ActRII antibody fixed unit dose treatment

Abstract

Provided herein are compositions and methods for subcutaneous administration of fixed unit doses of ActRII antibodies for the treatment of disease, where the treatment is administered across a range of subject weights. As provided herein, an ActRII antibody fixed unit dose can contain, for example, about 25 mg to about 600 mg, e.g., about 150 mg, of ActRII antibody in a volume of about 1 mL.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 373,684, filed August 26, 2022, and U.S. Provisional Patent Application No. 63 / 378,128, filed October 3, 2022, the contents of which are incorporated by reference in their entireties.

[0002] (Incorporated by reference to the sequence listing) The contents of the electronic sequence listing (VRNS_010_02WO_SeqList_ST26.xml, size: 4,428,735 bytes, created on August 25, 2023) are incorporated herein by reference in their entirety. [Background technology]

[0003] Therapeutic antibodies are often administered based on the subject's body weight. However, such customization requires, among other things, a medical professional to plan and administer the dose. An attractive alternative is to administer a fixed dose that can be administered to subjects across a range of body weights. An additional advantage is that subjects may even be able to self-administer the fixed dose at home, for example, using a handheld hypodermic syringe. However, for therapeutic antibodies, fixed doses require pharmacokinetic (PK) and pharmacodynamic (PD) optimization to achieve the desired range of exposure, while taking into account antigen affinity, antigen density, phagocytic clearance, IgG recycling, errors associated with incorrect self-administration, and the consequences of administration failure. The lack of such PK / PD optimization would result in ineffective dosing and hinder the effectiveness of otherwise life-saving therapies.

[0004] Treatment with ActRII antibodies is useful for various diseases, such as metabolic diseases, muscle wasting diseases, cardiac diseases, and liver diseases. Currently, the clinical use of such antibodies does not involve a fixed dosing paradigm. Therefore, there is a need for a PK / PD optimized fixed unit dose of ActRII antibodies that is applicable across a range of body weights and is useful for self-administration, and therefore, is provided herein. Summary of the Invention

[0005] Provided herein are compositions and methods for subcutaneous administration of a fixed unit dose of an ActRII antibody that can be used to treat various diseases, wherein the fixed unit dose is administered to subjects having a range of body weights. In exemplary embodiments, the pharmaceutical composition in fixed unit dose form comprises an ActRII antibody at a dose of about 25 mg to about 600 mg. In some exemplary embodiments, the pharmaceutical composition in fixed unit dose form comprises an ActRII antibody at a dose of about 100 mg to about 400 mg. In some exemplary embodiments, the fixed unit dose comprises an ActRII antibody at a dose of about 150 mg. In some exemplary embodiments, the fixed unit dose comprises an ActRII antibody at a dose of about 300 mg.

[0006] In some embodiments, the ActRII antibody comprises the CDR amino acid sequences of SEQ ID NOs: 1 to 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.

[0007] In some embodiments, 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.

[0008] In some embodiments, an ActRII antibody comprises one or more of the CDR amino acid sequences of SEQ ID NOs: 11-75. In some embodiments, an ActRII antibody comprises one or more of the CDR amino acid sequences of SEQ ID NOs: 76-81. In some embodiments, an ActRII antibody comprises one or more of the CDR amino acid sequences of SEQ ID NOs: 82-5049.

[0009] In some embodiments, the ActRII antibody is specific for ActRIIA and / or ActRIIB.

[0010] 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.

[0011] In some embodiments, the fixed unit dose is 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 volume. In some embodiments, the fixed unit dose is about 1 mL in volume. In some embodiments, the fixed unit dose is about 2 mL in volume. In some embodiments, the composition is housed in a syringe. In some embodiments, the syringe is a needle or syringe.

[0012] 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 the group consisting of exenatide, extended-release exenatide, dulaglutide, liraglutide, lixisenatide, semaglutide, tirzepatide, cotadutide, neuiglutide, oxyntomodulin, retatortide, albiglutide, veinaglutide, PEG-loxenatide, pembidutide, and danugliplon.

[0013] In some embodiments, 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.

[0014] In some embodiments, provided herein are methods of treating a disease in a subject in need thereof, comprising subcutaneously administering a fixed unit dose of an ActRII antibody to the subject. 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.

[0015] In some embodiments, the ActRII antibody fixed unit dose is administered to the subject about every day, about 6 times per week, about 5 times per week, about 4 times per week, about 3 times per week, about twice per week, about once per week, about once per 2 weeks, about every 3 weeks, about every 4 weeks, about every 5 weeks, about every 6 weeks, about every 7 weeks, or about every 8 weeks. In some embodiments, the ActRII antibody fixed unit dose is administered to the subject about once per week.

[0016] 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.

[0017] 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.

[0018] 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.

[0019] 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.

[0020] 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 before administration of the ActRII antibody fixed unit dose.

[0021] In some embodiments, the disease of interest is a metabolic disease, hi some embodiments, the metabolic disease is selected from the group consisting of obesity, diabetes, metabolic syndrome, antipsychotic-associated obesity, glucocorticoid-induced obesity, craniopharyngioma-associated hypothalamic obesity, and obesity-related monogenic disorders.

[0022] In some embodiments, the obesity-related monogenic disorder is one of Bardet-Biedl syndrome or obesity resulting 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.

[0023] In some embodiments, the metabolic disease is Prader-Willi syndrome.

[0024] In some embodiments, the subject's disease is a muscle wasting disease or sarcopenia. In some embodiments, the subject's disease is age-related muscle dysfunction. In some embodiments, the subject's disease is heart disease. In some embodiments, the subject's disease is liver disease.

[0025] In some embodiments, the subject has a body mass index (BMI) of 30 or greater. The method of 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 disorders. In some embodiments, the subject weighs less than or equal to about 200 kg. In some embodiments, the subject weighs more than about 200 kg.

[0026] In some embodiments, an ActRII antibody used in a method of treatment comprises the CDR amino acid sequences of SEQ ID NOs: 1-6. In some embodiments, an 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. In some embodiments, an ActRII antibody comprises the HC amino acid sequence of SEQ ID NO: 9, or a sequence having at least 80% sequence identity thereto, and the LC amino acid sequence of SEQ ID NO: 10, or a sequence having at least 80% sequence identity thereto.

[0027] In some embodiments, an ActRII antibody used in a method of treatment comprises one or more CDR amino acid sequences of SEQ ID NOs: 11-75. In some embodiments, an ActRII antibody used in a method of treatment comprises one or more CDR amino acid sequences of SEQ ID NOs: 76-81. In some embodiments, an ActRII antibody used in a method of treatment comprises one or more CDR amino acid sequences of SEQ ID NOs: 82-5049.

[0028] In some embodiments, the ActRII antibody is specific for ActRIIA and / or ActRIIB.

[0029] 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.

[0030] In some embodiments, the fixed unit dose is 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 volume.

[0031] In some embodiments, the fixed unit dose is contained in an injector configured for subcutaneous administration. In some embodiments, the injector is a needle or syringe. In some embodiments, the fixed unit dose is designed to be self-administered.

[0032] In some embodiments, the hormone agonist is administered as part of a combination therapy with an ActRII antibody of the disclosure.

[0033] In some embodiments, the hormone agonist is an incretin agonist. In some embodiments, the incretin agonist is selected from the group consisting of exenatide, extended-release exenatide, dulaglutide, liraglutide, lixisenatide, semaglutide, tirzepatide, cotadutide, neuiglutide, oxyntomodulin, retatortide, albiglutide, veinaglutide, PEG-loxenatide, pembidutide, and danugliplon. In some embodiments, 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.

[0034] In some embodiments, the hormonal agonist is administered before the ActRII antibody. In some embodiments, the ActRII antibody is administered before the hormonal agonist. In some embodiments, the ActRII antibody and the hormonal agonist are co-formulated to be administered as a combination therapy. [Brief explanation of the drawings]

[0035] [Figure 1] FIG. 1 is a schematic diagram of an exemplary clinical trial design conducted to evaluate the pharmacodynamics and pharmacokinetics of subcutaneous administration of an ActRII antibody (BYM338, also known as bimagrumab). [Figure 2] 1 is a table of subject demographics for the clinical trials shown in FIG. 1. [Figure 3] 2 is a table of the physical characteristics of the subjects prior to commencing the study shown in FIG. 1. [Figure 4] 2 is a table of summarized PK parameters Cmax and Cmin from the study shown in FIG. 1. [Figure 5] 2 is a table summarizing PK parameters, including Tmax and AUC, from the study shown in FIG. 1. [Figure 6] FIG. 2 is a semi-logarithmic graph of model-fitted mean serum concentration profiles for intravenous administration of bimagrumab at 210 mg and 700 mg concentrations from the study shown in FIG. 1. [Figure 7] 2 is a semi-logarithmic graph of model-fitted mean serum concentration profiles for subcutaneous infusion administration of bimagrumab at 1500 mg and 525 mg concentrations from the study shown in FIG. 1. [Figure 8] 2 is a semi-logarithmic graph of model-fitted mean serum concentration profiles for subcutaneous bolus administration of bimagrumab at concentrations of 150 mg, 300 mg, and 52.5 mg from the study shown in FIG. 1. [Figure 9] 2 is a table summarizing the lean body mass and fat mass results from the study shown in FIG. 1. [Figure 10] 2 is a line graph of the lean body mass results of intravenous infusion from the study shown in FIG. 1. [Figure 11] 2 is a line graph of the limb lean mass results of intravenous infusion from the study shown in FIG. 1. [Figure 12] 2 is a line graph of the subcutaneous injection lean body mass results from the study shown in FIG. 1. [Figure 13] 2 is a line graph of the subcutaneous injection limb lean mass results from the study shown in FIG. 1. [Figure 14] 2 is a line graph of the subcutaneous bolus lean body mass results from the study shown in FIG. 1. [Figure 15] 2 is a line graph of subcutaneous bolus limb lean mass results from the study shown in FIG. 1. [Figure 16] 2 is a line graph of intravenous infusion fat mass results from the study shown in FIG. 1. [Figure 17] 2 is a line graph of the subcutaneous injection fat mass results from the study shown in FIG. 1. [Figure 18] 2 is a line graph of subcutaneous bolus fat mass results from the study shown in FIG. 1. [Figure 19] 1 is a line graph of model-predicted receptor occupancy (RO) for bimagrumab and associated dosing effects on fat body mass (FBM) loss and lean body mass (LBM) gain. [Figure 20] 1 is a line graph and table of model-predicted times to reach various bimagrumab concentrations in a population of 2500 subjects, each weighing 100 kg, receiving weekly subcutaneous administration of 300 mg bimagrumab. Threshold levels of 5 μg / mL and 10 μg / mL are shown on the graph and in the table below. [Figure 21] 1 is a line graph and table of model-predicted times to reach various bimagrumab concentrations in a population of 2500 subjects weighing 60-140 kg receiving weekly subcutaneous administration of 300 mg bimagrumab. Times to threshold levels of 5 μg / mL and 10 μg / mL are shown in the table below. [Figure 22] 1 is a line graph of model-predicted bimagrumab concentrations over time in a population of subjects weighing 50-200 kg receiving 300 mg bimagrumab subcutaneously weekly without a loading dose on day 1. [Figure 23] 1 is a line graph of model-predicted change in total body fat mass over time in a population of subjects weighing 50-200 kg receiving 300 mg bimagrumab administered subcutaneously weekly without a loading dose on day 1. [Figure 24]1 is a line graph of model-predicted bimagrumab concentrations over time in a population of subjects weighing 50-200 kg receiving two doses of 300 mg bimagrumab subcutaneously on day 1 and 300 mg bimagrumab subcutaneously weekly. [Figure 25] 1 is a line graph of model-predicted change in total body fat mass over time in a population of subjects weighing 50-200 kg receiving two doses of 300 mg bimagrumab administered subcutaneously on day 1 and 300 mg bimagrumab administered subcutaneously weekly. [Figure 26] 1 is a line graph of model-predicted bimagrumab concentrations over time in a population of subjects weighing 50-200 kg receiving three doses of 300 mg bimagrumab subcutaneously on day 1 and 300 mg bimagrumab subcutaneously weekly. [Figure 27] 1 is a line graph of model-predicted change in total body fat mass over time in a population of subjects weighing 50-200 kg receiving three doses of 300 mg bimagrumab administered subcutaneously on day 1 and 300 mg bimagrumab administered subcutaneously weekly. [Figure 28] 1 is a line graph comparing model predictions of the effect of loading dose (0, 1, or 2 loading doses) on bimagrumab concentrations over time in a population of subjects weighing 100 kg receiving 300 mg bimagrumab subcutaneously weekly. [Figure 29] 1 is a line graph comparing model predictions of the effect of loading dose (0, 1, or 2 loading doses) on change in total body fat mass over time for a population of subjects weighing 100 kg receiving 300 mg of bimagrumab subcutaneously weekly. [Figure 30] 1 is a line graph of model-predicted bimagrumab concentrations over time in a population of subjects weighing 50-200 kg receiving 600 mg bimagrumab subcutaneously once weekly with no loading dose on day 1. [Figure 31] 1 is a line graph of model-predicted change in total body fat mass over time in a population of subjects weighing 50-200 kg receiving 600 mg bimagrumab administered subcutaneously weekly without a loading dose on day 1. [Figure 32]1 is a line graph of the model-predicted effect of bimagrumab concentration on fat mass and lean body mass in a population of subjects with individual variability in response. [Figure 33] Line graph of model-predicted bimagrumab concentrations over time in a population of subjects with individual response variability. Subjects ranged in weight from 50 to 200 kg and received 300 mg of bimagrumab subcutaneously weekly, with no loading dose on day 1. DETAILED DESCRIPTION OF THE INVENTION

[0036] I. Definition Unless otherwise defined herein, technical and scientific terms used herein shall have the same meaning as commonly understood by one of ordinary skill in the art. Generally, the nomenclature used in connection with, and techniques of, chemistry, molecular biology, cell biology, immunology, pharmacology, and protein chemistry described herein are those well known and commonly used in the art.

[0037] It must be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" refers to one or a mixture of such agents, reference to "a method" includes reference to equivalent steps and methods known to those skilled in the art, and so forth.

[0038] As used herein, the term "approximately" or "about" as applied to one or more values ​​of interest refers to values ​​that are similar in magnitude to and / or within a similar range of a stated 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 or lesser) of the stated reference value, unless otherwise stated or clear from the context (except where such number exceeds 100% of possible values).

[0039] As used herein, the terms "polypeptide," "peptide," and "protein" refer to polymers of amino acids of any length. These terms also encompass modified amino acid polymers, including, for example, disulfide bond formation, glycosylation, lipidation, phosphorylation, or conjugation with a labeling component.

[0040] As used herein, the terms "identity" and "identical," when referring to a comparison of two sequences, refer to the percentage of exact matches in an alignment of a sequence provided herein to a reference sequence, such as an alignment generated by the BLAST algorithm or other alignment algorithms known in the art. Identity can be calculated based on an alignment of the full-length sequence provided herein with the full-length reference sequence. Identity can also be calculated based on a partial alignment of the sequence provided herein with the reference sequence if the reference sequence is longer than the sequence provided herein. Identity can also be calculated based on a partial alignment of the sequence provided herein with the reference sequence if the reference sequence is shorter than the sequence provided herein. Thus, when aligning two sequences, according to the above, a query sequence "shares at least x% identity with" a subject sequence if, in the alignment of the two sequences, at least x% (truncated) of the residues in the subject sequence (the numerator is the number of exact matches and the denominator is the length of the query sequence) are aligned as exact matches with the corresponding residues in the query sequence. Alternatively, in some embodiments, the denominator may be the length of the query sequence minus any gaps of two or more mismatched residues. When the subject sequence has a variable position (e.g., a residue designated X), alignment to any residue in the query sequence is counted as a match.

[0041] As used herein, "antibody" includes reference to immunoglobulin molecules immunologically reactive with a particular antigen, including both polyclonal and monoclonal antibodies. The term includes humanized antibodies, chimeric antibodies (e.g., murine 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) containing VH and VL sequences linked together in a single chain, and single-chain antibody fragments (scAb). The term antibody also includes bivalent or bispecific molecules, diabodies, triabodies, and tetrabodies.

[0042] The terms "treatment," "treating," and the like are used herein generally to mean using a therapeutic agent to achieve a desired pharmacological and / or physiological effect. The effect may be prophylactic, in terms of completely or partially preventing a disease or its symptoms, e.g., reducing the likelihood that a disease or its symptoms will occur in a subject, and / or therapeutic, in terms of completely or partially reducing symptoms or partially or completely curing a disease and / or adverse effects caused by a disease. As used herein, "treatment" encompasses any treatment of a disease in a mammal, including (a) preventing a disease from occurring in a subject who may be susceptible to, but has not yet been diagnosed with, a disease; (b) inhibiting or delaying the onset or progression of a disease; or (c) relieving a disease, e.g., causing a regression of a disease or a symptom associated with a disease. A therapeutic agent may be administered before, during, or after the onset of a disease. Treatment of an ongoing disease, in which treatment stabilizes or reduces undesirable clinical symptoms in a patient, may be of particular interest. In some embodiments, treatment is performed before complete loss of function in the affected tissue. In some embodiments, the subject treatment is administered during the symptomatic stage of the disease, and in some embodiments, after the symptomatic stage of the disease.

[0043] The terms "disease" and "disorder" may be used interchangeably to describe any affliction that affects a subject and that has one or more symptoms.

[0044] As used herein, the term "dose" refers to the amount of a therapeutic agent administered to a subject to achieve a therapeutic objective.

[0045] As used herein, the term "fixed dose" refers to a dose that is not individualized to a particular subject. A fixed dose may be applicable to a population of subjects having a range of body weights.

[0046] 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 as, a lower concentration than, or a higher concentration than the fixed unit dose. In some embodiments, the loading dose is administered before the start of a treatment comprising periodic administration of a fixed unit dose. In some embodiments, the loading dose is administered simultaneously with the start of a treatment comprising periodic administration of a fixed unit dose.

[0047] 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., cows, sheep, pigs, horses, goats, etc.). In some embodiments, the subject is a human. In some embodiments, the subject is a non-human primate, e.g., a cynomolgus monkey. In some embodiments, the subject is a companion animal (e.g., a cat, a dog).

[0048] II.ActRII antibody The present disclosure provides compositions and methods for subcutaneous administration of an ActRII antibody in a fixed unit dose that can be used to treat a range of diseases, the fixed unit dose being administered to subjects having a range of body weights. In exemplary embodiments, the ActRII antibody fixed unit dose comprises about 25 mg to about 600 mg of subcutaneously administered ActRII antibody. In some exemplary embodiments, the ActRII antibody fixed unit dose comprises 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 periodic administration of ActRII antibody fixed unit doses may be used to treat diseases, including, but not limited to, metabolic diseases, muscle-wasting diseases, cardiac diseases, and liver diseases.

[0049] The fixed unit doses provided herein include ActRII antibodies that bind to the activin receptors ActRIIA and / or ActRIIB. Administration of ActRII antibodies has previously been shown in clinical trials to not only increase lean muscle mass, but also reduce body fat mass and improve glycemic control (International Publication Nos. 2010125003(A1), 2018116201(A1), and 2021044287(A1), the contents of which are incorporated in their entirety; Heymsfield et al. 2021;4(1):e2033457, JAMA).

[0050] Exemplary Antibodies In some embodiments, an exemplary antibody of the disclosure comprises the sequence of bimagrumab (BYM338). The following table provides the amino acid sequences of the relevant complementary determining regions (CDRs), variable heavy chain (VH), variable light chain (VL), heavy chain (HC), and light chain (LC) of bimagrumab. In some embodiments, an exemplary antibody of the disclosure comprises a sequence related to bimagrumab (BYM338).

[0051] [Table 1]

[0052] 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).

[0053] In some embodiments, an exemplary ActRII antibody of the present disclosure comprises 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).

[0054] In some embodiments, an exemplary ActRII antibody of the present disclosure comprises 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).

[0055] 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.

[0056] 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.

[0057] 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 of 10-20 pM.

[0058] In some embodiments, the ActRII antibody binds to ActRIIB with an affinity that is 5-fold higher, more preferably 10-fold, even more preferably 50-fold, and even more preferably 100-fold higher than to ActRIIA. In some embodiments, the ActRII antibody binds to ActRIIA with an affinity of greater than 100 pM (i.e., greater than 250 pM, 500 pM, 1 nM, 5 nM).

[0059] In some embodiments, ActRII antibodies of the present disclosure comprise one or more CDRs of SEQ ID NOs: 11-75, as provided in WO 2017156488, the entire contents of which are incorporated herein by reference. Note that the CDR sequences of SEQ ID NOs: 11-75 comprise combinations of the six CDRs described in WO 2017156488, and the ActRII antibody may be any of the A-series through H-series antibodies, for example, as provided in Table 1 of WO 2017156488.

[0060] In some embodiments, an ActRII antibody of the present disclosure comprises one or more CDRs of SEQ ID NOs: 76-81, as provided in WO2012064771, the entire contents of which are incorporated herein by reference. Note that the six CDR sequences of SEQ ID NOs: 76-81 correspond to the CDR sequences of SEQ ID NOs: 4-9, respectively, of WO2012064771, and the antibody is Ab-14E1.

[0061] In some embodiments, an ActRII antibody of the present disclosure comprises one or more CDRs of SEQ ID NOs: 82-5049, as provided in WO 2018183376, the entire contents of which are incorporated herein by reference. Note that the CDR sequences of SEQ ID NOs: 82-5049 comprise a combination of the six CDRs described in WO 2018183376, and the antibody is any of the ActRII antibodies of series A through H, as provided in WO 2018183376, e.g., in Tables 3A-3F.

[0062] III. ActRII Antibody Fixed Unit Dose The compositions and methods provided herein include ActRII antibody fixed unit doses configured to be administered subcutaneously. In exemplary embodiments, the ActRII antibody fixed unit doses of the present disclosure comprise about 25 mg to about 600 mg of ActRII antibody per fixed unit dose. In some exemplary embodiments, the ActRII antibody fixed unit doses of the present disclosure comprise about 100 mg to about 400 mg of ActRII antibody per fixed unit dose. In some exemplary embodiments, the ActRII antibody fixed unit doses comprise about 300 mg of ActRII antibody per fixed unit dose. In some exemplary embodiments, the ActRII antibody fixed unit doses comprise about 150 mg of ActRII antibody per fixed unit dose.

[0063] In other embodiments, the ActRII antibody fixed unit dose of the present disclosure comprises about 100 mg to about 400 mg of an ActRII antibody. In some embodiments, the ActRII antibody fixed unit dose of the present disclosure comprises about 100 mg to about 400 mg of an ActRII antibody administered subcutaneously weekly.

[0064] In exemplary embodiments, the ActRII antibody fixed unit dose comprises about 300 mg of ActRII antibody. In some exemplary embodiments, the composition comprises a fixed unit dose of about 300 mg of ActRII antibody administered subcutaneously weekly.

[0065] In exemplary embodiments, the ActRII antibody fixed unit dose comprises about 150 mg of ActRII antibody. In some exemplary embodiments, the composition comprises a fixed unit dose of about 150 mg of ActRII antibody administered subcutaneously weekly.

[0066] In some embodiments, the ActRII antibody may be present in the 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, the ActRII antibody is present at about 100 mg to about 400 mg per fixed unit dose. In exemplary embodiments, the ActRII antibody is present at about 300 mg per fixed unit dose. In other exemplary embodiments, the ActRII antibody is present at about 150 mg per fixed unit dose.

[0067] 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.

[0068] In some embodiments, an 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, an ActRII antibody fixed unit dose comprises a volume of about 1 mL. In some embodiments, an ActRII antibody fixed unit dose comprises a volume of about 2 mL. In some embodiments, an ActRII antibody fixed unit dose comprises any of the aforementioned concentrations in any of the aforementioned volumes.

[0069] In some embodiments, the ActRII antibody fixed unit dose is periodically administered to a subject having a body weight of 200 kg or less. In some embodiments, the ActRII antibody fixed unit dose is periodically administered to a subject having a body weight of 300 kg or less. In some embodiments, the ActRII antibody fixed unit dose is periodically administered as two fixed unit doses to a subject having a body weight of 200 kg or more. In some embodiments, the ActRII antibody fixed unit dose is periodically administered as two fixed unit doses to a subject having a body weight of 300 kg or more. In some embodiments, the number of ActRII antibody fixed unit doses periodically administered increases incrementally with the body weight of the subject. In some embodiments, the number of fixed unit doses increases about every 50 kg, about every 75 kg, about every 100 kg, about every 150 kg, about every 200 kg, or about every 300 kg of the subject's body weight.

[0070] In some embodiments, the ActRII antibody fixed unit dose is periodically administered to the subject daily, about 6 times per week, about 5 times per week, about 4 times per week, about 3 times per week, about 2 times per week, about once per week, or about once per 2 weeks. In some embodiments, the ActRII antibody fixed unit dose is periodically administered to the subject about every 3 weeks, about every 4 weeks, about every 5 weeks, about every 6 weeks, about every 7 weeks, or about every 8 weeks. In an exemplary embodiment, the ActRII antibody fixed unit dose is periodically administered to the subject about once per week.

[0071] In some embodiments, the ActRII antibody fixed unit dose is administered to a subject for about 1 month, about 2 months, about 3 months, about 6 months, about 1 year, about 2 years, about 5 years, or indefinitely.

[0072] loading dose 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 a desired serum concentration of the ActRII fixed unit dose treatment. Thus, some embodiments are provided herein that include one or more loading doses.

[0073] The loading dose may be administered by any route of administration, including but not limited to subcutaneous administration or intravenous administration, without subsequent subcutaneous administration of a fixed unit dose.

[0074] 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 the ActRII antibody fixed unit dose. 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 the ActRII antibody fixed unit dose. In some embodiments, one or more loading doses of an ActRII antibody are administered on the same day or within 24 hours of the ActRII antibody fixed unit dose. In some embodiments, one loading dose is administered. In some embodiments, two loading doses are administered. In some embodiments, three loading doses are administered.

[0075] In some embodiments, the loading dose may be administered intravenously at a concentration of about 3 mg / kg to about 50 mg / kg of subject body weight, and all amounts therebetween. In some embodiments, the ActRII antibody loading dose is administered intravenously at about 30 mg / kg of subject body weight. In some embodiments, the ActRII antibody loading dose is administered intravenously at about 10 mg / kg of subject body weight.

[0076] 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 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.

[0077] 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 in a fixed unit dose of about 300 mg. In some embodiments, the ActRII antibody loading dose is administered subcutaneously in a fixed unit dose of about 150 mg.

[0078] In some embodiments, the ActRII antibody loading dose is administered subcutaneously. In some embodiments, the ActRII antibody loading dose is administered intravenously.

[0079] In some embodiments, one or more ActRII antibody loading doses are administered intravenously prior to administration of an ActRII antibody fixed unit dose of the disclosure.

[0080] In some embodiments, one or more ActRII antibody loading doses are administered subcutaneously prior to administration of an ActRII antibody fixed unit dose of the disclosure.

[0081] device 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 within an autoinjector or other mechanical injection device. In some embodiments, such ActRII antibody fixed unit doses are administered via a needle or syringe.

[0082] In some embodiments, such ActRII antibody fixed unit doses are administered to subjects having a range of body weights via an auto-injector or other mechanical injection device. In some embodiments, the ActRII antibody fixed unit doses are designed to be self-administered via an auto-injector or other mechanical injection device.

[0083] In some embodiments, the ActRII antibody fixed unit dose is designed to be administered via a needle or syringe to subjects having a range of body weights. In some embodiments, the ActRII antibody fixed unit dose is designed to be self-administered via a needle or syringe.

[0084] In an exemplary embodiment, a composition comprising a fixed unit dose of about 300 mg of an ActRII antibody is designed to be administered subcutaneously weekly via an auto-injector or other mechanical injection device.

[0085] In an exemplary embodiment, a composition comprising a fixed unit dose of about 300 mg of an ActRII antibody is designed to be administered subcutaneously weekly via needle or syringe.

[0086] In another exemplary embodiment, a composition comprising a fixed unit dose of about 150 mg of an ActRII antibody is designed to be administered subcutaneously weekly via an autoinjector or other mechanical injection device.

[0087] In an exemplary embodiment, a composition comprising a fixed unit dose of about 150 mg of an ActRII antibody is designed to be administered subcutaneously weekly via needle or syringe.

[0088] Subjects and Treatment Provided herein is a method for treating a disease in a subject in need thereof, comprising subcutaneously administering a fixed unit dose of an ActRII antibody to the subject, wherein the fixed unit dose is administered to subjects having a range of body weights. The ActRII antibody fixed unit dose as part of the treatment provided herein may be used to treat diseases including, but not limited to, metabolic diseases, muscle wasting diseases, age-related muscle degeneration, heart diseases, and liver diseases.

[0089] In exemplary embodiments, therapies provided herein comprising an ActRII antibody in a fixed unit dose of about 25 mg to about 600 mg are useful for treating metabolic diseases, muscle-wasting diseases, age-related muscle degeneration, cardiac diseases, and liver diseases. In some exemplary embodiments, therapies provided herein comprising an ActRII antibody in a fixed unit dose of about 100 mg to about 400 mg are useful for treating metabolic diseases, muscle-wasting diseases, age-related muscle degeneration, cardiac diseases, and liver diseases. In some exemplary embodiments, therapies provided herein comprising an ActRII antibody in a fixed unit dose of about 300 mg are useful for treating metabolic diseases, muscle-wasting diseases, age-related muscle degeneration, cardiac diseases, and liver diseases. In other exemplary embodiments, therapies provided herein comprising an ActRII antibody in a fixed unit dose of about 150 mg are useful for treating metabolic diseases, muscle-wasting diseases, age-related muscle degeneration, cardiac diseases, and liver diseases.

[0090] In some embodiments, the treatments provided herein comprising a fixed unit dose of an ActRII antibody may be used to treat cardiac diseases, 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.

[0091] In some embodiments, the treatments provided herein comprising a fixed unit dose of an ActRII antibody may be used to treat liver diseases, including but not limited to non-alcoholic fatty liver disease, e.g., non-alcoholic steatohepatitis.

[0092] In some embodiments, the treatments provided herein comprising a fixed unit dose of an ActRII antibody may 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 obesity-related complex and single-gene disorders. Monogenic obesity disorders in humans can include, but are not limited to, Bardet-Biedl syndrome and disorders resulting 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 combinations thereof. Metabolic disorders can also be associated with complex genetic disorders, such as Prader-Willi syndrome.

[0093] In exemplary embodiments, therapies provided herein comprising an ActRII antibody in a fixed unit dose of about 25 mg to about 600 mg are useful for treating obesity. In exemplary embodiments, therapies provided herein comprising an ActRII antibody in a fixed unit dose of about 100 mg to about 400 mg are useful for treating obesity. In some exemplary embodiments, therapies provided herein comprising an ActRII antibody in a fixed unit dose of about 300 mg are useful for treating obesity. In other exemplary embodiments, therapies provided herein comprising an ActRII antibody in a fixed unit dose of about 150 mg are useful for treating obesity.

[0094] In some embodiments, treatments comprising a fixed unit dose of an ActRII antibody may be used to treat obesity-related disorders, including, but not limited to, glucose intolerance, prediabetes, type II diabetes, insulin resistance, high triglycerides, overweight-related physical disorders, osteoporosis, kidney disease, obstructive sleep apnea, sex hormone disorders, endocrine reproductive disorders, osteoarthritis, gastrointestinal cancer, dyslipidemia, hypertension, heart failure, coronary heart disease, stroke, and / or cholelithiasis.

[0095] The treatment comprising the ActRII antibody fixed unit dose can be used to treat overweight subjects.In some embodiments, the subject has a BMI of 30 or more.In some embodiments, the subject has a BMI of 27 or more.In some embodiments, the subject has a BMI of 27 or more and has obesity-related disorders.

[0096] Treatments comprising fixed unit doses of an ActRII antibody of the present disclosure may be used to treat subjects with lack of glycemic control.

[0097] Treatment can be administered to subjects of any age, including those under the age of 18. In some embodiments, the subject may be over 18, over 30, or over 40 years old. In some embodiments, the subject may be over 50, over 60, or over 80 years old.

[0098] In some embodiments, a treatment comprising a fixed unit dose of an ActRII antibody reduces body fat mass in a subject. In some embodiments, the fixed unit dose of an ActRII antibody reduces body fat mass in a subject by at least 5% (e.g., 5% to 30%) over the treatment period.

[0099] In some embodiments, treatment comprising an ActRII antibody fixed unit dose increases lean body mass in a subject. In some embodiments, the fixed unit dose increases the subject's lean body mass by at least 1% (e.g., 1% to 10%) over the treatment period.

[0100] In some embodiments, treatment comprising a fixed unit dose of an ActRII antibody reduces body fat mass and increases lean body mass in a subject. In some embodiments, the fixed unit dose of an ActRII antibody reduces body fat mass by at least 5% (e.g., 5% to 30%) and increases lean body mass by at least 1% (e.g., 1% to 10%) in a subject over the treatment period.

[0101] In some embodiments, treatment comprising a fixed unit dose of an ActRII antibody reduces body fat mass and maintains lean body mass in a subject. In some embodiments, the fixed unit dose of an ActRII antibody reduces body fat mass by at least 5% (e.g., 5% to 30%) and maintains lean body mass in a subject over the treatment period.

[0102] In some embodiments, a treatment comprising an ActRII fixed unit dose reduces body weight in a subject, hi some embodiments, an ActRII antibody fixed unit dose reduces body weight in a 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.

[0103] In some embodiments, a treatment comprising an ActRII fixed unit dose reduces central adiposity in a subject. In some embodiments, an ActRII antibody fixed unit dose reduces central adiposity in a subject by at least 2% (e.g., 2% to 20%) over the treatment period.

[0104] In some embodiments, a treatment comprising an ActRII fixed unit dose reduces liver fat and / or non-hepatic visceral fat in a subject. In some embodiments, an ActRII antibody fixed unit dose reduces central fat accumulation in a subject by at least 2% (e.g., 2% to 20%) over the treatment period as assessed by magnetic resonance imaging (MRI).

[0105] In some embodiments, body fat mass in response to an ActRII fixed unit dose is measured using bioelectrical impedance analysis (BIA), dual X-ray absorptiometry (DXA), magnetic resonance imaging (MRI), and / or waist circumference.

[0106] In some embodiments, the treatment comprising an ActRII fixed unit dose improves glycemic control in a subject.

[0107] In some embodiments, glycemic control in response to a fixed unit dose of ActRII is measured by glucose and insulin levels and applies the HOMA2 model (www.dtu.ox.ac.uk / homacalculator / ).

[0108] In some embodiments, the effectiveness of treatment may be determined by measuring the "Ctrough" or minimum serum concentration of an ActRII antibody in a subject. In some embodiments, the effectiveness of treatment is assessed as a serum concentration that is about 500%, about 400%, about 300%, about 200%, about 100%, about 90%, about 80%, or about 75% of the desired "Ctrough." In some embodiments, the desired "Ctrough" is about 1 μg / mL to about 10 μg / mL. In some embodiments, the desired "Ctrough" is about 3 μg / mL to about 30 μg / mL. In some embodiments, the desired "Ctrough" 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.

[0109] In some embodiments, the effectiveness of the ActRII fixed unit dose is determined by an improvement of about 100%, about 90%, about 80%, about 75%, about 50%, or about 25% in at least one of the following measurements: Body weight, bioelectrical impedance analysis (BIA) measurements of lean body mass and / or fat mass, waist-to-hip ratio, waist-to-height ratio, dual x-ray absorptiometry (DXA) measurements of lean body mass and / or fat mass, magnetic resonance imaging (MRI) measurements of lean body mass and / or fat mass, waist circumference, BMI reduction, blood lipid profile, leptin, lectin, adiponectin, and adipsin levels, IL-8 and / or IL-6 levels; urinary biomarkers, hemoglobin A1c (HgbA1c) levels, hand dynamism measurements indicating muscle strength, glucose levels, insulin levels; short physical performance battery (SPPB), assessment of the impact of weight on quality of life (IWQoL-Lite for CT), assessment of the Short Form(36) Health Survey (SF-36), homeostasis model assessment 2 (HOMA2), and physical activity monitoring by actigraphy.

[0110] Combination therapy In some embodiments, the ActRII antibody pharmaceutical composition is administered as part of a combination therapy with an incretin agonist or another hormone agonist, which may be administered as part of the same or a separate formulation as the ActRII antibody, and may be administered at the same time or at a different time than the ActRII antibody.

[0111] Incretin agonists suitable for combination therapy with ActRII antibodies include, but are not limited to, exenatide, sustained-release exenatide, dulaglutide, liraglutide, lixisenatide, semaglutide, tirazepatide, cotadutide, neuiglutide, oxyntomodulin (e.g., mazudutide), retatortide, albiglutide, veinaglutide, PEG-pegloxenatide, pembidutide, and danugliplon (as described in WO 2023 / 028606, the entire contents of which are incorporated herein by reference).Other hormone agonists suitable for combination therapy with ActRII antibodies include, but are not limited to, long-acting amylin receptor agonists, such as caglilintide, dual amylin-calcitonin receptor agonist (DACRA), and peptide YY agonists.

[0112] In some embodiments, the incretin agonist or other hormone agonist 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 onwards. In some embodiments, the incretin agonist or other hormone agonist is administered weekly at a dose of about 5.0 mg, about 10 mg, or about 15 mg.

[0113] In some embodiments, both the ActRII antibody and the incretin agonist or other hormone agonist are administered subcutaneously according to any of the doses described above.

[0114] In some embodiments, the ActRII antibody is administered prior to the incretin agonist or other hormone agonist, ie, 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 before administration of the incretin agonist or other hormone agonist.

[0115] In some embodiments, the incretin agonist or other hormone agonist is administered before the ActRII antibody, hi 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 before the ActRII antibody.

[0116] In some embodiments, the ActRII antibody and the incretin agonist or other hormone agonist are administered without regard to the order of administration.

[0117] In some embodiments, the ActRII antibody and the incretin agonist or other hormone agonist are administered essentially simultaneously, hi some embodiments, the ActRII antibody and the incretin agonist or other hormone agonist are administered in the same formulation.

[0118] IV. Pharmaceutical Compositions The compositions provided herein containing fixed unit doses of ActRII antibodies are configured for subcutaneous administration. In an exemplary embodiment, the compositions are formulated as pharmaceutical compositions containing ActRII antibodies containing 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 comprising 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.

[0119] In some embodiments, the pharmaceutical composition includes an excipient or carrier, such as an aqueous carrier. Various aqueous carriers, such as buffered saline, can be used. The pharmaceutical composition may contain pharmaceutically acceptable auxiliary substances necessary to approximate physiological conditions, such as pH and buffering agents, toxicity control agents, e.g., disodium phosphate dihydrate, monosodium 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 active agent in these formulations can vary and is selected based on fluid volume, viscosity, and body weight according to the particular mode of administration selected and the patient's needs (e.g., Remington's Pharmaceutical Science (15th ed., 1980) and Goodman & Gillman, The Pharmacological Basis of Therapeutics (Hardman et al., eds., 1996)). Pharmaceutical compositions may contain pharmaceutically acceptable auxiliary substances, such as substances that contribute to the stability and activity of the pharmacologically active agent or agents, including, but not limited to, trehalose, sucrose, or other sugars, and polysorbate 20, polysorbate 60, polysorbate 80, or other emulsifiers or stabilizers.

[0120] Co-formulation In some embodiments, the ActRII antibody pharmaceutical composition is co-formulated with an incretin agonist or another hormone agonist. Incretin agonists suitable for co-formulation include, but are not limited to, exenatide, extended-release exenatide, dulaglutide, liraglutide, lixisenatide, semaglutide, tirazepatide, cotadutide, neuiglutide, oxyntomodulin (e.g., mazudutide), retatortide, albiglutide, veinaglutide, PEG-loxenatide, pembidutide, and danugliplon (as described in WO 2023 / 028606, the entire contents of which are incorporated herein by reference). In some embodiments, the incretin agonist is present in the pharmaceutical composition with the ActRII antibody at a dose of about 0.005 mg to about 3.0 mg. In some embodiments, the incretin agonist is present in the pharmaceutical composition with the ActRII antibody at a dose of about 0.05 mg to about 2.0 mg. In some embodiments, the incretin agonist is present in the pharmaceutical composition with the ActRII antibody at a dose of about 0.5 mg to about 1.0 mg. In some embodiments, the concentration of the incretin agonist may vary or increase over time during treatment.

[0121] 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.

[0122] 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 caglilintide, dual amylin calcitonin receptor agonist (DACRA), and peptide YY agonists. [Example]

[0123] Example 1: Clinical trial methodology to evaluate subcutaneous administration of ActRII antibodies The objective of this study was to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) effects of subcutaneous (sc) administration of bimagrumab, an ActRII antibody. The pharmacodynamic effects of interest in this study were fat mass and lean body mass.

[0124] Primary endpoint 1. To evaluate the safety and tolerability of different sc administrations of bimagrumab. 2. To determine the local tolerability of sc bimagrumab administration. 3. To evaluate the pharmacokinetics of different sc versus intravenous (iv) administration of bimagrumab.

[0125] Endpoints for the primary endpoint 1. Physical examination / weight 2. Vital Signs 3. ECG 4. Safety Testing Laboratory 5. Adverse events (AE) / serious adverse events (SAE) 6. Pain assessment using a visual analog scale (VAS) 7. Investigator assessment of tenderness, erythema / redness, and induration / swelling 8. PK (sampling of complete profile after first and last dose and before dose during treatment) 9. Basic PK parameters: Cmax, Tmax, Cmin, AUCtau, AUClast (after the last dose only), Racc

[0126] Secondary endpoints To determine the absolute bioavailability of bimagrumab given by sc administration.

[0127] Endpoints for secondary endpoints Because bimagrumab exhibited target-mediated drug disposition (TMDD), absolute bioavailability was determined by modeling, in which the drug binds to its pharmacological target with such high affinity that it influences its pharmacokinetic properties.

[0128] exploratory item Objective To investigate the pharmacodynamics and PK / PD relationships of different sc and iv administration regimens of bimagrumab.

[0129] Endpoints for exploratory items Pharmacokinetics (PK): Full PK profile after the first and last dose during treatment and before dosing, and trough samples before each dose. Pharmacodynamics: Lean body mass (LBM), including appendicular LBM, by dual-energy X-ray absorptiometry (DXA) before and during treatment and at the end of the follow-up period.

[0130] Study design This was an exploratory, randomized, placebo-controlled, multiple-dose study in elderly, healthy male and female subjects aged 70 years or older. The study was designed with a total of seven treatment arms receiving either active treatment or placebo in a parallel-group comparative design (see Figure 1).

[0131] This study was designed to combine evaluation of the safety / tolerability and pharmacokinetic and pharmacodynamic properties of multiple doses of bimagrumab given as different sc or iv regimens every 4 weeks, and as a more frequent weekly sc dosing regimen. The sc dosing every 4 weeks was administered using an infusion pump.

[0132] A total of 91 male or female elderly subjects with stable health and medication were enrolled and randomized in the study. Overall, demographic characteristics were generally balanced between the different dose groups (see Figures 2 and 3). The subjects' mean (SD) age 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 population involved was primarily Caucasian (89%) with a high proportion of Hispanic / Latino (28.6%). Of the 91 subjects enrolled, 49 were women.

[0133] treatment group Subjects were assigned to one of the following treatment groups: Intravenous infusion (Cohorts 1 and 2) 8 active + 2 placebo per cohort, n=20: 700 mg administered by iv infusion over 30 minutes every 4 weeks at weeks 0, 4, and 8. Total dose given over the study: 700 mg x 3 = 2100 mg 210 mg administered by iv infusion over 30 minutes every 4 weeks at weeks 0, 4, and 8. Total dose given over the study: 210 mg x 3 = 630 mg. High-volume and medium-volume sc (Cohorts 3 and 4) - 12 active + 2 placebo per cohort, n=28: 1500 mg (10 mL) administered by sc infusion over 30 minutes at weeks 0, 4, and 8 every 4 weeks. Total dose given over the study: 1500 mg x 3 = 4500 mg 525 mg (3.5 mL) administered by sc infusion over 10 minutes every 4 weeks at weeks 0, 4, and 8. Total dose given over the study: 525 mg x 3 = 1575 mg Low-volume sc (Cohorts 5, 6, and 7) 12 active + 2 placebo per cohort, n=43: 300 mg (2 mL) administered by sc injection (bolus) weekly until week 11. Total dose given over the study: 300 x 12 = 3600 mg 150 mg (1 mL) administered by sc injection (bolus) weekly until week 11. Total dose given over the study: 150 x 12 = 1800 mg 52.5 mg (0.35 mL) administered by sc injection (bolus) weekly until week 11. Total dose given over the study: 52.5 x 12 = 630 mg

[0134] Pharmacodynamic evaluation Dual-energy X-ray absorptiometry (DXA) was used to assess changes in body composition, including total lean body mass (LBM) and fat body mass (FBM), as well as appendicular skeletal mass index (ASMI). DXA machines use an X-ray source that generates and splits two wavelengths to measure bone mineral content and soft tissue, from which fat mass and lean body mass (or lean mass) are estimated.

[0135] Safety evaluation Safety assessments consisted of collecting all adverse events (AEs) and serious adverse events (SAEs). Regular monitoring of hematology, blood chemistry, and urine was performed at the Clinical Research Center, with regular assessments of vital signs, physical status, and weight, as well as ECG. Local tolerability assessments were also performed, and immunogenicity (IG) samples were collected.

[0136] Pharmacokinetic evaluation Pharmacokinetic (PK) samples were obtained and evaluated in all subjects at all dose levels using a validated bridging enzyme-linked immunosorbent assay (ELISA) method. The expected lower limit of quantification (LLOQ) was 0.176 μg / mL. The linear trapezoidal rule was used for AUC calculation. Because bimagrumab exhibits a nonlinear PK profile, also known as TMDD, the AUC inf The half-life (T1 / 2), clearance (CL), and volume of distribution (V) were obtained using noncompartmental analysis (NCA). The AUC obtained from the dosing interval after the first and last doses tau Using this value, the accumulation ratio (R acc ) to [(AUCtau, last dose) / (AUC tau , first dose). Because bimagrumab exhibits a nonlinear PK profile and CL is dependent on bimagrumab concentration, AUC cannot be used to estimate absolute bioavailability and dose proportionality. Therefore, a model-based approach was used to characterize the subcutaneous Bioavailability

[0137] Example 2: Pharmacokinetic results of a clinical trial to evaluate subcutaneous administration of ActRII antibodies Notably, the 300 mg subcutaneous bolus dose did not show detectable TMDD effects, indicating that with this administration method, the 300 mg dose was high enough to maintain saturation of clearance. As demonstrated in Figure 8, a 300 mg subcutaneous (sc) bolus dose of ActRII antibody is predicted to maintain serum concentrations above 10 μg / mL at relatively stable levels from about day 15 to about day 85. Similarly, a 150 mg subcutaneous bolus dose of ActRII antibody is predicted to maintain serum concentrations at approximately 10 μg / mL from about day 29 to about day 85.

[0138] Intravenous Cohorts 1 and 2 (iv infusion): As expected, TMDD was observed in the concentration-time profiles. Variability was moderate, with coefficients of variation (CV, range 17-47% CV) of approximately 30-40%. Accumulation ratios based on AUCtau were relatively low (range 1.15-1.37), but Cmin suggested that steady state may not have been reached over 3 months of administration. As expected with iv administration, peak-to-trough ratios were relatively large.

[0139] subcutaneous Cohorts 3 and 4 (sc infusion): Absorption of bimagrumab after sc infusion was relatively slow (Tmax approximately 1 week after administration). A TMDD profile was observed only at the low dose (525 mg) (Figure 7). Variability was moderate (range 29-39% CV). The accumulation ratio based on AUCtau was slightly higher than that after iv infusion (1.72-1.92), but it could also be observed from Cmin that steady state may not have been reached over 3 months of administration. The peak-to-trough ratio was moderate.

[0140] Cohorts 5, 6, and 7 (sc bolus): Absorption of bimagrumab after sc bolus was faster at lower doses after the first dose (Figure 8). The concentration-time profile was relatively flat after the final dose, with a low peak-to-trough ratio. The variability of PK parameters was relatively high, with CVs of approximately 50% for 300 mg and 150 mg and approximately 100% for 52.5 mg. The accumulation ratio based on AUCtau was much higher than in the iv and sc infusion groups. For most subjects, steady state based on Cmin was reached after nine weekly doses (day 57). Notably, TMDD profiles could be observed at lower doses (i.e., 52.5 mg and 150 mg) but not at 300 mg, demonstrating that concentrations were high enough to maintain saturation of clearance at the 300 mg subcutaneous bolus.

[0141] Example 3: Pharmacodynamic results of a clinical trial to evaluate subcutaneous administration of ActRII antibodies Administration via intravenous and subcutaneous routes (both bolus and infusion) showed similar effects on increasing lean body mass and decreasing fat mass.

[0142] LBM and limb LBM A dose-dependent plateau effect was observed at the end of each treatment period (day 85) with lean body mass gain of the order of 1.5–2 kg at the maximum dose (i.e., an increase of approximately 4–6% from baseline), regardless of whether bimagrumab was administered iv or sc (bolus and infusion).

[0143] FBM Regardless of whether bimagrumab was administered IV or SC (bolus and infusion), a dose-dependent linear reduction in total body fat mass of approximately 2-3 kg was observed at the end of each treatment period (day 85) at the highest dose. At the highest dose, this fat loss further increased to approximately 3-4 kg in the IV and SC infusion groups and was maintained in the highest-dose SC infusion group during the follow-up treatment period.

[0144] Example 4: Model prediction of subcutaneous administration of ActRII antibody A computational model of the effects of the ActRII antibody bimagrumab on PK and PD was developed based on the clinical trials described above (Examples 1-3). The model predicts full ActRII receptor occupancy (RO) with ActRII serum concentrations of approximately 10 μg / mL for the majority of subjects (FIG. 19).

[0145] The effect of the loading dose was modeled to predict the number of subjects across a range of weights with ActRII serum concentrations above an RO of 10 μg / mL and to predict the time required to reach this concentration.

[0146] Figure 20 shows the predicted time to reach various bimagrumab concentrations in a population of 2500 subjects, each weighing 100 kg, receiving 300 mg of bimagrumab subcutaneously weekly without a loading dose. The 5 μg / mL and 10 μg / mL threshold levels are shown on the graph and in the table below. Figure 21 shows the predicted time to reach various bimagrumab concentrations in a population of 2500 subjects weighing 60 to 140 kg.

[0147] Figure 22 shows predicted bimagrumab concentrations over time in a population of subjects weighing 50-200 kg receiving 300 mg of bimagrumab administered subcutaneously weekly without a loading dose on day 1. Figure 23 shows the predicted timing of change in total body fat mass in a population of subjects weighing 50-200 kg receiving 300 mg of bimagrumab administered subcutaneously weekly without a loading dose on day 1.

[0148] Figure 24 shows predicted bimagrumab concentrations over time in a population of subjects weighing 50-200 kg receiving 300 mg bimagrumab subcutaneously in two doses on day 1 (i.e., one loading dose) and 300 mg bimagrumab subcutaneously once weekly. Notably, the time to reach a median serum concentration of 10 μg / mL for all subjects decreased with loading dose on day 1. Figure 25 shows the timing of change in total body fat mass in a population of subjects weighing 50-200 kg receiving 300 mg bimagrumab subcutaneously in two doses on day 1 (i.e., one loading dose) and 300 mg bimagrumab subcutaneously once weekly.

[0149] Figure 26 shows bimagrumab concentrations over time in a population of subjects weighing 50-200 kg receiving 300 mg of bimagrumab administered subcutaneously in 3 doses on day 1 (i.e., 2 loading doses) and 300 mg of bimagrumab administered subcutaneously once weekly. Figure 27 shows the timing of change in total body fat mass in a population of subjects weighing 50-200 kg receiving 300 mg of bimagrumab administered subcutaneously in 3 doses on day 1 (i.e., 2 loading doses) and 300 mg of bimagrumab administered subcutaneously once weekly.

[0150] Figure 28 shows a comparison of the effect of loading dose (0, 1, or 2 loading doses) on bimagrumab exposure in a population of subjects weighing 100 kg receiving 300 mg of bimagrumab subcutaneously weekly. Figure 29 shows a comparison of the effect of loading dose (0, 1, or 2 loading doses) for a population of subjects weighing 100 kg receiving 300 mg of bimagrumab subcutaneously weekly.

[0151] Figures 30 and 31 show that increasing the bimagrumab dose to 600 mg has little effect on the timing of exposure.

[0152] Group modeling including individual differences The model described herein predicts that 300 mg administered subcutaneously weekly without a loading dose will be sufficient to achieve a serum concentration of at least 10 μg / mL for most subjects. However, when population-specific variability in response is considered, the concentration of bimagrumab required to have a maximal effect on fat mass and lean body mass in a population increases to approximately 10-30 μg / mL, as shown in Figure 32. As shown in Figure 33, in a model that accounts for population-specific variability in response, subjects with higher body weights will not reach 10 μg / mL with 300 mg administered subcutaneously weekly and will require a loading dose.

Claims

1. A pharmaceutical composition in fixed unit dose form comprising an ActRII antibody, said ActRII antibody being present in an amount of from about 25 mg to about 600 mg per fixed unit dose, said composition being adapted for subcutaneous administration.

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

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

4. 3. 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 to 4, wherein the ActRII antibody comprises the CDR amino acid sequences of SEQ ID NOs: 1 to 6.

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

12. 12. The pharmaceutical composition of any one of claims 1-11, 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.

13. 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. 13. The pharmaceutical composition of any one of claims 1 to 12, wherein the fixed unit dose has 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. 15. The pharmaceutical composition of claim 14, wherein the fixed unit dose is 1 mL in volume.

16. 15. The pharmaceutical composition of claim 14, wherein the fixed unit dose is 2 mL in volume.

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

18. 18. The pharmaceutical composition of claim 17, wherein the injector 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. 20. The pharmaceutical composition of claim 19, wherein the hormone agonist is an incretin agonist.

21. 21. The pharmaceutical composition of claim 20, wherein the incretin agonist is selected from the group consisting of exenatide, extended-release exenatide, dulaglutide, liraglutide, lixisenatide, semaglutide, tirzepatide, cotadutide, neuiglutide, oxyntomodulin, retatortide, albiglutide, veinaglutide, PEG-loxenatide, pembidutide, and danugliplon.

22. 20. 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 said subject a fixed unit dose of an ActRII antibody.

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

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

28. 28. The method of any one of claims 23-27, wherein the ActRII antibody fixed unit dose is administered to the subject daily, about 6 times per week, about 5 times per week, about 4 times per week, about 3 times per week, about twice per week, about once per week, about once per 2 weeks, about every 3 weeks, about every 4 weeks, about every 5 weeks, about every 6 weeks, about every 7 weeks, or about every 8 weeks.

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

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

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

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

34. 31. 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. 35. The method of claim 34, wherein the ActRII antibody loading dose is administered at a dose of about 210 mg.

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

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

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

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

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

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

43. 41. 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 before administration of the ActRII antibody fixed unit dose.

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

45. 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, craniopharyngioma-associated hypothalamic obesity, and obesity-associated single-gene disorders.

46. 46. ​​The method of claim 45, wherein the obesity-related monogenic disorder is one of Bardet-Biedl syndrome or obesity resulting from mutations in one or more of the genes including 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. 45. The method of claim 44, wherein the metabolic disease is Prader-Willi syndrome.

48. The method according to any one of claims 23 to 43, wherein the disease is a muscle wasting disease or sarcopenia.

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

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

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

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

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

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

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

56. 55. The method of any one of claims 23 to 54, wherein the subject weighs more than about 200 kg.

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

58. 57. 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 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.

59. 57. 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 having at least 80% sequence identity thereto, and the LC amino acid sequence of SEQ ID NO: 10, or a sequence having at least 80% sequence identity thereto.

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

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

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

64. 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. 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. 65. The method of any one of claims 23-64, wherein the fixed unit dose is 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 volume.

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

68. 67. The method of claim 66, wherein the fixed unit dose is 2 mL in volume.

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

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

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

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

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

74. 74. The method of claim 73, wherein the incretin agonist is selected from exenatide, extended-release exenatide, dulaglutide, liraglutide, lixisenatide, semaglutide, tirzepatide, cotadutide, neuiglutide, oxyntomodulin, retatortide, albiglutide, veinaglutide, PEG-loxenatide, pembidutide, and danugliplon.

75. 73. 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. 76. The method of any one of claims 72-75, wherein the hormone agonist is administered before the ActRII antibody.

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

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

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