loading doses of an ActRII antibody are administered to a subject in need thereof on day 0 or week 0 prior to administration of a fixed unit dose of an ActRII antibody. In some embodiments, one or more loading doses of an ActRII antibody are provided 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks prior to administration of a fixed unit dose of an ActRII antibody. In some embodiments, one or more loading doses of an ActRII antibody are administered on the same day or within 24 hours of a fixed unit dose of an ActRII antibody. In some embodiments, one loading dose is administered. In some embodiments, two loading doses are administered. In some embodiments, three loading doses are administered.

[0118] In some embodiments, the loading dose can be administered intravenously at a concentration of about 3 mg / kg / subject's body weight to about 50 mg / kg / subject's body weight, and all amounts therebetween. In some embodiments, the ActRII antibody loading dose is administered intravenously at about 30 mg / kg / subject's body weight. In some embodiments, the ActRII antibody loading dose is administered intravenously at about 10 mg / kg / subject's body weight.

[0119] In some embodiments, the ActRII antibody loading dose is administered at a dose of about 150 mg to about 4500 mg. In some embodiments, the ActRII antibody loading dose is administered at a dose of about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about In some embodiments, the ActRII antibody loading dose is administered at a dose of about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2500 mg, about 3000 mg, about 4000 mg, about 4500 mg, about 5000 mg, about 5500 mg, or about 6000 mg. In some embodiments, the ActRII antibody loading dose is administered at a dose of about 210 mg. In some embodiments, the ActRII antibody loading dose is administered at a dose of about 700 mg.

[0120] In some embodiments, the ActRII antibody loading dose is administered at a dose of about 25 mg to about 600 mg. In some embodiments, the ActRII antibody loading dose is administered at a dose of about 100 mg to about 400 mg. In some embodiments, the ActRII antibody loading dose is administered at a dose of about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, or about 600 mg. In some embodiments, the ActRII antibody loading dose is administered subcutaneously at a fixed unit dose of about 300 mg. In some embodiments, the ActRII antibody loading dose is administered subcutaneously as a fixed unit dose of about 150 mg.

[0121] In some embodiments, the ActRII antibody loading dose is administered subcutaneously. In some embodiments, the ActRII antibody loading dose is administered intravenously.

[0122] In some embodiments, one or more ActRII antibody loading doses are administered intravenously prior to administration of a fixed unit dose of an ActRII antibody of the present disclosure.

[0123] In some embodiments, one or more ActRII antibody loading doses are administered subcutaneously prior to administration of a fixed unit dose of an ActRII antibody of the present disclosure.

[0124] Device

[0125] As described herein, the fixed unit doses of the present disclosure are configured for subcutaneous administration. In some embodiments, such ActRII antibody fixed unit doses are contained in an autoinjector or other mechanical injection device. In some embodiments, such ActRII antibody fixed unit doses are administered via a needle or syringe.

[0126] In some embodiments, such ActRII antibody fixed unit doses are administered to subjects with a range of body weights via an autoinjector or other mechanical injection device. In some embodiments, the ActRII antibody fixed unit dose is designed to be self-administered via an autoinjector or other mechanical injection device.

[0127] In some embodiments, the ActRII antibody fixed unit dose is designed to be administered via needle or syringe to subjects with a range of body weights. In some embodiments, the ActRII antibody fixed unit dose is designed to be self-administered via needle or syringe.

[0128] In an exemplary embodiment, a fixed unit dose composition comprising about 300 mg of an ActRII antibody is designed to be administered subcutaneously and weekly via an autoinjector or other mechanical injection device.

[0129] In an exemplary embodiment, a fixed unit dose composition comprising about 300 mg of an ActRII antibody is designed to be administered subcutaneously and weekly via needle or syringe.

[0130] In other exemplary embodiments, a fixed unit dose composition comprising about 150 mg of an ActRII antibody is designed for subcutaneous and weekly administration via an autoinjector or other mechanical injection device.

[0131] In an exemplary embodiment, a fixed unit dose composition comprising about 150 mg of an ActRII antibody is designed to be administered subcutaneously and weekly via needle or syringe.

[0132] Subjects and treatment

[0133] Provided herein are methods of treating a disease in a subject in need thereof, comprising subcutaneously administering to the subject a fixed unit dose of an ActRII antibody, wherein the fixed unit dose is administered to subjects having a range of body weights. As part of the treatments provided herein, the ActRII antibody fixed unit dose may be used to treat a variety of diseases including, but not limited to, metabolic diseases, muscular dystrophy, age-related muscle degeneration, heart disease, and liver disease.

[0134] In exemplary embodiments, the treatments provided herein comprising an ActRII antibody at a fixed unit dose of about 25 mg to about 600 mg can be used to treat metabolic diseases, muscular dystrophy, age-related muscle degeneration, heart disease, and liver disease. In some exemplary embodiments, the treatments provided herein comprising an ActRII antibody at a fixed unit dose of about 100 mg to about 400 mg can be used to treat metabolic diseases, muscular dystrophy, age-related muscle degeneration, heart disease, and liver disease. In some exemplary embodiments, the treatments provided herein comprising an ActRII antibody at a fixed unit dose of about 300 mg can be used to treat metabolic diseases, muscular dystrophy, age-related muscle degeneration, heart disease, and liver disease. In other exemplary embodiments, the treatments provided herein comprising an ActRII antibody at a fixed unit dose of about 150 mg can be used to treat metabolic diseases, muscular dystrophy, age-related muscle degeneration, heart disease, and liver disease.

[0135] In some embodiments, the treatments provided herein comprising a fixed unit dose of an ActRII antibody can be used to treat heart disease, including but not limited to heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, and heart failure with moderately reduced ejection fraction.

[0136] In some embodiments, the treatments provided herein comprising a fixed unit dose of an ActRII antibody can be used to treat liver disease, including but not limited to non-alcoholic fatty liver disease, such as non-alcoholic steatohepatitis.

[0137] In some embodiments, the treatments provided herein comprising a fixed unit dose of an ActRII antibody can be used to treat metabolic diseases including, but not limited to, metabolic syndrome, prediabetes, insulin resistance, obesity, diabetes (type I and type II), antipsychotic-associated obesity, glucocorticoid-induced obesity, hypothalamic obesity associated with craniopharyngioma, and complex disorders and monogenic disorders associated with obesity. Monogenic disorders associated with obesity in humans may include, but are not limited to, Barder-Biedel syndrome, and disorders arising from mutations in one or more of the following genes: ADCY3, ALMS1, ARL6, BBS1, BBS2, BBS4, BBS5, BBS7, BBS9, BBS10, BBS12, BDNF, CCDC28B, CEP290, CREBBP, EP300, GNAS, IER3IP1, MKKS, MKS1, MRAP2, NTRK2, PCSK1, PHF6, POMC, SH2B1, SIM1, TMEM67, TRIM32, TTC8, and VPS13B, or a combination thereof. Metabolic disorders may also be associated with complex genetic disorders such as Prader-Willi syndrome.

[0138] In exemplary embodiments, the treatments provided herein comprising an ActRII antibody at a fixed unit dose of about 25 mg to about 600 mg can be used to treat obesity. In exemplary embodiments, the treatments provided herein comprising an ActRII antibody at a fixed unit dose of about 100 mg to about 400 mg can be used to treat obesity. In some exemplary embodiments, the treatments provided herein comprising an ActRII antibody at a fixed unit dose of about 300 mg can be used to treat obesity. In other exemplary embodiments, the treatments provided herein comprising an ActRII antibody at a fixed unit dose of about 150 mg can be used to treat obesity.

[0139] In some embodiments, a therapy comprising a fixed unit dose of an ActRII antibody can be used to treat obesity-related conditions including, but not limited to, glucose intolerance, prediabetes, type II diabetes, insulin resistance, high triglycerides, physical impairment related to overweight, osteoporosis, kidney disease, obstructive sleep apnea, sex hormone impairment, endocrine and reproductive disorders, osteoarthritis, gastrointestinal cancer, dyslipidemia, hypertension, heart failure, coronary artery disease, stroke, and / or gallstones.

[0140] A treatment comprising a fixed unit dose of an ActRII antibody can be used to treat an overweight subject. In some embodiments, the subject has a BMI of 30 or greater. In some embodiments, the subject has a BMI of 27 or greater. In some embodiments, the subject has a BMI of 27 or greater and suffers from an obesity-related disorder.

[0141] Therapies comprising fixed unit doses of ActRII antibodies of the disclosure can be used to treat subjects with lack of glycemic control.

[0142] Treatment can be administered to subjects of any age, including subjects under the age of 18. In some embodiments, the subject can be over 18 years old, over 30 years old, or over 40 years old. In some embodiments, the subject can be over 50 years old, over 60 years old, or over 80 years old.

[0143] In some embodiments, treatment comprising a fixed unit dose of an ActRII antibody reduces fat mass in a subject. In some embodiments, the fixed unit dose of an ActRII antibody reduces fat mass in a subject by at least 5% (e.g., 5%-30%) over the treatment period.

[0144] In some embodiments, treatment comprising a fixed unit dose of an ActRII antibody increases lean mass in a subject. In some embodiments, the fixed unit dose increases lean mass in a subject by at least 1% (e.g., 1%-10%) over the treatment period.

[0145] In some embodiments, a treatment comprising a fixed unit dose of an ActRII antibody reduces fat mass and increases lean body mass in a subject. In some embodiments, the fixed unit dose of an ActRII antibody reduces fat mass in a subject by at least 5% (e.g., 5%-30%) and increases lean body mass by at least 1% (e.g., 1%-10%) over the treatment period.

[0146] In some embodiments, treatment comprising a fixed unit dose of an ActRII antibody reduces fat mass and maintains lean body mass in a subject. In some embodiments, the fixed unit dose of an ActRII antibody reduces fat mass in a subject by at least 5% (e.g., 5%-30%) and maintains lean body mass over the treatment period.

[0147] In some embodiments, treatment comprising an ActRII fixed unit dose reduces body weight in a subject. In some embodiments, the ActRII antibody fixed unit dose reduces body weight in the subject by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% over the treatment period.

[0148] In some embodiments, a treatment comprising an ActRII fixed unit dose reduces central obesity in a subject. In some embodiments, an ActRII antibody fixed unit dose reduces central obesity in a subject by at least 2% (e.g., 2%-20%) over the treatment period.

[0149] In some embodiments, a treatment comprising an ActRII fixed unit dose reduces liver fat and / or non-liver visceral fat in a subject. In some embodiments, the ActRII antibody fixed unit dose reduces central obesity in the subject by at least 2% (e.g., 2%-20%) over the treatment period, as assessed by magnetic resonance imaging (MRI).

[0150] In some embodiments, fat mass in response to a fixed unit dose of ActRII is measured using bioelectrical impedance analysis (BIA), dual X-ray absorptiometry (DXA), magnetic resonance imaging (MRI), and / or waist circumference.

[0151] In some embodiments, a treatment comprising an ActRII fixed unit dose improves glycemic control in a subject.

[0152] In some embodiments, glycemic control in response to a fixed unit dose of ActRII is measured by glucose and insulin levels and the HOMA2 model (www.dtu.ox.ac.uk / homacalculator / ) is applied.

[0153] In some embodiments, the "C trough" or lowest serum concentration of an ActRII antibody in a subject can be measured to determine the efficacy of the treatment. In some embodiments, the efficacy of the treatment is assessed as a serum concentration of about 500%, about 400%, about 300%, about 200%, about 100%, about 90%, about 80%, or about 75% of the desired "C trough". In some embodiments, the desired "C trough" is about 1 μg / ml to about 10 μg / ml. In some embodiments, the desired "C trough" is about 3 μg / ml to about 30 μg / ml. In some embodiments, the desired "C trough" is about 2.5 μg / ml, about 5 μg / ml, about 10 μg / ml, about 15 μg / ml, about 20 μg / ml, about 25 μg / ml, about 30 μg / ml, or about 35 μg / ml.

[0154] In some embodiments, the efficacy of an ActRII fixed unit dose is determined by about 100%, about 90%, about 80%, about 75%, about 50%, or about 25% improvement in at least one of the following measurements: body weight; bioelectrical impedance analysis (BIA) measurement of lean body mass and / or fat mass; waist-to-hip ratio; waist-to-height ratio; dual X-ray absorptiometry (DXA) measurement of lean body mass and / or fat mass; magnetic resonance imaging (MRI) measurement of lean body mass and / or fat mass; waist circumference; BMI reduction; lipid profile; leptin, lectin, adiponectin, and lipopolysaccharide levels; IL-8 and / or IL-6 levels; urine biomarkers; hemoglobin A1c (HgbA1c) level; hand dynamometer to demonstrate muscle strength; glucose level; insulin level; short physical performance battery (SPPB); Impact of Weight on Quality of Life (IWQoL-Lite for CT) assessment; Short Form (36) Health Survey (SF-36) assessment; Homeostasis Model Assessment 2 (HOMA2); and physical activity monitoring via wrist actigraphy.

[0155] Combination therapy

[0156] In some embodiments, an ActRII antibody pharmaceutical composition is administered as part of a combination therapy with an incretin agonist or another hormone agonist. The incretin agonist or other hormone agonist may be administered as part of the same or separate formulation as the ActRII antibody and may be administered at the same time as the ActRII antibody or at a different time.

[0157] Incretin agonists suitable for combination therapy with ActRII antibodies include, but are not limited to, exenatide, exenatide extended release, dulaglutide, liraglutide, lixisenatide, semaglutide, telpotide, cotidulide, noriglutide, oxyntomodulin (e.g., mastitutide), retaglutide, albiglutide, benaglutide, PEG-loxenatide, pegvitide, and danglitazone (as described in WO 2023 / 028606, which is incorporated herein by reference in its entirety). Other hormone agonists suitable for combination therapy with ActRII antibodies include, but are not limited to, long-acting amylin receptor agonists such as canagliflozin, dual amylin calcitonin receptor agonists (DACRAs), and peptide YY agonists.

[0158] In some embodiments, the incretin agonist or other hormone agonist dose is administered weekly at a dose of about 0.25 mg from about week 0 to about week 4, at a dose of about 0.5 mg from about week 5 to about week 8, at a dose of about 1.0 mg from about week 8 to about week 12, at a dose of about 1.7 mg from about week 12 to about week 15, at a dose of about 2.4 mg from about week 16 to about week 20, and at a dose of about 2.4 mg from about week 20 and thereafter. In some embodiments, the incretin agonist or other hormone agonist dose is administered weekly at a dose of about 5.0 mg, about 10 mg, or about 15 mg.

[0159] In some embodiments, both the ActRII antibody and the incretin agonist or other hormone agonist are administered subcutaneously according to any of the above dosages.

[0160] In some embodiments, the ActRII antibody is administered prior to an incretin agonist or other hormone agonist. In some embodiments, the ActRII antibody is administered at least 12 weeks, at least 10 weeks, at least 8 weeks, at least 6 weeks, at least 4 weeks, at least 2 weeks, at least 1 week, at least 1 day, or at least 1 hour prior to administration of an incretin agonist or other hormone agonist.

[0161] In some embodiments, the incretin agonist or other hormone agonist is administered prior to the ActRII antibody. In some embodiments, the incretin agonist or other hormone agonist is administered at least 2 weeks, at least 1 week, at least 5 days, at least 4 days, at least 2 days, at least 1 day, at least 6 hours, or at least 1 hour prior to the ActRII antibody.

[0162] In some embodiments, the ActRII antibody and the incretin agonist or other hormone agonist are administered regardless of the order of administration.

[0163] In some embodiments, the ActRII antibody and the incretin agonist or other hormone agonist are administered substantially simultaneously. In some embodiments, the ActRII antibody and the incretin agonist or other hormone agonist are administered in the same formulation.

[0164] IV. Pharmaceutical Compositions

[0165] The compositions provided herein comprising fixed unit doses of ActRII antibodies are configured for subcutaneous administration. In exemplary embodiments, the compositions are formulated as pharmaceutical compositions comprising an ActRII antibody comprising the sequences of SEQ ID NOs: 1-6 and / or SEQ ID NOs: 7 and 8. In some exemplary embodiments, the composition is formulated as a pharmaceutical composition that includes an ActRII antibody comprising the sequence of SEQ ID NO:7, or a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or the sequence of SEQ ID NO:8, or a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0166] In some embodiments, pharmaceutical composition includes excipient or carrier such as aqueous carrier. Various aqueous carriers can be used, such as buffered saline. Pharmaceutical composition can contain pharmaceutically acceptable auxiliary substances, such as those auxiliary substances required for approximate physiological conditions such as pH and buffer, toxic antagonists such as disodium hydrogen phosphate dihydrate, sodium dihydrogen phosphate, sodium acetate, sodium chloride, potassium chloride, calcium chloride, hydrochloric acid, sodium hydroxide, L-histidine, L-histidine hydrochloride and sodium lactate. The concentration of the activating agent in these preparations can vary, and according to the needs of selected specific administration mode and patient, based on fluid volume, viscosity and body weight, select (for example, Remington's Pharmaceutical Science (15th edition, 1980) and Goodman & Gillman, The Pharmacological Basis of Therapeutics (Hardman et al., editor, 1996)). The pharmaceutical compositions may contain pharmaceutically acceptable auxiliary substances, such as those that contribute to the stability and activity of one or more pharmacologically active agents, including but not limited to trehalose, sucrose or other sugars and polysorbate 20, polysorbate 60, polysorbate 80 or other emulsifiers or stabilizers.

[0167] Co-formulation

[0168] In some embodiments, the ActRII antibody pharmaceutical composition is co-formulated with an incretin agonist or another hormone agonist. Suitable incretin agonists for co-formulation include, but are not limited to, exenatide, exenatide extended release, dulaglutide, liraglutide, lixisenatide, semaglutide, telpotide, cotidol, noliglutide, oxyntomodulin (e.g., mastitutide), retaglutide, albiglutide, benaglutide, PEG-loxenatide, pegvitide, and danglitazone (as described in WO 2023 / 028606, which is incorporated herein by reference in its entirety). In some embodiments, the incretin agonist is present in a pharmaceutical composition with an ActRII antibody at a dose of about 0.005 mg to about 3.0 mg. In some embodiments, the incretin agonist is present in a pharmaceutical composition with an ActRII antibody at a dose of about 0.05 mg to about 2.0 mg. In some embodiments, the incretin agonist is present in a pharmaceutical composition with an ActRII antibody at a dose of about 0.5 mg to about 1.0 mg. In some embodiments, the concentration of the incretin agonist can be varied or gradually increased during treatment.

[0169] In some embodiments, the incretin agonist is present in the pharmaceutical composition at a dose of about 0.005 mg to about 3.0 mg, and the ActRII antibody is present at a dose of about 25 mg to about 600 mg. In some embodiments, the incretin agonist is present in the pharmaceutical composition at a dose of about 0.005 mg to about 3.0 mg, and the ActRII antibody is present at a dose of about 100 mg to about 400 mg. In some embodiments, the incretin agonist is present in the pharmaceutical composition at a dose of about 0.005 mg to about 3.0 mg, and the ActRII antibody is present at a dose of about 300 mg. In some embodiments, the incretin agonist is present in the pharmaceutical composition at a dose of about 0.005 mg to about 3.0 mg, and the ActRII antibody is present at a dose of about 150 mg.

[0170] Other hormone agonists suitable for co-formulation with ActRII antibodies in pharmaceutical compositions include, but are not limited to, long-acting amylin receptor agonists such as canagliflozin, dual amylin calcitonin receptor agonists (DACRAs), and peptide YY agonists. Example

[0171] Example 1: Clinical Study Methods for Evaluating Subcutaneous Administration of ActRII Antibodies

[0172] The aim of this study was to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) effects of subcutaneous (sc) administration of bimalumab, an ActRII antibody. The pharmacodynamic effects of interest in this study were fat mass and lean body mass.

[0173] Main objectives

[0174] 1. To evaluate the safety and tolerability of different subcutaneous dosing regimens of bimalumab.

[0175] 2. Determining the Local Tolerability of SC Administration of Bimalumab

[0176] 3. Evaluate the pharmacokinetics of different sc dosings of bimalumab relative to intravenous (iv) dosing

[0177] End point for the primary objective

[0178] 1. Physical Examination / Weight

[0179] 2. Vital signs

[0180] 3.ECG

[0181] 4. Safety Laboratory

[0182] 5. Adverse events (AEs) / serious adverse events (SAEs)

[0183] 6. Pain assessment using the visual analogue scale (VAS)

[0184] 7. Investigator's evaluation of tenderness, erythema / redness, and induration / swelling

[0185] 8. PK (sampling of the complete profile after the first and last doses and before the dose during treatment)

[0186] 9. Basic PK parameters: Cmax, Tmax, Cmin, AUCtau, AUClast (only after the last dose), Racc

[0187] Secondary Objectives

[0188] The absolute bioavailability of bimalumab given by sc administration was determined.

[0189] Endpoints of secondary objectives

[0190] Absolute bioavailability was determined by modeling because bimalumab exhibits target-mediated drug disposition (TMDD), in which the drug binds to its pharmacological target with such high affinity that this affects its pharmacokinetic profile.

[0191] Exploratory goals

[0192] To explore the pharmacodynamics and PK / PD relationships of different sc and iv dose regimens of bimalumab.

[0193] Endpoints for exploratory objectives

[0194] Pharmacokinetics (PK): Complete PK profiles after the first and last dose and before dose during the treatment period, as well as trough samples before each dose. Pharmacodynamics: Lean body mass (LBM), including limb LBM, by dual-energy X-ray absorptiometry (DXA) before and during treatment and at the end of the follow-up period.

[0195] Study Design

[0196] This is an exploratory, randomized, placebo-controlled, multiple-dose study in healthy elderly male and female subjects aged 70 years and older. It was designed with a total of 7 treatment groups receiving either active or placebo in a parallel group comparative design, see Figure 1 .

[0197] This study was designed to evaluate the safety / tolerability and pharmacokinetic and pharmacodynamic characteristics of multiple doses of bimalumab given as different sc or iv regimens every 4 weeks, in combination with a more frequent weekly sc dosing schedule. The sc dosing every 4 weeks was administered using an infusion pump.

[0198] A total of 91 male or female elderly subjects with stable health and medication use were enrolled in the study and randomized. Overall, demographic characteristics were generally balanced between the different dose groups (see Figure 2 and 3 The mean (SD) age of the subjects was 74.5 (4.25) years, height was 164.12 (9.70) cm, weight was 75.77 (14.81) kg, and BMI was 27.95 (3.75) kg / m 2 The subject population involved was predominantly Caucasian (89%), with a high proportion of Hispanic / Latino (28.6%). Of the 91 subjects enrolled, 49 were female.

[0199] Treatment Arm

[0200] Subjects were assigned to one of the following treatment arms:

[0201] Intravenous infusion (Cohorts 1 and 2): 8 active ingredients + 2 placebos / cohort; n=20:

[0202] o 700 mg by iv infusion over 30 minutes, every 4 weeks at weeks 0, 4, and 8. Total dose administered during the study: 700 mg x 3 = 2100 mg

[0203] o 210 mg by iv infusion over 30 minutes, every 4 weeks at weeks 0, 4, and 8. Total dose administered during the study: 210 mg x 3 = 630 mg

[0204] High and medium volume sc (cohorts 3 and 4) each 12 active ingredients + 2 placebos / cohort; n=28:

[0205] o 1500 mg (10 mL) by sc infusion over 30 minutes, given every 4 weeks at Weeks 0, 4, and 8.

[0206] Total dose administered during the study: 1500 mg x 3 = 4500 mg

[0207] o 525 mg (3.5 mL) by sc infusion over 10 minutes, given every 4 weeks at Weeks 0, 4, and 8.

[0208] Total dose administered during the study: 525 mg x 3 = 1575 mg

[0209] Low volume sc (cohorts 5, 6, and 7) 12 active ingredients + 2 placebos / cohort; n=43:

[0210] o 300 mg (2 mL) by sc injection (bolus), given weekly until week 11. Total dose administered within the study: 300 x 12 = 3600 mg

[0211] o 150 mg (1 mL) by sc injection (bolus), given weekly until week 11. Total dose administered within the study: 150 x 12 = 1800 mg

[0212] o 52.5 mg (0.35 mL) by sc injection (bolus), given weekly until week 11. Total dose administered within the study: 52.5 x 12 = 630 mg

[0213] Pharmacodynamic evaluation

[0214] Dual-energy X-ray absorptiometry (DXA) is used to assess changes in body composition, including total lean body mass (LBM) and fat body mass (FBM), as well as the skeletal mass index (ASMI). DXA instruments use an X-ray source that generates and splits into two wavelengths to measure bone mineral mass and soft tissue, from which fat and fat-free mass (or lean body mass) are estimated.

[0215] Safety evaluation

[0216] Safety evaluation consisted of collecting all adverse events (AEs) and serious adverse events (SAEs). Regular monitoring of hematology, blood chemistry, and urine was performed at the research center, and regular evaluation of vital signs, physical condition, body weight, and ECG was completed. Local tolerance evaluation was also performed, and immunogenicity (IG) samples were collected.

[0217] Pharmacokinetic evaluation

[0218] Pharmacokinetic (PK) samples were obtained and evaluated in all subjects at all dose levels using a validated bridging enzyme-linked immunosorbent assay (ELISA) method with an expected lower limit of quantification (LLOQ) of 0.176 μg / mL. The linear trapezoidal rule was used for AUC calculations. Because bimalumab exhibits a nonlinear PK profile, also known as TMDD, noncompartmental analysis (NCA) could not be used to derive AUC. inf , half-life (T1 / 2) and clearance (CL) and volume of distribution (V). Accumulation ratio (R acc ) using the AUC obtained from the dosing interval after the first and last doses tau The value was calculated as [(AUC tau , last dose) / (AUC tau , first dose)]. Since bimalumab exhibits a nonlinear PK profile where CL depends on bimalumab concentration, AUC cannot be used to infer absolute bioavailability and dose proportionality. Therefore, a model-based approach was used to characterize subcutaneous bioavailability.

[0219] Example 2: Pharmacokinetic Results of a Clinical Study Evaluating Subcutaneous Administration of ActRII Antibodies

[0220] Notably, the 300 mg subcutaneous bolus dose showed no detectable TMDD effect, indicating that the 300 mg dose is high enough to maintain saturation of clearance for this route of administration. Figure 8 As demonstrated in the literature, a 300 mg subcutaneous (sc) bolus dose of an ActRII antibody is predicted to maintain serum concentrations above 10 μg / ml, at a relatively steady-state level, from about day 15 to about day 85. Similarly, a 150 mg subcutaneous bolus dose of an ActRII antibody is predicted to maintain serum concentrations at approximately 10 μg / ml from about day 29 to about day 85.

[0221] intravenous

[0222] Cohorts 1 and 2 (iv infusion): As expected, TMDD was observed in the concentration-time curves. Variability was moderate, with a coefficient of variation (CV; range 17% to 47% CV) of approximately 30-40%. Cumulative ratios based on AUCtau were relatively low (range 1.15 to 1.37), but based on Cmin, it was observed that steady-state may not be achieved with three monthly doses. As expected with iv administration, peak-to-trough ratios were relatively large.

[0223] subcutaneous

[0224] Cohorts 3 and 4 (sc infusion): Absorption of bimalumab following sc infusion was relatively slow (Tmax approximately one week post-dose). TMDD profiles were only observed at the lower dose (525 mg). Figure 7 Variability was moderate (with a CV range of 29% to 39%). Cumulative ratios based on AUCtau were slightly higher than those with iv infusion (between 1.72 and 1.92), but steady-state may not be achieved with three monthly administrations, as can be seen based on Cmin. Peak-to-trough ratios were moderate.

[0225] Cohorts 5, 6, and 7 (sc bolus): Absorption of bimalumab following sc bolus was more rapid at low doses after the first dose ( Figure 8 ). The concentration-time curves were relatively flat after the last dose, with low peak-to-trough ratios. The variability of the PK parameters was relatively high, with CVs of approximately 50% for 300 mg and 150 mg and approximately 100% for 52.5 mg. The cumulative ratios based on AUCtau were much higher than those in the iv and sc infusion groups. For most subjects, steady state based on Cmin was achieved after 9 weekly doses (day 57). It is noteworthy that TMDD curves could be observed at low doses (i.e., 52.5 mg and 150 mg), but not at 300 mg, confirming that for a 300 mg subcutaneous bolus, the concentration was high enough to maintain saturation of clearance.

[0226] Example 3: Pharmacodynamic Results of a Clinical Study Evaluating Subcutaneous Administration of ActRII Antibodies

[0227] Administration via intravenous and subcutaneous routes (both bolus and infusion) showed similar effects on lean body mass gain and fat body mass loss.

[0228] LBM and limb LBM

[0229] Regardless of whether bimalumab was administered iv or sc (bolus and infusion), a dose-dependent plateau effect was observed at the end of each treatment period (day 85) with an increase in lean body mass of approximately 1.5-2 kg at the maximum dose (i.e., a -4-6% increase from baseline).

[0230] FBM

[0231] Regardless of whether bimalumab was administered IV or SC (bolus and infusion), a dose-dependent linear reduction in total body fat mass of up to 2 to 3 kg at the highest dose was observed at the end of each treatment period (Day 85). For the highest dose, this fat loss further increased to 3 to 4 kg in the IV and SC infusion groups during the follow-up treatment period and was maintained in the highest dose SC infusion group.

[0232] Example 4: Model prediction of subcutaneous administration of ActRII antibodies

[0233] Based on the clinical studies described above (Examples 1-3), a computational model of the effects of the ActRII antibody bimalumab on PK and PD was developed. The model predicted that for most subjects, full ActRII receptor occupancy (RO) ( Figure 19 ).

[0234] The effect of the loading dose was modeled to predict the number of subjects across a range of body weights who would have an ActRII serum concentration above 10 μg / ml RO and the time required to reach this concentration.

[0235] Figure 20 The predicted time to reach various bimalumab concentrations in a population of 2500 subjects, each weighing 100 kg, with 300 mg of bimalumab administered weekly and subcutaneously without a loading dose is shown. Threshold levels of 5 μg / ml and 10 μg / ml are indicated in the figure and table below. Figure 21 Shown are the predicted times to reach various bimalumab concentrations in a population of 2500 subjects weighing 60 to 140 kg.

[0236] Figure 22 Shown are predicted bimalumab concentrations over time in a subject population weighing 50 to 200 kg, with weekly and subcutaneous administration of 300 mg bimalumab without a loading dose on Day 1. Figure 23 The predicted timing of total fat body mass change in a subject population weighing 50 to 200 kg with weekly and subcutaneous administration of 300 mg of bimalumab without a loading dose on day 1 is shown.

[0237] Figure 24Shown are predicted bimalumab concentrations over time in a subject population weighing 50 to 200 kg, with weekly and subcutaneous administration of 300 mg bimalumab, with two doses of 300 mg bimalumab administered subcutaneously on Day 1 (i.e., with a loading dose). Notably, the time to reach a median serum concentration of 10 μg / ml was reduced for all subjects with a loading dose on Day 1. Figure 25 Shown is the timing of changes in total fat body mass in a subject population weighing 50 to 200 kg with weekly and subcutaneous administration of 300 mg bimalumab, with two doses of 300 mg bimalumab administered subcutaneously on day 1 (ie, with a loading dose).

[0238] Figure 26 Shown are bimalumab concentrations over time in a subject population weighing 50 to 200 kg, with 300 mg bimalumab administered weekly and subcutaneously, with three doses of 300 mg bimalumab administered subcutaneously on day 1 (ie, with two loading doses). Figure 27 Shown is the timing of changes in total fat body mass in a subject population weighing 50 to 200 kg with weekly and subcutaneous administration of 300 mg of bimalumab, with three doses of 300 mg of bimalumab administered subcutaneously on day 1 (ie, with two loading doses).

[0239] Figure 28 Shown is a comparison of the effect of loading dose (0, 1, or 2 loading doses) on bimalumab exposure in a population of subjects weighing 100 kg, in which 300 mg of bimalumab was administered weekly and subcutaneously. Figure 29 Shown is a comparison of the effects of a loading dose (0, 1 or 2 loading doses) for a subject population weighing 100 kg, in which 300 mg of bimalumab was administered weekly and subcutaneously.

[0240] Figure 30 and Figure 31 showed that increasing the dose of bimalumab to 600 mg had little effect on the timing of exposure.

[0241] Population modeling including individual variability

[0242] The model described herein predicts that 300 mg administered weekly and subcutaneously (without a loading dose) would be sufficient to achieve a serum concentration of at least 10 μg / ml in most subjects. However, when individual response variability within the population is taken into account, as Figure 32 As shown in Figure 2, the concentration of bimalumab required to have a maximal effect on fat and lean body mass in the population increased to approximately 10-30 μg / ml. Figure 33As shown in , in a model which takes into account the variability of individual responses within the population, subjects with higher body weight did not reach 10 μg / ml with 300 mg administered weekly and subcutaneously and required a loading dose.

Claims

1. A pharmaceutical composition comprising an ActRII antibody in fixed unit dose form, wherein the ActRII antibody is present at about 25 mg to about 600 mg per fixed unit dose, and wherein the composition is configured for subcutaneous administration.

2. The pharmaceutical composition of claim 1, wherein the ActRII antibody is present at about 100 to about 400 mg per fixed unit dose.

3. The pharmaceutical composition of claim 2, wherein the ActRII antibody is present at about 150 mg per fixed unit dose.

4. The pharmaceutical composition of claim 2, wherein the ActRII antibody is present at about 300 mg per fixed unit dose.

5. The pharmaceutical composition of any one of claims 1-4, wherein the ActRII antibody comprises the CDR amino acid sequence of SEQ ID NO: 1-6.

6. The pharmaceutical composition of any one of claims 1-5, wherein the ActRII antibody comprises: a VH amino acid sequence of SEQ ID NO: 7, or a sequence having at least 80% sequence identity thereto, and a VL amino acid sequence of SEQ ID NO: 8, or a sequence having at least 80% sequence identity thereto.

7. The pharmaceutical composition of any one of claims 1-6, wherein the ActRII antibody comprises: the amino acid sequence of SEQ ID NO: 9, or a sequence having at least 80% sequence identity thereto, and the amino acid sequence of SEQ ID NO: 10, or a sequence having at least 80% sequence identity thereto.

8. The pharmaceutical composition of any one of claims 1-4, wherein the ActRII antibody comprises one or more of the CDR amino acid sequences of SEQ ID NOs: 11-75.

9. The pharmaceutical composition of any one of claims 1-4, wherein the ActRII antibody comprises one or more of the CDR amino acid sequences of SEQ ID NOs: 76-81.

10. The pharmaceutical composition of any one of claims 1-4, wherein the ActRII antibody comprises one or more of the CDR amino acid sequences of SEQ ID NOs: 82-5049.

11. The pharmaceutical composition of any one of claims 1-7, wherein the ActRII antibody is specific for ActRIIA and / or ActRIIB.

12. The pharmaceutical composition of any one of claims 1-11, wherein the ActRII antibody is present in a fixed unit dose at a concentration of about 25 mg / ml, about 50 mg / ml, about 75 mg / ml, about 100 mg / ml, about 125 mg / ml, about 150 mg / ml, about 175 mg / ml, about 200 mg / ml, about 225 mg / ml, about 250 mg / ml, about 275 mg / ml, about 300 mg / ml, about 325 mg / ml, about 350 mg / ml, about 375 mg / ml, about 400 mg / ml, about 425 mg / ml, about 450 mg / ml, about 475 mg / ml, about 500 mg / ml, about 525 mg / ml, about 550 mg / ml, about 575 mg / ml, or about 600 mg / ml.

13. The pharmaceutical composition of claim 12, wherein the ActRII antibody is present in the fixed unit dose at a concentration of about 150 mg / ml.

14. The pharmaceutical composition of any one of claims 1-12, wherein the fixed unit dose is a volume of about 0.25 ml, about 0.5 ml, about 0.75 ml, about 1.0 ml, about 1.24 ml, about 1.5 ml, about 1.75 ml, about 2.0 ml, about 2.25 ml, about 2.5 ml, about 2.75 ml, about 3.0 ml, about 3.25 ml, about 3.5 ml, about 3.75 ml, about 4.0 ml, about 4.25 ml, about 4.5 ml, about 4.75 ml, or about 5.0 ml.

15. The pharmaceutical composition according to claim 14, wherein the fixed unit dose is a volume of 1 ml.

16. The pharmaceutical composition of claim 14, wherein the fixed unit dose is a volume of 2 ml.

17. The pharmaceutical composition according to any one of claims 1 to 16, wherein the pharmaceutical composition is contained in a syringe.

18. The pharmaceutical composition according to claim 17, wherein the syringe is a needle or a syringe.

19. The pharmaceutical composition according to any one of claims 1 to 18, wherein the pharmaceutical composition comprises a hormone agonist.

20. The pharmaceutical composition of claim 19, wherein the hormone agonist is an incretin agonist.

21. The pharmaceutical composition of claim 20, wherein the incretin agonist is selected from the group consisting of exenatide, exenatide extended release, dulaglutide, liraglutide, lixisenatide, semaglutide, telpotide, cotidol, noriglutide, oxyntomodulin, retaglutide, albiglutide, benaglutide, PEG-loxenatide, pegvitide, and danglitazone.

22. The pharmaceutical composition of claim 19, wherein the hormone agonist is selected from the group consisting of a long-acting amylin receptor agonist, a dual amylin calcitonin receptor agonist (DACRA), and a peptide YY agonist.

23. A method of treating a disease in a subject in need thereof, comprising subcutaneously administering to the subject a fixed unit dose of an ActRII antibody.

24. The method of claim 23, wherein the ActRII antibody is present at about 25 mg to about 600 mg per fixed unit dose.

25. The method of claim 24, wherein the ActRII antibody is present at about 100 mg to about 400 mg per fixed unit dose.

26. The method of claim 25, wherein the ActRII antibody is present at about 150 mg per fixed unit dose.

27. The method of claim 25, wherein the ActRII antibody is present at about 300 mg per fixed unit dose.

28. The method of any one of claims 23-27, wherein the ActRII antibody fixed unit dose is administered to the subject daily, about six times a week, about five times a week, about four times a week, about three times a week, about twice a week, about once a week, about once every two weeks, about once every three weeks, about once every four weeks, about once every five weeks, about once every six weeks, about once every seven weeks, or about once every eight weeks.

29. The method of claim 28, wherein the ActRII antibody fixed unit dose is administered to the subject approximately once a week.

30. The method of any one of claims 23-29, wherein administration of an ActRII antibody loading dose precedes administration of an ActRII antibody fixed unit dose.

31. The method of claim 30, wherein the ActRII antibody loading dose is administered intravenously at about 3 mg / kg to about 50 mg / kg.

32. The method of claim 31, wherein the ActRII antibody loading dose is administered intravenously at about 10 mg / kg.

33. The method of claim 31, wherein the ActRII antibody loading dose is administered intravenously at about 30 mg / kg.

34. The method of claim 30, wherein the ActRII antibody loading dose is administered at a dose of about 150 mg to about 4,500 mg.

35. The method of claim 34, wherein the ActRII antibody loading dose is administered at a dose of about 210 mg.

36. The method of claim 34, wherein the ActRII antibody loading dose is administered at a dose of about 700 mg.

37. The method of claim 30, wherein the ActRII antibody loading dose is administered at a dose of about 25 mg to about 600 mg.

38. The method of claim 37, wherein the ActRII antibody loading dose is administered at a dose of about 100 mg to about 400 mg.

39. The method of claim 38, wherein the ActRII antibody loading dose is administered at a dose of about 150 mg.

40. The method of claim 38, wherein the ActRII antibody loading dose is administered at a dose of about 300 mg.

41. The method of any one of claims 34-40, wherein the ActRII antibody load is administered intravenously.

42. The method of any one of claims 34-40, wherein the ActRII antibody loading is administered subcutaneously.

43. The method of any one of claims 30-40, wherein the ActRII antibody loading dose is administered about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, or about 5 weeks prior to administration of the ActRII antibody fixed unit dose.

44. The method of any one of claims 23-43, wherein the disease is a metabolic disease.

45. The method of claim 44, wherein the metabolic disease is selected from the group consisting of obesity, diabetes, metabolic syndrome, antipsychotic-associated obesity, glucocorticoid-induced obesity, hypothalamic obesity associated with craniopharyngioma, and monogenic disorders associated with obesity.

46. The method of claim 45, wherein the monogenic disorder associated with obesity is Barder-Biedel syndrome, or one of the obesity resulting from mutations in one or more genes comprising ADCY3, ALMS1, ARL6, BBS1, BBS2, BBS4, BBS5, BBS7, BBS9, BBS10, BBS12, BDNF, CCDC28B, CEP290, CREBBP, EP300, GNAS, IER3IP1, MKKS, MKS1, MRAP2, NTRK2, PCSK1, PHF6, POMC, SH2B1, SIM1, TMEM67, TRIM32, TTC8, and VPS13B.

47. The method of claim 44, wherein the metabolic disease is Prader-Willi syndrome.

48. The method of any one of claims 23-43, wherein the disease is muscular dystrophy or sarcopenia.

49. The method of any one of claims 23-43, wherein the disease is aging-related muscle dysfunction.

50. The method of any one of claims 23-43, wherein the disease is heart disease.

51. The method of any one of claims 23-43, wherein the disease is liver disease.

52. The method of any one of claims 23-51, wherein the subject has a body mass index (BMI) of 30 or greater.

53. The method of any one of claims 23-51, wherein the subject has a body mass index (BMI) of 27 or greater.

54. The method of claim 53, wherein the subject suffers from an obesity disorder.

55. The method of any one of claims 23-54, wherein the subject weighs about 200 kg or less.

56. The method of any one of claims 23-54, wherein the subject weighs greater than about 200 kg.

57. The method of any one of claims 23-56, wherein the ActRII antibody comprises the CDR amino acid sequences of SEQ ID NOs: 1-6.

58. The method of any one of claims 23-56, wherein the ActRII antibody comprises: a VH amino acid sequence of SEQ ID NO:7, or a sequence with at least 80% sequence identity thereto, and a VL amino acid sequence of SEQ ID NO:8, or a sequence with at least 80% sequence identity thereto.

59. The method of any one of claims 23-56, wherein the ActRII antibody comprises: the HC amino acid sequence of SEQ ID NO:9, or a sequence with at least 80% sequence identity thereto, and the LC amino acid sequence of SEQ ID NO:10, or a sequence with at least 80% sequence identity thereto.

60. The method of any one of claims 23-56, wherein the ActRII antibody comprises the CDR amino acid sequences of SEQ ID NOs: 11-75.

61. The method of any one of claims 23-56, wherein the ActRII antibody comprises the CDR amino acid sequences of SEQ ID NOs: 76-81.

62. The method of any one of claims 23-56, wherein the ActRII antibody comprises the CDR amino acid sequences of SEQ ID NOs: 82-5049.

63. The method of any one of claims 23-62, wherein the ActRII antibody is specific for ActRIIA and / or ActRIIB.

64. The method of any one of claims 23-63, wherein the ActRII antibody is present in the fixed unit dose at a concentration of about 25 mg / ml, about 50 mg / ml, about 75 mg / ml, about 100 mg / ml, about 125 mg / ml, about 150 mg / ml, about 175 mg / ml, about 200 mg / ml, about 225 mg / ml, about 250 mg / ml, about 275 mg / ml, about 300 mg / ml, about 325 mg / ml, about 350 mg / ml, about 375 mg / ml, about 400 mg / ml, about 425 mg / ml, about 450 mg / ml, about 475 mg / ml, about 500 mg / ml, about 525 mg / ml, about 550 mg / ml, about 575 mg / ml, or about 600 mg / ml.

65. The method of claim 64, wherein the ActRII antibody is present in the fixed unit dose at a concentration of about 150 mg / ml.

66. The method of any one of claims 23-64, wherein the fixed unit dose is in a volume of about 0.25 ml, about 0.5 ml, about 0.75 ml, about 1.0 ml, about 1.24 ml, about 1.5 ml, about 1.75 ml, about 2.0 ml, about 2.25 ml, about 2.5 ml, about 2.75 ml, about 3.0 ml, about 3.25 ml, about 3.5 ml, about 3.75 ml, about 4.0 ml, about 4.25 ml, about 4.5 ml, about 4.75 ml, or about 5.0 ml.

67. The method of claim 66, wherein the fixed unit dose is a volume of 1 ml.

68. The method of claim 66, wherein the fixed unit dose is a volume of 2 ml.

69. The method of any one of claims 23-68, wherein the fixed unit dose is contained in a syringe.

70. The method of claim 69, wherein the injector is a needle or a syringe.

71. The method of any one of claims 23-70, wherein the fixed unit dose is designed to be self-administered.

72. The method of any one of claims 23-71, wherein the hormone agonist is administered as part of a combination therapy.

73. The method of claim 72, wherein the hormone agonist is an incretin agonist.

74. The method of claim 73, wherein the incretin agonist is selected from the group consisting of exenatide, extended-release exenatide, dulaglutide, liraglutide, lixisenatide, semaglutide, telpotide, cotiduptide, noriglutide, oxyntomodulin, retaglutide, albiglutide, benaglutide, PEG-loxenatide, pegvitide, and danglitazone.

75. The method of claim 72, wherein the hormone agonist is selected from the group consisting of a long-acting amylin receptor agonist, a dual amylin calcitonin receptor agonist (DACRA), and a peptide YY agonist.

76. The method of any one of claims 72-75, wherein the hormone agonist is administered prior to the ActRII antibody.

77. The method of any one of claims 72-75, wherein the ActRII antibody is administered prior to the hormone agonist.

78. The method of any one of claims 72-75, wherein the ActRII antibody is co-formulated with a hormone agonist.

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