Anti-activin A antibodies, compositions and uses thereof

Abstract

Provided herein are antibody agents that specifically bind to activin A, as well as compositions that include the activin A antibody agents, and methods of making and using them. The present disclosure provides novel high affinity activin A antibody agents. In particular, the agents provided can be used, for example, to bind to activin A and / or to reduce the activity and / or levels of free / active activin A in relevant systems (e.g., in vitro, in cells, in tissues, and / or in subjects).

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 257,067, filed October 18, 2021, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Activin A is a member of the transforming growth factor beta (TGFb) superfamily. Activin A can be expressed in various cells, and the expression of activin A can be upregulated in response to stimuli such as inflammation. Summary of the Invention [Means for solving the problem]

[0003] The present disclosure provides novel high-affinity activin A antibody agents. Among other things, the provided agents can be used, for example, to bind to activin A and / or to reduce the activity and / or levels of free / active activin A in relevant systems (e.g., in vitro, in cells, in tissues, and / or in a subject).

[0004] For example, in some embodiments, the present disclosure provides novel activin A antibody agents with improved binding kinetics, binding affinity, pharmacokinetics, and / or function. In some embodiments, the activin A antibody agents disclosed herein bind to activin A with high specificity. In some embodiments, the activin A antibody agents have a K of about 5 pM to about 1000 pM (e.g., about 6.17 pM to about 960 pM) when assessed, for example, in an assay that measures antibody binding affinity, e.g., a surface plasmon resonance assay (Biacore). DIn some embodiments, a provided activin A antibody agent may exhibit preferential binding to activin A relative to one or more TGF beta family members other than activin A. In some such embodiments, preferential binding may be assessed, for example, by contacting the activin A antibody agent with activin A and one or more other TGF beta family members simultaneously. Alternatively, or additionally, in some embodiments, preferential binding may be assessed in comparison to a suitable reference activin A antibody agent, and may reflect, for example, a higher level of binding to activin A relative to one or more other TGF beta family members than observed with the reference antibody.

[0005] In some embodiments, the activin A antibody agents disclosed herein inhibit the activity of activin A and / or reduce the level of activin A (e.g., the level of free and / or active activin A in a blood, plasma, serum and / or urine sample) when administered to a cell, tissue or subject.

[0006] In some embodiments, the activin A antibody agent can be used to prevent, reduce, treat, and / or reverse any one, all, and / or combination of cachexia, mass loss (e.g., muscle mass loss, lean mass loss, fat mass loss, and / or bone mass loss, and / or organ mass loss), weight loss (e.g., unintentional weight loss due to cachexia), aging, liver damage (e.g., fibrosis, cirrhosis, degeneration), kidney damage (e.g., fibrosis), or cancer, cancer metastasis, chemotherapy-induced toxicity (e.g., nephrotoxicity), chemotherapy resistance, and / or hypertension. In some embodiments, cachexia, mass loss (e.g., muscle mass loss, lean mass loss, fat mass loss, bone mass loss, and / or organ mass loss), weight loss (e.g., unintentional weight loss due to cachexia), aging, liver damage (e.g., fibrosis, degeneration, cirrhosis (e.g., alcoholic and / or non-alcoholic cirrhosis)), kidney damage (e.g., fibrosis), cancer, cancer metastasis, chemotherapy-induced toxicity (e.g., nephrotoxicity and / or hepatotoxicity), chemotherapy resistance, and / or hypertension are associated with increased actin A.

[0007] In some embodiments, the activin A antibody agents disclosed herein are useful in treating conditions or diseases associated with increased activin A, such as (i) disorders of the hypothalamic-pituitary-gonadal axis (e.g., associated with increased FSH levels); (ii) fibrodysplasia ossificans progressiva (FOP); (iii) pulmonary arterial hypertension and / or hypertension; (iv) anorexia-cachexia disorders associated with chronic diseases such as cancer, chronic kidney disease, chronic heart failure, COPD, elderly and muscle immobility, ICU patients (e.g., weight loss, decreased food intake, decreased fat mass, muscle wasting, loss of functional muscle mass and strength, bone loss, anemia, and / or fatigue); (v) anemia; (vi) metabolic diseases (e.g., obesity, type 2 diabetes, and / or metabolic syndrome). (vii) inflammatory diseases (e.g., inflammatory bowel disease, pancreatitis, allergic asthma, COVID, acute respiratory distress syndrome, atopic dermatitis, pre-eclampsia, acute liver injury, acute kidney injury, tubulointerstitial nephritis); (viii) autoimmune disorders (e.g., SLE or rheumatoid arthritis); (ix) fibrotic diseases (e.g., idiopathic pulmonary fibrosis, NASH, cirrhosis, chronic kidney disease, Alport syndrome, endometriosis); (x) cancer; (xi) cancer treatment-related toxicity (e.g., chemotherapy-induced nephrotoxicity and / or hepatotoxicity); (xii) aging (e.g., senescence); or (xiii) chemotherapy resistance, or a combination thereof. Among other things, the present disclosure provides compositions comprising new and improved activin A antibody agents, as well as methods of making and using the same.

[0008] In some embodiments, provided herein are antibody agents comprising a polypeptide that binds to activin A, the polypeptide comprising at least one light chain complementarity determining region (LC CDR) and / or at least one heavy chain complementarity determining region (HC CDR).

[0009] In some embodiments, the antibody agent is or comprises: (i) an intact IgA, IgG, IgD, IgE, or IgM antibody; (ii) an antibody fragment; (iii) a single domain antibody; (iv) a single chain Fv; or (v) a polypeptide comprising an antigen-binding domain specifically fused to an Fc domain.

[0010] In some embodiments, the antibody agent has a binding affinity (K D ), e.g., in a Fab format, binds to human activin A. In some embodiments, the binding affinity is determined by a binding affinity determination assay, such as a surface plasmon resonance assay, an octet assay, or an equivalent assay.

[0011] In some embodiments, the antibody agent comprises one, two, or three LC CDRs, e.g., LC CDR1, LC CDR2, and / or LC CDR3 of any one of clones A-R, e.g., as provided in Table 1. In some embodiments, the antibody agent comprising LC CDR1, LC CDR2, and / or LC CDR3 can specifically bind to activin A.

[0012] In some embodiments, the antibody agent comprises (i) the LC CDR1, LC CDR2, and LC CDR3 sequences provided in Table 1, (ii) a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity to the LC CDR1, LC CDR2, and LC CDR3 sequences provided in Table 1, or (iii) a sequence having at least 5, 10, or 20 substitutions to the LC CDR1, LC CDR2, and LC CDR3 sequences provided in Table 1.

[0013] In some embodiments, the antibody agent comprises (i) an LC CDR1 provided in Table 1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto, (ii) an LC CDR2 provided in Table 1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto, and / or (iii) an LC CDR3 provided in Table 1. CDR3 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to the LC CDR3 provided in Table 1.

[0014] In some embodiments, an antibody agent comprises one, two, or three HC CDRs, e.g., HC CDR1, HC CDR2, and / or HC CDR3 of any one of clones A-R, e.g., as provided in Table 2. In some embodiments, an antibody agent comprising HC CDR1, HC CDR2, and / or HC CDR3 can specifically bind to activin A.

[0015] In some embodiments, the antibody agent comprises (i) the HC CDR1, HC CDR2, and HC CDR3 sequences provided in Table 1, (ii) a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the HC CDR1, HC CDR2, and HC CDR3 sequences provided in Table 1, or (iii) a sequence having at least 5, 10, or 20 substitutions to the HC CDR1, HC CDR2, and HC CDR3 sequences provided in Table 1.

[0016] In some embodiments, the antibody agent comprises (i) an HC CDR1 provided in Table 2, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; (ii) an HC CDR2 provided in Table 2, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; and / or (iii) an HC CDR3 provided in Table 2. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to a HC CDR3 provided in Table 2.

[0017] In some embodiments, an antibody agent comprises one, two, or three LC CDRs (e.g., LC CDR1, LC CDR2, and / or LC CDR3 of any one of clones A-R, e.g., as provided in Table 1) and one, two, or three HC CDRs (e.g., HC CDR1, HC CDR2, and / or HC CDR3 of any one of clones A-R, e.g., as provided in Table 2). In some embodiments, an antibody agent comprising LC CDR1, LC CDR2, and / or LC CDR3 and HC CDR1, HC CDR2, and / or HC CDR3 can specifically bind to activin A.

[0018] In some embodiments, the antibody agent comprises one, two, or three LC CDRs provided in Table 1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, and one, two, or three HC CDRs provided in Table 2, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto.

[0019] In some embodiments, the antibody agent comprises (a) (i) a LC CDR1 provided in Table 1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto, (ii) a LC CDR2 provided in Table 1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto, and / or (iii) a LC CDR3 provided in Table 1. a light chain comprising (i) an HC CDR1 provided in Table 2 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; and (b) (i) an HC CDR1 provided in Table 2 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; and / or (iii) a heavy chain comprising an HC CDR2 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to an HC CDR2 provided in Table 2; and / or (iv) an HC CDR3 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to an HC CDR3 provided in Table 2.

[0020] In some embodiments, an antibody agent comprising a light chain comprising a variable region (VL) comprising at least one LC CDR provided in Table 1 comprises at least one framework region (FR) provided in Table 1, or a sequence having at least 92% identity thereto. In some embodiments, an antibody agent comprising a VL comprises, for example, one, two, three, or four FR regions as provided in Table 1, or a sequence having at least 92% identity thereto.

[0021] In some embodiments, the antibody agent comprising a light chain comprising a variable region (VL) is selected from the group consisting of: (i) the sequence of SEQ ID NO: 8, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; (ii) the sequence of SEQ ID NO: 13, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto; 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 13; (iii) a sequence of SEQ ID NO: 18, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 18; (iv) a sequence of SEQ ID NO: 22, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; , 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions to SEQ ID NO: 22; (v) a sequence of SEQ ID NO: 33 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto. (vi) the sequence of SEQ ID NO: 37 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 37; (vii) the sequence of SEQ ID NO: 45 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto;or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 45; (viii) a sequence of SEQ ID NO: 50 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 50; (ix) a sequence of SEQ ID NO: 58 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto; (x) a sequence of SEQ ID NO: 65 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto or a sequence having at least 5, 10, or 20 substitutions thereto; (xi) a sequence of SEQ ID NO: 74 or a sequence having at least 85% identity thereto; (xii) a sequence having 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 74; (xiii) a sequence of SEQ ID NO: 82, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 82. (xiii) the sequence of SEQ ID NO: 90 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 90; (xiv) the sequence of SEQ ID NO: 99 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto;or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 99.

[0022] In some embodiments, an antibody agent comprising a heavy chain comprising a variable region (VH) comprising at least two HC CDRs provided in Table 2 comprises at least one framework region (FR) provided in Table 2, or a sequence having at least 92% identity thereto. In some embodiments, an antibody agent comprising a VH comprises, for example, one, two, three, or four FR regions as provided in Table 2, or a sequence having at least 92% identity thereto.

[0023] In some embodiments, the antibody agent comprising a VH is selected from the group consisting of: (i) a sequence of SEQ ID NO: 110, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; (ii) a sequence of SEQ ID NO: 117, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto; (iii) a sequence of SEQ ID NO: 122 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto or a sequence having at least 5, 10, or 20 substitutions thereto; (iv) a sequence of SEQ ID NO: 126 or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto or a sequence having at least 5, 10, or 20 substitutions thereto; , 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 126; (v) a sequence of SEQ ID NO: 131 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 131; (vi) the sequence of SEQ ID NO: 137, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 137; (vii) the sequence of SEQ ID NO: 142, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto;or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 142; (viii) a sequence of SEQ ID NO: 146 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 146; (ix) a sequence of SEQ ID NO: 154 or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92% identity thereto; (x) a sequence of SEQ ID NO: 160 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto or a sequence having at least 5, 10, or 20 substitutions thereto; (xi) a sequence of SEQ ID NO: 166 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto or a sequence having at least 5, 10, or 20 substitutions thereto; (xii) a sequence of SEQ ID NO: 176 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions to SEQ ID NO: 176; or 20 substitutions; (xiii) a sequence of SEQ ID NO: 183 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 183; (xiv) a sequence of SEQ ID NO: 187 or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% identity thereto;or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with SEQ ID NO: 187; (xv) the sequence of SEQ ID NO: 193, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with SEQ ID NO: 193; (xvi) the sequence of SEQ ID NO: 199, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with SEQ ID NO: 199. (xvii) the sequence of SEQ ID NO: 206 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 206; or (xviii) the sequence of SEQ ID NO: 211 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 211.

[0024] In some embodiments, the antibody agent comprises a VL polypeptide and a VH polypeptide. In some embodiments, the antibody agent comprises (i) a sequence of SEQ ID NO: 8, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto, and a sequence of SEQ ID NO: 110, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto. %, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions to SEQ ID NO: 110; (ii) a sequence of SEQ ID NO: 13, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto, and a sequence of SEQ ID NO: 117, or at least 85%, 86%, (iii) a sequence having 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions to SEQ ID NO: 117; (iv) a sequence having 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions to SEQ ID NO: 18; (iv) a sequence of SEQ ID NO: 22 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; (iv) a sequence of SEQ ID NO: 22 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% identity thereto;or 99% identical thereto, or a sequence having at least 5, 10, or 20 substitutions to SEQ ID NO: 22, and the sequence of SEQ ID NO: 126, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto, or a sequence having at least 5, 10, or 20 substitutions to SEQ ID NO: 126; (v) the sequence of SEQ ID NO: 8, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto, or a sequence having at least 5, 10, or 20 substitutions to SEQ ID NO: 126; a sequence having 0%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 8, and a sequence of SEQ ID NO: 131, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 131; (vi) a sequence of SEQ ID NO: 33; or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions to SEQ ID NO: 33, and the sequence of SEQ ID NO: 137, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions to SEQ ID NO: 137. (vii) a sequence of SEQ ID NO: 37 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 37, and a sequence of SEQ ID NO: 142 or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% identity thereto,or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions to SEQ ID NO: 142, (viii) a sequence of SEQ ID NO: 37, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto, and a sequence of SEQ ID NO: 146, or at least 85%, 86%, 87%, 88%, 89% identity thereto. , 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 146, (ix) a sequence of SEQ ID NO: 45 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 45, and a sequence of SEQ ID NO: 154. (x) the sequence of SEQ ID NO: 50 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 154; (x) the sequence of SEQ ID NO: 50 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 50; (xi) a sequence of SEQ ID NO: 58 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; (xi) a sequence of SEQ ID NO: 58 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto,or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions to SEQ ID NO: 58, and the sequence of SEQ ID NO: 166, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto, (xii) a sequence of SEQ ID NO: 65, or at least 85%, 86%, 87%, 88%, 89% identity thereto, a sequence having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto or at least 5, 10, or 20 substitutions to SEQ ID NO: 65, and a sequence of SEQ ID NO: 176 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto or at least 5, 10, or 20 substitutions thereto; (xiii) a sequence of SEQ ID NO: 74 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions to SEQ ID NO: 74, and the sequence of SEQ ID NO: 183, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions to SEQ ID NO: 183. (xiv) a sequence of SEQ ID NO: 74 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 74, and a sequence of SEQ ID NO: 187 or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% identity thereto,or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions to SEQ ID NO: 187, (xv) a sequence of SEQ ID NO: 82, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions to SEQ ID NO: 82, and a sequence of SEQ ID NO: 193, or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto. 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 193, (xvi) a sequence of SEQ ID NO: 90 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 90, and a sequence of SEQ ID NO: 199, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 199; (xvii) a sequence of SEQ ID NO: 99 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 99; a sequence having 5, 10, or 20 substitutions, and a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the sequence of SEQ ID NO: 206 or a sequence having at least 5, 10, or 20 substitutions to SEQ ID NO: 206; or (xviii) a sequence of SEQ ID NO: 99 or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% identity to the sequence of SEQ ID NO: 206,Sequences having 98% or 99% identity or at least 5, 10 or 20 substitutions to SEQ ID NO: 99, and sequences of SEQ ID NO: 211 or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% thereto, or a sequence having 99% identity or at least 5, 10, or 20 substitutions relative to SEQ ID NO: 211.

[0025] In some embodiments, an antibody agent comprising a VH comprises the sequence of at least one constant region (CH). In some embodiments, the at least one constant region comprises an Fc domain. In some embodiments, the Fc domain comprises a mammalian Fc domain, e.g., a mouse, rat, rabbit, primate, human, or livestock Fc domain (e.g., a dog, cat, bovine, or horse Fc domain). In some embodiments, the Fc domain is selected from the Fc domains of immunoglobulin isotypes. In some embodiments, the immunoglobulin isotype comprises IgA, IgG, IgM, or IgE.

[0026] In some embodiments, the antibody agent comprises (i) a light chain (LC) comprising: (a) one, two, or three LC CDRs provided in Table 1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto; (b) at least one FR provided in Table 1, or a sequence having at least 92% identity thereto; (c) a constant region (CL); and (ii) a light chain (LC) comprising: (a) one, two, or three LC CDRs provided in Table 2, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto; (b) at least one CDR, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto; (b) at least one FR provided in Table 1, or a sequence having at least 92% identity thereto; and (c) a heavy chain (HC) comprising at least one constant region.

[0027] In some embodiments, the antibody agent comprises: (i) a sequence of SEQ ID NO: 9, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto, and a sequence of SEQ ID NO: 111, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto; (ii) a sequence of SEQ ID NO: 14 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto or a sequence having at least 5, 10, or 20 substitutions thereto and a sequence of SEQ ID NO: 118 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto or a sequence having at least 5, 10, or 20 substitutions thereto and a sequence of SEQ ID NO: 119 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto or a sequence having at least 5, 10, or 20 substitutions thereto and a sequence of SEQ ID NO: 120 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto or a sequence having at least 5, 10, or 20 substitutions thereto and a sequence of SEQ ID NO: 121 (iii) a sequence of SEQ ID NO: 19 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto or a sequence having at least 5, 10, or 20 substitutions thereto, and a sequence of SEQ ID NO: 123 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto or a sequence having at least 5, 10, or 20 substitutions thereto. (iv) a sequence of SEQ ID NO:23 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; (iv) a sequence of SEQ ID NO:23 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto.or 20 substitutions, and the sequence of SEQ ID NO: 127 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 127; (v) the sequence of SEQ ID NO: 9 or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto. or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 9, and a sequence of SEQ ID NO: 132 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 132; (vi) a sequence of SEQ ID NO: 34 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, a sequence having 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to, or a sequence having at least 5, 10, or 20 substitutions with, SEQ ID NO: 34, and a sequence of SEQ ID NO: 138, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; (vii) a sequence of SEQ ID NO: 38, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to, or a sequence having at least 5, 10 or 20 substitutions to, SEQ ID NO: 38, and a sequence of SEQ ID NO: 143 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, or a sequence having at least 5, 10 or 20 substitutions to, SEQ ID NO: 143.or 20 substitutions, (viii) a sequence of SEQ ID NO: 38 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto, and a sequence of SEQ ID NO: 147 or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto. 99% identity to, or a sequence having at least 5, 10, or 20 substitutions to, SEQ ID NO: 147; (ix) a sequence of SEQ ID NO: 46 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto or a sequence having at least 5, 10, or 20 substitutions thereto; and a sequence of SEQ ID NO: 155 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto. a sequence having 1%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions to SEQ ID NO: 155, (x) a sequence of SEQ ID NO: 51, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto, and a sequence of SEQ ID NO: 16 ... (xi) a sequence of SEQ ID NO: 59 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto;or 20 substitutions, and the sequence of SEQ ID NO: 167 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 167; (xii) a sequence of SEQ ID NO: 66 or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto. (xiii) a sequence of SEQ ID NO: 75 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto, (xiv) a sequence of SEQ ID NO: 75 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto, a sequence having 1%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 75, and the sequence of SEQ ID NO: 184, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 184; (xiv) a sequence of SEQ ID NO: 75; or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, or a sequence having at least 5, 10 or 20 substitutions to SEQ ID NO: 75, and the sequence of SEQ ID NO: 188, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, or a sequence having at least 5, 10 or 20 substitutions to SEQ ID NO: 188or 20 substitutions, (xv) a sequence of SEQ ID NO: 83 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 83, and a sequence of SEQ ID NO: 194 or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or (xvi) a sequence of SEQ ID NO: 91 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto or a sequence having at least 5, 10, or 20 substitutions thereto, and a sequence of SEQ ID NO: 200 or at least 85%, 86%, 87%, 88%, 89% identity thereto; (xvii) a sequence of SEQ ID NO: 100 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto or a sequence having at least 5, 10, or 20 substitutions thereto; and SEQ ID NO: 100 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto or a sequence having at least 5, 10, or 20 substitutions thereto; (xviii) the sequence of SEQ ID NO: 100 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 207; or (xviii) the sequence of SEQ ID NO: 100 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto;or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 100, and the sequence of SEQ ID NO: 212, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or at least Includes sequences with 5, 10, or 20 substitutions.

[0028] In some embodiments, the activin A antibody agent is characterized in that when tested in an assay that assesses activin A activity and / or levels, the antibody agent reduces activin A activity and / or levels or prevents an increase in activin A activity and / or levels compared to a comparator drug.

[0029] In some embodiments, the activin A is or comprises free and / or active activin A.

[0030] In some embodiments, the activin A antibody agent reduces plasma, blood, serum and / or urine levels of activin A. In some embodiments, the activin A antibody agent reduces activin A levels to less than about 500 pg / mL.

[0031] In some embodiments, the activin A antibody agent prevents an increase in activin A levels in plasma, blood, serum and / or urine. In some embodiments, the activin A antibody agent prevents an increase in activin A levels above about 500 pg / mL.

[0032] In some embodiments, the activin A antibody agent reduces, e.g., inhibits, activin A activity. In some embodiments, the activin A antibody agent reduces, e.g., inhibits, the activity and / or level of activin A (e.g., plasma and / or urinary activin A, e.g., free and / or active activin A) by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or about 100%.

[0033] In some embodiments, disclosed herein is a nucleic acid encoding an activin A antibody agent. In some embodiments, the nucleic acid encoding an activin A antibody agent is DNA. In some embodiments, the nucleic acid encoding an activin A antibody agent is RNA, for example, mRNA.

[0034] Also disclosed herein, in some embodiments, is a vector comprising a nucleic acid encoding an activin A antibody.

[0035] In some embodiments, the present disclosure provides a host cell comprising the vector disclosed herein.

[0036] In some embodiments, disclosed herein is a composition comprising an activin A antibody agent. In some embodiments, the composition is or comprises a pharmaceutical composition.

[0037] In some embodiments, disclosed herein are methods that include contacting a cell, tissue, or subject with an activin A antibody agent (e.g., a composition, e.g., a pharmaceutical composition, that includes an activin A antibody agent). In some embodiments, the method includes administering to the cell, tissue, or subject an activin A antibody agent (e.g., a composition, e.g., a pharmaceutical composition, that includes an activin A antibody agent).

[0038] In some embodiments, the method is a therapeutic method.

[0039] In some embodiments, the method is a prophylactic method.

[0040] In some embodiments, a subject disclosed herein has a condition or disorder associated with increased activin A. In some embodiments, the condition or disorder is selected from cachexia, mass loss (e.g., muscle mass loss, lean mass loss, fat mass loss, bone mass loss, and / or organ mass loss), weight loss (e.g., unintentional weight loss due to cachexia), aging, liver damage (e.g., fibrosis, degeneration, cirrhosis (e.g., alcoholic and / or non-alcoholic cirrhosis)), kidney damage (e.g., fibrosis), cancer, cancer metastasis, chemotherapy-induced toxicity (e.g., nephrotoxicity and / or hepatotoxicity), chemotherapy resistance, and / or hypertension.

[0041] In some embodiments, the condition or disorder is (i) a disorder of the hypothalamic pituitary gonadal axis (e.g., associated with increased FSH levels); (ii) fibrodysplasia ossificans progressiva (FOP); (iii) pulmonary arterial hypertension and / or hypertension; (iv) anorexia-cachexia disorders associated with chronic diseases such as cancer, chronic kidney disease, chronic heart failure, COPD, elderly and muscle immobility, ICU patients (e.g., weight loss, reduced food intake, reduced fat mass, muscle wasting, functional muscle loss, muscle strength loss, and bone loss, anemia and / or fatigue); (v) anemia; (vi) metabolic diseases (e.g., obesity, type 2 diabetes, and / or is metabolic syndrome); (vii) inflammatory diseases (e.g., inflammatory bowel disease, pancreatitis, allergic asthma, COVID, acute respiratory distress syndrome, atopic dermatitis, pre-eclampsia, acute liver injury, acute kidney injury, tubulointerstitial nephritis); (viii) autoimmune disorders (e.g., SLE or rheumatoid arthritis); (ix) fibrotic diseases (e.g., idiopathic pulmonary fibrosis, NASH, cirrhosis, chronic kidney disease, Alport syndrome, endometriosis); (x) cancer; (xi) cancer treatment-related toxicity (e.g., chemotherapy-induced nephrotoxicity and / or hepatotoxicity); (xii) aging (e.g., senescence); or (xiii) chemoresistance.

[0042] In some embodiments, disclosed herein are methods of treating and / or reversing mass loss in a subject, comprising administering to the subject an activin A antibody agent (e.g., a composition comprising an activin A antibody agent, e.g., a pharmaceutical composition). In some embodiments, mass comprises fat mass, lean mass, muscle mass, bone mass, organ mass, or a combination thereof.

[0043] In some embodiments, disclosed herein are methods of treating and / or reversing weight loss in a subject, comprising administering to the subject an activin A antibody agent (e.g., a composition comprising an activin A antibody agent, e.g., a pharmaceutical composition). In some embodiments, the weight loss is unintentional weight loss, e.g., as observed in cachexia.

[0044] In some embodiments, disclosed herein are methods of treating and / or reversing aging in a subject, comprising administering to the subject an activin A antibody agent (e.g., a composition comprising an activin A antibody agent, e.g., a pharmaceutical composition).

[0045] In some embodiments, disclosed herein are methods of treating and / or reversing liver damage in a subject, comprising administering to the subject an activin A antibody agent (e.g., a composition comprising an activin A antibody agent, e.g., a pharmaceutical composition). In some embodiments, the liver damage comprises acute liver injury, liver necrosis, liver fibrosis, liver inflammation, liver degeneration, cirrhosis (e.g., alcoholic and / or non-alcoholic cirrhosis), altered liver function, elevated levels of one or more liver enzymes, or a combination thereof.

[0046] In some embodiments, disclosed herein are methods of treating and / or reversing kidney damage in a subject, comprising administering to the subject an activin A antibody agent (e.g., a composition comprising an activin A antibody agent, e.g., a pharmaceutical composition). In some embodiments, the kidney damage comprises acute kidney injury, kidney fibrosis, kidney inflammation, altered kidney function, or a combination thereof.

[0047] In some embodiments, disclosed herein are methods of treating and / or reversing cachexia in a subject, comprising administering to the subject an activin A antibody agent (e.g., a composition comprising an activin A antibody agent, e.g., a pharmaceutical composition). In some embodiments, the cachexia is tumor-induced. In some embodiments, the cachexia comprises anorexia, muscle loss, fat mass loss, weight loss, or a combination thereof.

[0048] In some embodiments, disclosed herein are methods of treating and / or reversing a SAR-CoV-2 infection in a subject, comprising administering to the subject an activin A antibody agent (e.g., a composition comprising an activin A antibody agent, e.g., a pharmaceutical composition).

[0049] In some embodiments, disclosed herein are methods of reducing and / or preventing cancer growth in a subject, comprising administering to the subject an activin A antibody agent (e.g., a composition comprising an activin A antibody agent, e.g., a pharmaceutical composition). In some embodiments, the cancer comprises colorectal cancer, colon cancer, gastric cancer, sarcoma, lymphoma, leukemia, head and neck cancer, thymic cancer, epithelial cancer, salivary cancer, liver cancer, stomach cancer, thyroid cancer, lung cancer, ovarian cancer, breast cancer, prostate cancer, esophageal cancer, pancreatic cancer, glioma, leukemia, lymphoma, multiple myeloma, renal cell carcinoma, bladder cancer, cervical cancer, choriocarcinoma, oral cancer, skin cancer, melanoma, endometrial cancer, myofibrosis, bone cancer, or brain cancer. In some embodiments, the cancer is colorectal cancer.

[0050] In some embodiments, disclosed herein are methods of reducing and / or preventing chemotherapy resistance in a subject, comprising administering to the subject an activin A antibody agent (e.g., a composition comprising an activin A antibody agent, e.g., a pharmaceutical composition). In some embodiments, chemotherapy resistance is associated with activin A expression. In some embodiments, chemotherapy resistance is reduced and / or prevented in a subject having cancer who has or is being administered chemotherapy (e.g., as described herein). In some embodiments, the cancer comprises colorectal cancer, colon cancer, gastric cancer, sarcoma, lymphoma, leukemia, head and neck cancer, thymic cancer, epithelial cancer, salivary cancer, liver cancer, stomach cancer, thyroid cancer, lung cancer, ovarian cancer, breast cancer, prostate cancer, esophageal cancer, pancreatic cancer, glioma, leukemia, lymphoma, multiple myeloma, renal cell carcinoma, bladder cancer, cervical cancer, choriocarcinoma, oral cancer, skin cancer, melanoma, endometrial cancer, myofibrosis, bone cancer, or brain cancer. In some embodiments, the cancer is colon cancer.

[0051] In some embodiments, disclosed herein are methods for preventing and / or reducing cell migration in vivo in a subject, comprising administering to the subject an activin A antibody agent (e.g., a composition comprising an activin A antibody agent, e.g., a pharmaceutical composition).

[0052] In some embodiments, disclosed herein are methods for reducing and / or preventing metastasis in a subject, comprising administering to the subject an activin A antibody agent (e.g., a composition comprising an activin A antibody agent, e.g., a pharmaceutical composition).

[0053] In some embodiments, disclosed herein are methods of reducing and / or preventing chemotherapy-induced toxicity in a subject, comprising administering to the subject an activin A antibody agent (e.g., a composition comprising an activin A antibody agent, e.g., a pharmaceutical composition). In some embodiments, the chemotherapy-induced toxicity is or comprises nephrotoxicity. In some embodiments, the chemotherapy is cisplatin-based chemotherapy. In some embodiments, the chemotherapy is not cisplatin-based chemotherapy.

[0054] In some embodiments, disclosed herein are methods for reducing and / or preventing hypertension in a subject, comprising administering to the subject an activin A antibody agent (e.g., a composition comprising an activin A antibody agent, e.g., a pharmaceutical composition).

[0055] In some embodiments of any of the methods disclosed herein, the activin A antibody agent reduces, e.g., inhibits, the activity of activin A. In some embodiments, the activin A antibody agent reduces, e.g., inhibits, the activity and / or level of activin A (e.g., plasma and / or urinary activin A, e.g., free and / or active activin A) by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or about 100%.

[0056] In some embodiments of any of the methods disclosed herein, the activin A is or comprises free and / or active activin A.

[0057] In some embodiments of any of the methods disclosed herein, the activin A antibody agent reduces plasma, blood, serum and / or urine levels of activin A. In some embodiments, the activin A antibody agent reduces activin A levels to less than about 500 pg / mL.

[0058] In some embodiments of any of the methods disclosed herein, the activin A antibody agent prevents an increase in activin A levels in plasma, blood, serum, and / or urine. In some embodiments, the activin A antibody agent prevents an increase in activin A levels above about 500 pg / mL. [Brief explanation of the drawings]

[0059] [Figure 1A] 1 is a graph showing the binding affinity of three exemplary activin A antibody agents (clones B-D) to biotinylated activin A as measured by surface plasmon resonance assay. Graph shows data for biotinylated human activin A Fc bound to a chip with 9 nM, 3 nM, 1 nM, 0.33 nM, or 0.11 nM Fab of clone B in solution. [Figure 1B] 1 is a graph showing the binding affinity of three exemplary activin A antibody agents (clones B-D) to biotinylated activin A as measured by surface plasmon resonance assay. 2 is a graph showing data for biotinylated human activin A Fc bound to a chip with 9 nM, 3 nM, 1 nM, 0.33 nM, or 0.11 nM Fab of clone C in solution. [Figure 1C] 1 is a graph showing the binding affinity of three exemplary activin A antibody agents (clones B-D) to biotinylated activin A as measured by surface plasmon resonance assay. Graph shows data for biotinylated human activin A Fc bound to a chip with 9 nM, 3 nM, 1 nM, 0.33 nM, or 0.11 nM Fab of clone D in solution.

[0060] [Figure 2]Figures A-D show the inhibition of activin A activity by two exemplary anti-activin A antibodies. The assay used to measure activin A activity is the activin 2B receptor / SMAD reporter assay described in Example 2. Figure A is a graph showing activin A activity. Figure B is a graph showing the activity of an IgG1 isotype control. Figure C is a graph showing the inhibition of activin A activity by anti-activin antibody clone B. Figure D is a graph showing the inhibition of activin A activity by anti-activin antibody clone C.

[0061] [Figure 3] Figures A-D show the inhibition of BMP9 activity by two exemplary anti-activin A antibodies, but not by the SMAD reporter assay described in Example 2. Figure A shows BMP9 activity. Figure B shows the activity of an IgG1 isotype control. Figure C shows the inhibition of BMP9 activity by anti-activin A antibody clone B. Figure D shows the inhibition of BMP9 activity by anti-activin A antibody clone C.

[0062] [Figure 4] AB show pharmacokinetic data following intravenous administration of two exemplary anti-activin A antibodies in mice. A shows data with anti-activin A antibody clone B, and B shows data with anti-activin A antibody clone C.

[0063] [Figure 5] AB show pharmacokinetic data involving subcutaneous administration of two exemplary anti-activin A antibodies in mice. A shows data with anti-activin A antibody clone B, and B shows data with anti-activin A antibody clone C.

[0064] [Figure 6]1A-B show pharmacokinetic data following intravenous administration of two exemplary anti-activin A antibodies in primates. A shows data with anti-activin A antibody clone B, and B shows data with anti-activin A antibody clone C.

[0065] [Figure 7A] Figures 7A-7B show the prevention and cessation of weight loss by an exemplary anti-activin A antibody in mice with activin A-induced weight loss. For Figures 7A-7B, animals were divided into four groups and treated as follows: null vector and IgG1 isotype (black circles), null vector and clone C (purple boxes), high-dose AAV-activin A and IgG1 isotype (black triangles), and high-dose AAV-activin A and clone C (purple triangles). Figure 7A is a graph from a prevention study showing reduced weight loss in mice treated with an exemplary anti-activin A antibody one day prior to administration of high-dose AAV-activin A (compare purple downward-pointing triangles with black upward-pointing triangles). Data analyzed by ANCOVA with day 0 body weight as a covariate, followed by multiple t-tests. *P<0.05, ***P<0.005 compared to null vector. ###P<0.005 compared to AAV-activin A and IgG1 isotype control. [Figure 7B]Figures 7A-7B show the prevention and cessation of weight loss by an exemplary anti-activin A antibody in mice with activin A-induced weight loss. For Figures 7A-7B, animals were divided into four groups and treated as follows: null vector and IgG1 isotype (black circles), null vector and clone C (purple boxes), high-dose AAV-activin A and IgG1 isotype (black triangles), and high-dose AAV-activin A and clone C (purple triangles). Figure 7B is a graph from a treatment study showing the cessation of weight loss in mice treated with an exemplary anti-activin A antibody after the mice achieved 10% weight loss (compare purple downward-pointing triangles with black upward-pointing triangles). Data analyzed by ANCOVA with day 0 body weight as a covariate followed by multiple t-tests. *P<0.05, ***P<0.005 compared to null vector. ###P<0.005 compared to AAV-activin A and IgG1 isotype control. [Figure 7C] Figures 7C-7D show the prevention and cessation of weight loss by an exemplary anti-activin A antibody in mice with activin A-induced weight loss. For Figures 7C-7D, mice were administered a low dose of AAV-INHBA to increase circulating activin A levels (approximately 3 ng / mL) as reported in patients. This dose allowed mice to be studied chronically. For Figure 7C, mice were divided into four groups and administered the following: null vector and IgG1 isotype 10 mg / kg (gray diamonds), AAV-activin A and IgG1 isotype control 10 mg / kg (black diamonds), AAV-activin A and clone C 1 mg / kg (red inverted triangles), and AAV-activin A and clone C 10 mg / kg (purple circles). Figure 7C is a graph from a treatment study showing complete reversal of mouse weight loss in a dose-dependent manner, in which an exemplary anti-activin A antibody (clone C) was administered subcutaneously after the mice had achieved 20% weight loss. The arrow indicates the dosing of clone C. ***P<0.005 compared to null vector and ###P<0.005 compared to AAV-activin A and IgG1 isotype controls. [Figure 7D]Figures 7C-7D show the prevention and halting of weight loss by an exemplary anti-activin A antibody in mice with activin A-induced weight loss. For Figures 7C-7D, mice were administered a low dose of AAV-INHBA to increase circulating activin A levels (approximately 3 ng / mL) as reported in patients. This dose allowed mice to be studied chronically. For Figure 7D, mice were divided into four groups and treated as follows: null vector and IgG1 isotype 10 mg / kg (gray diamonds), AAV-activin A and IgG1 isotype control 10 mg / kg (black diamonds), AAV-activin A and clone C 1 mg / kg (red diamonds), and AAV-activin A and clone C 10 mg / kg (purple triangles). Figure 7D is a graph from a treatment study in which an exemplary anti-activin A antibody (clone B) was administered subcutaneously after mice achieved 20% weight loss, demonstrating complete reversal of mouse weight loss in a dose-dependent manner. Arrows indicate dosing of clone B. ***P<0.005 compared to null vector and ###P<0.005 compared to AAV-activin A and IgG1 isotype controls.

[0066] [Figure 8A] Figures 8A-8D show the prevention and reversal of organ mass loss by a single dose of an exemplary anti-activin A antibody. High doses of AAV-activin A were administered. Figure 8A shows that a single dose of an exemplary anti-activin A antibody prevents myocardial loss in a prophylactic setting. Mean values ​​adjusted for differences between treatment groups in terminal body weight. Analysis by ANCOVA with terminal body weight as a covariate followed by a multiple t-test. ***P<0.005 compared to null vector. ††P<0.01†††P<0.005 compared to AAV-activin A and IgG1 isotype control. [Figure 8B]Figures 8A-8D show the prevention and reversal of organ mass loss by a single dose of an exemplary anti-activin A antibody. High doses of AAV-activin A were administered. Figure 8B shows that a single dose of an exemplary anti-activin A antibody reverses myocardial loss in a therapeutic setting. Mean values ​​adjusted for differences between treatment groups in terminal body weight. Analysis by ANCOVA with terminal body weight as a covariate followed by a multiple t-test. ***P<0.005 compared to null vector. ††P<0.01†††P<0.005 compared to AAV-activin A and IgG1 isotype control. [Figure 8C] Figures 8A-8D show the prevention and reversal of organ mass loss by a single dose of an exemplary anti-activin A antibody. High doses of AAV-activin A were administered. Figure 8C shows that a single dose of an exemplary anti-activin A antibody in a prophylactic setting prevents liver mass loss after 6 days. Mean values ​​adjusted for differences between treatment groups in terminal body weight. Analysis by ANCOVA with terminal body weight as a covariate followed by a multiple t-test. ***P<0.005 compared to null vector. ††P<0.01†††P<0.005 compared to AAV-activin A and IgG1 isotype control. [Figure 8D] Figures 8A-8D show the prevention and reversal of organ mass loss by a single dose of an exemplary anti-activin A antibody. High doses of AAV-activin A were administered. Figure 8D shows that a single dose of an exemplary anti-activin A antibody administered within 2 days reverses liver mass loss in a therapeutic setting. Mean values ​​adjusted for differences between treatment groups in terminal body weight. Analysis by ANCOVA with terminal body weight as a covariate followed by a multiple t-test. ***P<0.005 compared to null vector. ††P<0.01†††P<0.005 compared to AAV-activin A and IgG1 isotype control. [Figure 8E]Figures 8E-8H show the prevention and reversal of organ mass loss with a single dose of an exemplary anti-activin A antibody. Lower doses of AAV-activin A were administered chronically. An exemplary anti-activin A antibody was administered 12 days after AAV injection and once weekly for two weeks. Figure 8E shows the reversal of cardiac mass loss with administration of 10 mg / kg of an exemplary anti-activin A antibody. *P<0.05, ***P<0.006 compared to null vector. #P<0.05, ###P<0.005 compared to AAV-activin A and IgG1 isotype control. [Figure 8F] Figures 8E-8H show prevention and reversal of organ mass loss with a single dose of an exemplary anti-activin A antibody. Lower doses of AAV-activin A were administered chronically. An exemplary anti-activin A antibody was administered 12 days after AAV injection and once weekly for two weeks. Figure 8F shows reversal of liver mass loss. *P<0.05, ***P<0.006 compared to null vector. #P<0.05, ###P<0.005 compared to AAV-activin A and IgG1 isotype control. [Figure 8G] Figures 8E-8H show prevention and reversal of organ mass loss with a single dose of an exemplary anti-activin A antibody. Lower doses of AAV-activin A were administered chronically. The exemplary anti-activin A antibody was administered 12 days after AAV injection and once weekly for two weeks. Reversal of pancreatic mass loss (Figure 8G) was observed with 1 mg / kg of the exemplary anti-activin A antibody, with a greater effect than observed with 10 mg / kg of the exemplary anti-activin A antibody. *P<0.05, ***P<0.006 compared to null vector. #P<0.05, ###P<0.005 compared to AAV-activin A and IgG1 isotype control. [Figure 8H]Figures 8E-8H show the prevention and reversal of organ mass loss with a single dose of an exemplary anti-activin A antibody. Lower doses of AAV-activin A were administered chronically. An exemplary anti-activin A antibody was administered 12 days after AAV injection and once weekly for two weeks. Figure 8H shows the reversal of kidney mass loss with administration of 10 mg / kg of an exemplary anti-activin A antibody. *P<0.05, ***P<0.006 compared to null vector. #P<0.05, ###P<0.005 compared to AAV-activin A and IgG1 isotype control.

[0067] [Figure 9A] Figure 9A shows that overexpression of activin A causes fibrosis and necrosis in mouse liver. Figure 9A shows a graph from acute overexpression of activin A (6 days) showing inflammatory cell infiltration in control and activin A-overexpressing mice. ***P<0.005 compared to null vector via exact Wilcoxon rank sum test for tissue type. [Figure 9B] Figure 9B shows that overexpression of activin A causes fibrosis and necrosis in mouse liver. Figure 9B is a graph from acute overexpression of activin A (6 days) showing fibrosis (collagen deposition) in control and activin A-overexpressing mice. ***P<0.005 compared to null vector via exact Wilcoxon rank sum test for histology. [Figure 9C] Figure 9C shows that overexpression of activin A causes fibrosis and necrosis in mouse liver. Figure 9C shows a graph from acute overexpression of activin A (6 days) showing hepatocellular necrosis in control and activin A-overexpressing mice. ***P<0.005 compared to null vector via exact Wilcoxon rank sum test for tissue type. [Figure 9D]Overexpression of activin A induces fibrosis and necrosis in mouse liver. Figures 9D–9L show gene expression data from chronic overexpression of activin A. COL1A (Figure 9D), COL3A (Figure 9E), COL4A (Figure 9F), smooth muscle actin (ATAC2, Figure 9G), fibronectin (FN1, Figure 9H), and TGF-beta (Figure 9I) levels were increased in the livers of mice chronically overexpressing activin A from 39 to 51 days. Comparison with the null vector group is by multiple t-test at day 39, *P<0.05, **P<0.01, ***P<0.001. [Figure 9E] Overexpression of activin A induces fibrosis and necrosis in mouse livers. Figures 9D–9L show gene expression data from chronic overexpression of activin A. COL1A (Figure 9D), COL3A (Figure 9E), COL4A (Figure 9F), smooth muscle actin (ATAC2, Figure 9G), fibronectin (FN1, Figure 9H), and TGF-beta (Figure 9I) levels were increased in the livers of mice chronically overexpressing activin A from 39 to 51 days. The acute senescence marker p15 was unchanged. Comparison with the null vector group is by multiple t-test at day 39, *P<0.05, **P<0.01, ***P<0.001. [Figure 9F] Overexpression of activin A induces fibrosis and necrosis in mouse livers. Figures 9D–9L show gene expression data from chronic overexpression of activin A. COL1A (Figure 9D), COL3A (Figure 9E), COL4A (Figure 9F), smooth muscle actin (ATAC2, Figure 9G), fibronectin (FN1, Figure 9H), and TGF-beta (Figure 9I) levels were increased in the livers of mice chronically overexpressing activin A from 39 to 51 days. The acute senescence marker p15 was unchanged. Comparison with the null vector group is by multiple t-test at day 39, *P<0.05, **P<0.01, ***P<0.001. [Figure 9G]Overexpression of activin A induces fibrosis and necrosis in mouse livers. Figures 9D–9L show gene expression data from chronic overexpression of activin A. COL1A (Figure 9D), COL3A (Figure 9E), COL4A (Figure 9F), smooth muscle actin (ATAC2, Figure 9G), fibronectin (FN1, Figure 9H), and TGF-beta (Figure 9I) levels were increased in the livers of mice chronically overexpressing activin A from 39 to 51 days. The acute senescence marker p15 was unchanged. Comparison with the null vector group is by multiple t-test at day 39, *P<0.05, **P<0.01, ***P<0.001. [Figure 9H] Overexpression of activin A induces fibrosis and necrosis in mouse livers. Figures 9D–9L show gene expression data from chronic overexpression of activin A. COL1A (Figure 9D), COL3A (Figure 9E), COL4A (Figure 9F), smooth muscle actin (ATAC2, Figure 9G), fibronectin (FN1, Figure 9H), and TGF-beta (Figure 9I) levels were increased in the livers of mice chronically overexpressing activin A from 39 to 51 days. The acute senescence marker p15 was unchanged. Comparison with the null vector group is by multiple t-test at day 39, *P<0.05, **P<0.01, ***P<0.001. [Figure 9I] Overexpression of activin A induces fibrosis and necrosis in mouse livers. Figures 9D–9L show gene expression data from chronic overexpression of activin A. COL1A (Figure 9D), COL3A (Figure 9E), COL4A (Figure 9F), smooth muscle actin (ATAC2, Figure 9G), fibronectin (FN1, Figure 9H), and TGF-beta (Figure 9I) levels were increased in the livers of mice chronically overexpressing activin A from 39 to 51 days. The acute senescence marker p15 was unchanged. Comparison with the null vector group is by multiple t-test at day 39, *P<0.05, **P<0.01, ***P<0.001. [Figure 9J]Figures 9D-9L show gene expression data from chronic overexpression of activin A, which leads to fibrosis and necrosis in mouse livers. Figures 9J-9L show the levels of senescence markers p16 and p21 in the livers of mice chronically overexpressing activin A from 39 to 51 days. The acute senescence marker p15 remained unchanged. Comparison with the null vector group is by multiple t-test at day 39, *P<0.05, **P<0.01, ***P<0.001. [Figure 9K] Figures 9D-9L show gene expression data from chronic overexpression of activin A, which leads to fibrosis and necrosis in mouse livers. Figures 9J-9L show the levels of senescence markers p16 and p21 in the livers of mice chronically overexpressing activin A from 39 to 51 days. The acute senescence marker p15 remained unchanged. Comparison with the null vector group is by multiple t-test at day 39, *P<0.05, **P<0.01, ***P<0.001. [Figure 9L] Figures 9D-9L show gene expression data from chronic overexpression of activin A, which leads to fibrosis and necrosis in mouse livers. Figures 9J-9L show the levels of senescence markers p16 and p21 in the livers of mice chronically overexpressing activin A from 39 to 51 days. The acute senescence marker p15 remained unchanged. Comparison with the null vector group is by multiple t-test at day 39, *P<0.05, **P<0.01, ***P<0.001.

[0068] [Figure 10A] Figure 10A shows that acute overexpression of high doses of AAV-activin A (6 days) increases liver enzymes. Figure 10A shows a graph showing an increase in circulating ALT in control mice or mice overexpressing activin A (AAV-activin A). **P<0.01, ***P<0.005 compared to null vector via Kruskal-Wallis (non-parametric ANOVA). [Figure 10B]Figure 10B shows that acute overexpression of high doses of AAV-activin A (6 days) increases liver enzymes. Figure 10B shows an increase in circulating AST in control mice or mice overexpressing activin A (AAV-activin A). **P<0.01, ***P<0.005 compared to null vector via Kruskal-Wallis (non-parametric ANOVA). [Figure 10C] Figures 10C-D show that acute overexpression of high-dose AAV-activin A (6 days) increases liver enzymes. Figures 10C-D show chronic overexpression of low-dose AAV-activin A. Figure 10C shows a graph showing circulating ALT. AAV-activin A animals were therapeutically treated with a control antibody or an exemplary anti-activin A antibody. An exemplary anti-activin A mAb completely reversed the increases in circulating ALT and AST induced by AAV-activin A. ***P<0.005 compared to null vector or ###P<0.005 compared to AAV-activin A isotype control via ANOVA. [Figure 10D] Figures 10C-D show that acute overexpression of high-dose AAV-activin A (6 days) increases liver enzymes. Figures 10C-D show chronic overexpression of low-dose AAV-activin A. Figure 10D shows a graph showing circulating AST in control mice or mice overexpressing activin A (AAV-activin A). AAV-activin A animals were therapeutically treated with a control antibody or an exemplary anti-activin A antibody. An exemplary anti-activin A mAb completely reversed the increases in circulating ALT and AST induced by AAV-activin A. ***P<0.005 compared to null vector or ###P<0.005 compared to AAV-activin A isotype control via ANOVA.

[0069] [Figure 11]A-B show that acute overexpression of activin A (6 days) causes fibrosis and tubular degeneration in mouse kidneys. A is a graph showing collagen deposition (fibrosis) in control mice or mice overexpressing activin A. B is a graph showing tubular degeneration in control mice or mice overexpressing activin A. For histological types, ***P<0.005 compared to null vector via exact Wilcoxon rank sum test.

[0070] [Figure 12] A-F show prevention of weight loss, fat mass loss, and muscle mass loss in an orthotopic MC38 colorectal cancer model. Mice were left untreated (sham), intrasplenic injected with MC38 cancer cells, and administered an exemplary anti-activin A antibody, or intrasplenic injected with MC38 cancer cells and administered a control antibody. A shows body weight change, B shows carcass weight, C shows adipose tissue weight, D shows gastrocnemius muscle weight, E shows tibialis muscle weight, and F shows food intake. Data analysis using ANOVA *P<0.05, **P<0.01, and ***P<0.005 compared to MC38 mice with IgG1 isotype control.

[0071] [Figure 13] Figures A-C show primary tumors and liver metastases in the MC38 colorectal cancer model. Figure A shows tumor weights in the spleens of mice not inoculated with MC38 cells (left bar), mice inoculated with MC38 tumor cells in the spleen and treated with a control antibody (center bar), and mice inoculated with MC38 tumor cells and treated with an exemplary anti-activin A antibody (right bar). The exemplary anti-activin A antibody reduced primary tumor weight. Data analysis using ANOVA, *P<0.05 compared to MC38 mice with an IgG1 isotype control. Figures B and C each contain three image panels showing representative livers from two sham mice (left panel), two MC38-inoculated mice treated with an anti-activin A antibody (center panel), and two MC38-inoculated mice treated with a control antibody (right panel). The exemplary anti-activin A antibody prevented liver metastases.

[0072] [Figure 14] Figures A-B show the prevention of chemotherapy-induced nephrotoxicity in Wistar rats. An exemplary anti-activin A antibody (20 mg / kg, days 1 and 3) or a control antibody was administered (pretreatment) prior to cisplatin treatment (5 mg / kg IP). Figure A shows serum creatinine, and Figure B shows serum blood urea nitrogen (BUN) 5 days after cisplatin treatment in adults (6-7 weeks). The exemplary anti-activin A antibody partially prevented nephrotoxicity via one-way ANOVA; *P<0.05, ****P<0.0001.

[0073] [Figure 15] A-B show atrophy and anti-apoptosis in hepatocytes with chronic overexpression of activin A. A shows hepatic muRF1 gene expression in control mice or mice overexpressing activin A for 39-51 days, and B shows BCL2 gene expression in control mice or mice overexpressing activin A for 39-51 days. Comparison with the null vector group is by multiple t-test at day 39, *P<0.05, and ***P<0.001.

[0074] [Figure 16] Chronic overexpression of activin A induces bone loss. Femoral bone mineral density images using X-ray computed tomography are shown from individual control mice carrying a null vector (n=8) or mice overexpressing activin A for 39 (n=7) or 51 (n=3) days.

[0075] [Figure 17]Figures A-E summarize that chronic overexpression of activin A causes bone loss as measured by X-ray computed tomography and dual-energy X-ray absorptiometry (DEXA). Using X-ray computed tomography, A shows a decrease in femoral trabecular bone volume / total volume, B shows a decrease in femoral trabecular number, C shows a decrease in femoral trabecular thickness, and D shows a decrease in femoral trabecular spacing induced by activin A overexpression compared to mice expressing a null vector. Figure E shows a reduction in whole-body bone mineral density in mice caused by activin A overexpression compared to null vector control mice.

[0076] [Figure 18] We show that chronic overexpression of actin A caused a sustained increase in water intake in mice compared to control mice without actin A overexpression. The increase in water intake is due to activin A causing thirst, dehydration, and a surrogate for hypertension. DETAILED DESCRIPTION OF THE INVENTION

[0077] definition In this application, unless otherwise clear from the context, (i) the term "a" may be understood to mean "at least one," (ii) the term "or" may be understood to mean "and / or," (iii) the terms "comprising" and "including" may be understood to encompass the itemized components or steps, whether presented by themselves or with one or more additional components or steps, (iv) the terms "about" and "approximately" may be understood to allow for standard variations that would be understood by one of ordinary skill in the art, and (v) when ranges are specified, both endpoints are included.

[0078] Activin A: The term "activin A" is used herein to refer to an activin A polypeptide as understood in the art. Activin A is a member of the TGF-beta superfamily. Activin A is also known as the activin beta A chain or the inhibin beta A chain. Under physiological conditions, activin A can form a homodimer composed of two β subunits of inhibin linked by a disulfide bridge, referred to as the βA / βA homodimer. Activin A protein is encoded by the INHBA gene. The amino acid sequence of full-length activin A and / or the nucleic acid encoding it can be found in public databases such as GenBank, UniProt, and Swiss-Prot. For example, the amino acid sequence of human activin A (SEQ ID NO:215), in which residues 1-20 represent the signal peptide and residues 311-426 represent the TGF-beta family signature sequence, can be found under UniProt / Swiss-Prot accession number P08476, and the nucleic acid sequence encoding human activin A (SEQ ID NO:216) can be found under accession number NM_002192.3. Those skilled in the art will understand that the sequences provided in SEQ ID NOs:215 and 216 are exemplary, and that certain variations (including, e.g., conservative substitutions in SEQ ID NO:215, codon-optimized variants of SEQ ID NO:216, etc.) will be understood to also be or encode human activin A. Furthermore, those skilled in the art will understand that homologs and orthologs of human activin A are known and / or are known by exercise or by routine skill in the art, for example, based on the degree of sequence identity, the presence of one or more characteristic sequence elements, and / or one or more shared activities. As is clear from the context, the term "activin A" may be used in reference to monomeric activin A and / or homodimeric activin A.

[0079] Activin A polypeptide: The phrase "activin A polypeptide" is used herein to refer to a polypeptide that shares significant sequence identity and / or at least one characteristic sequence element with a suitable reference polypeptide, such as, for example, (a) human activin A, e.g., as set forth in SEQ ID NO: 215; (b) rhesus activin A, e.g., as set forth in SEQ ID NO: 219 (see XP_028701686.1); (c) canine activin A, e.g., as set forth in SEQ ID NO: 220 (see XP_038279632.1); and / or (d) feline activin A, e.g., as set forth in SEQ ID NO: 221 (see NP_001009856.1). In some embodiments, the activin A polypeptide is or comprises a fragment of a parent activin A polypeptide (e.g., of SEQ ID NO: 215, or a homolog, ortholog, or variant thereof [e.g., a functional variant]). In some embodiments, the activin A polypeptide shares at least one characteristic sequence element with a reference activin A polypeptide (e.g., of SEQ ID NO: 215, or a homolog, ortholog, or variant [e.g., functional variant] thereof). Alternatively or additionally, in some embodiments, the activin A polypeptide shares significant amino acid sequence identity with a related reference polypeptide (e.g., of SEQ ID NO: 215, or a homolog, ortholog, or variant [e.g., functional variant] thereof). For example, in some embodiments, the activin A polypeptide shares at least 50% with the reference activin A. In some embodiments, the activin A polypeptide is characterized by the ability to activate a receptor that binds to activin A, e.g., a type II receptor or a type I receptor, and in some such embodiments, such ability is comparable to that of a suitable reference activin A (e.g., of SEQ ID NO: 215, or a homolog, ortholog, or variant [e.g., functional variant] thereof).For example, in some embodiments, the activin A polypeptide activates the type II or type I receptor with a binding affinity reasonably comparable to that of a suitable reference activin A (e.g., of SEQ ID NO: 215, or a homolog, ortholog, or variant [e.g., functional variant] thereof). In some embodiments, the activin A polypeptide is characterized by competing with a suitable reference activin A (e.g., of SEQ ID NO: 215, or a homolog, ortholog, or variant [e.g., functional variant] thereof) for binding to and / or activating the type II or type I receptor. In some such embodiments, such competition is observed over a range of concentrations (e.g., the range may span 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or more). In some embodiments, the activin A polypeptide is or comprises a polypeptide having at least 50% identity to SEQ ID NO: 215.

[0080] About: The term "about," when used herein with respect to a value, refers to a value that is similar in context to the referenced value. Generally, a person of ordinary skill in the art familiar with the context will understand the reasonable degree of variation encompassed by "about" in that context. For example, in some embodiments, the term "about" can encompass a range of values ​​that are within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less of the reference value.

[0081] Administration: As used herein, the term "administration" typically refers to administering a composition to a subject or system, e.g., to achieve delivery of an agent that is, is contained in, or is otherwise delivered by the composition. Those skilled in the art will recognize various routes that may be utilized for administration to a subject, e.g., an animal or a human, under appropriate circumstances. In some embodiments, the animal is a companion animal, e.g., a domestic animal such as a dog or cat, and in some embodiments, the animal is an animal used for agriculture (e.g., farming [e.g., cattle, sheep, or horses]) or recreation. For example, in some embodiments, administration can be systemic or local. Those skilled in the art will recognize appropriate routes of administration for use with particular therapies described herein, including, for example, bronchial (e.g., by bronchial infusion), buccal, transdermal (which may be or include, e.g., one or more of topical, intradermal, interdermal, transdermal, etc., into the dermis), enteral, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, intraspecific organ (e.g., intrahepatic), mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., by intratracheal infusion), intravaginal, intravitreal, etc. In some embodiments, administration may be by injection (e.g., intramuscular, intravenous, or subcutaneous injection). In some embodiments, injection may include bolus injection, infusion, perfusion, or infusion. In some embodiments, administration may involve only a single dose. In some embodiments, administration may include the application of a number of doses. In some embodiments, administration may involve administration that is intermittent (e.g., multiple doses separated in time) and / or periodic (e.g., individual doses separated by a common period of time) administration. In some embodiments, administration may involve continuous administration (e.g., perfusion) for at least a selected period of time. In some embodiments, the antibody agent may be formulated for oral delivery. For example, one of skill in the art will understand that the antibody agents disclosed herein may be formulated for oral delivery using technology developed by Oramed (https: / / www.oramed.com / ) or Premas (https: / / www.premasbiotech.com / ).

[0082] Adult: As used herein, the term "adult" refers to a human over the age of 18. In some embodiments, a human adult has a weight within the range of about 90 pounds to about 250 pounds.

[0083] Affinity: As known in the art, "affinity" is a measure of the tightness with which two or more binding partners associate with one another. Those skilled in the art will be knowledgeable of various assays that can be used to assess affinity and will also recognize appropriate controls for such assays. In some embodiments, affinity is assessed in a quantitative assay. In some embodiments, affinity (e.g., of one binding partner at a time) is assessed across multiple concentrations. In some embodiments, affinity is assessed in the presence of one or more potential competitors (e.g., that may be present in a relevant physiological situation). In some embodiments, affinity is assessed relative to a reference (e.g., having a known affinity above a certain threshold [see "positive control"] or having a known affinity below a certain threshold [see "negative control"]). In some embodiments, affinity may be assessed relative to a concurrent reference, and in some embodiments, affinity may be assessed relative to a background reference. Typically, when affinity is assessed relative to a reference, it is assessed under comparable conditions.

[0084] "Affinity matured" (or "affinity matured antibody"): As used herein, refers to an antibody with one or more modifications in one or more CDRs or their FRs that result in an improvement in the affinity of the antibody for antigen compared to a parent antibody that does not have those modification(s). In some embodiments, an affinity matured antibody has nanomolar or even picomolar affinity for the target antigen. Affinity matured antibodies can be produced by any of a variety of procedures known in the art. Marks et al., BioTechnology 10:779-783 (1992) describe affinity matured antibodies. H and V LAffinity maturation by domain shuffling has been described. Random mutagenesis of CDR and / or framework residues is described by Barbas et al., Proc. Nat. Acad. Sci. USA 91:3809-3813 (1994), Schier et al., Gene 169:147-155 (1995), Yelton et al., J. Immunol. 155:1994-2004 (1995), Jackson et al., J. Immunol. 154(7):3310-9 (1995), and Hawkins et al., J. Mol. Biol. 226:889-896 (1992).

[0085] Agent: As used herein, the term "agent" can refer to a physical entity or phenomenon. In some embodiments, an agent can be characterized by a particular feature and / or effect. In some embodiments, an agent can be a compound, molecule, or entity of any chemical class, including, for example, a small molecule, polypeptide, nucleic acid, sugar, lipid, metal, or combinations or complexes thereof. In some embodiments, the term "agent" can refer to a compound, molecule, or element that comprises a polymer. In some embodiments, the term can refer to a compound or element that comprises one or more polymer moieties. In some embodiments, the term "agent" can refer to a compound, molecule, or element that is substantially free of a particular polymer or polymer moiety. In some embodiments, the term can refer to a compound, molecule, or element that lacks or is substantially free of any polymer or polymer moiety.

[0086] Agonist: Those skilled in the art will understand that the term "agonist" can be used to refer to an agent, condition, or event whose presence, level, degree, type, or form correlates with an increase in the level or activity of another agent (i.e., a stimulated agent or a target agent). Generally, an agonist can be or include any chemical class of agent, including, for example, small molecules, polypeptides, nucleic acids, carbohydrates, lipids, metals, and / or any other entity that exhibits related activation activity. In some embodiments, an agonist can be direct (in which case the agonist directly affects its target). In some embodiments, an agonist can be indirect (in which case the agonist affects something other than binding to the target, e.g., by interacting with a regulator of the target such that the level or activity of the target is altered).

[0087] Amino acid: As used herein in its broadest sense, refers to any compound and / or substance that can be incorporated into a polypeptide chain, for example, through one or more peptide bond formats. In some embodiments, an amino acid has the general structure HN-C(H)(R)-COOH. In some embodiments, an amino acid is a naturally occurring amino acid. In some embodiments, an amino acid is a non-naturally occurring amino acid. In some embodiments, an amino acid is a D-amino acid. In some embodiments, an amino acid is an L-amino acid. "Standard amino acid" refers to any of the 20 standard L-amino acids commonly found in naturally occurring peptides. "Non-standard amino acid" refers to any amino acid other than the standard amino acids, whether it is synthetically prepared or obtained from a natural source. In some embodiments, an amino acid, including the carboxy- and / or amino-terminal amino acids in a polypeptide, may contain structural modifications compared to the general structures above. For example, in some embodiments, an amino acid may be modified relative to the general structure by methylation, amidation, acetylation, pegylation, glycosylation, phosphorylation, and / or substitution (e.g., of an amino group, a carboxylic acid group, one or more protons, and / or a hydroxyl group). In some embodiments, such modifications may, for example, alter the circulating half-life of a polypeptide containing the modified amino acid compared to one containing the same amino acid except for the unmodified amino acid. In some embodiments, such modifications do not significantly alter the relevant activity of a polypeptide containing the modified amino acid compared to one containing the same amino acid except for the unmodified amino acid. As will be clear from the context, in some embodiments, the term "amino acid" may be used to refer to a free amino acid. In some embodiments, the term may be used to refer to an amino acid residue of a polypeptide.

[0088] Animal: As used herein, refers to a member of the animal kingdom. In some embodiments, "animal" refers to a human, and unless otherwise specified, in many embodiments, a human can be of either sex and / or at any stage of development. In some embodiments, "animal" refers to a non-human animal, and unless otherwise specified, in many embodiments, a non-human animal can be of either sex and / or at any stage of development. In certain embodiments, the non-human animal is a mammal (e.g., a rodent, mouse, rat, rabbit, monkey, dog, cat, sheep, cow, primate, and / or pig). In some embodiments, the animal can be, for example, a mammal, bird, reptile, amphibian, fish, insect, worm, etc. In some embodiments, the animal can be a transgenic animal, a genetically modified animal, and / or a clone.

[0089] Antagonist: As used herein, those skilled in the art will understand that the term "antagonist" can be used to refer to an agent, condition, or event whose presence, level, degree, type, or form correlates with a decrease in the level or activity of another agent (i.e., an inhibitor or target agent). Generally, an antagonist can be or include any chemical class of agent, including, for example, small molecules, polypeptides, nucleic acids, carbohydrates, lipids, metals, and / or any other entity that exhibits related inhibitory activity. In some embodiments, an antagonist can be direct (in which case it directly affects its target). In some embodiments, an antagonist can be indirect (in which case it affects something other than binding to the target, e.g., by interacting with a regulator of the target such that the level or activity of the target is altered).

[0090] Antibody: As used herein, the term "antibody" refers to a polypeptide containing sufficient standard immunoglobulin sequence elements to confer specific binding to a particular target antigen. As is known in the art, intact antibodies, as produced in nature, are approximately 150 kD tetrameric agents composed of two identical heavy chain polypeptides (about 50 kD each) and two identical light chain polypeptides (about 25 kD each) that associate with each other into what is commonly referred to as a "Y-shaped" structure. Each heavy chain consists of at least four domains (each about 110 amino acids long)—an amino-terminal variable (VH) domain (located at the tip of the Y structure), followed by three constant domains, CH1, CH2, and carboxy-terminal CH3 (located at the base of the stem of the Y). A short region known as the "switch" connects the heavy chain variable and constant regions. A "hinge" connects the CH2 and CH3 domains to the rest of the antibody. Two disulfide bonds in this hinge region connect the two heavy chain polypeptides to each other in an intact antibody. Each light chain consists of two domains: an amino-terminal variable (VL) domain followed by a carboxy-terminal constant (CL) domain separated from each other by another "switch." An intact antibody tetramer is composed of two heavy-light chain dimers, in which the heavy and light chains are linked to each other by one disulfide bond and two other disulfide bonds connect the heavy chain hinge regions to form a tetramer. Naturally produced antibodies are typically glycosylated in the CH2 domain. Each domain of a natural antibody has a structure characterized by an "immunoglobulin fold," formed by two beta sheets (e.g., three-, four-, or five-stranded sheets) packed together into an antiparallel beta barrel. Each variable domain contains three hypervariable loops known as "complement determining regions" (CDR1, CDR2, and CDR3) and four somewhat invariant "framework" regions (FR1, FR2, FR3, and FR4).When a natural antibody folds, the FR regions form beta sheets, providing a structural framework for the domain, and the CDR loop regions of both the heavy and light chains join in three-dimensional space to create a single hypervariable antigen-binding site located at the tip of a Y-structure. The Fc region of a naturally occurring antibody binds to elements of the complement system and also to receptors on effector cells, including, for example, effector cells that mediate cytotoxicity. As is known in the art, the affinity and / or other binding properties of the Fc region for an Fc receptor can be modulated through glycosylation or other modifications. In some embodiments, antibodies produced and / or utilized in accordance with the present disclosure comprise a glycosylated Fc domain, including Fc domains with modified or engineered glycosylation. In some embodiments, antibodies produced and / or utilized in accordance with the present disclosure comprise one or more modifications on the Fc domain, e.g., effector-null mutations, e.g., LALA, LAGA, FEGG, AAGG, or AAGA mutations. For the purposes of this disclosure, in certain embodiments, any polypeptide or polypeptide complex that contains a sufficient immunoglobulin domain sequence as found in a natural antibody may be referred to and / or used as an "antibody," regardless of whether such polypeptide is produced naturally (e.g., generated by an organism in response to an antigen) or by recombinant engineering, chemical synthesis, or other artificial systems or methodologies. In some embodiments, an antibody is polyclonal; in some embodiments, an antibody is monoclonal. In some embodiments, an antibody has constant region sequences characteristic of canine, feline, murine, rabbit, primate, or human antibodies. In some embodiments, antibody sequence elements are human, humanized, primatized, chimeric, etc., as known in the art. Furthermore, as used herein, the term "antibody" can, in appropriate embodiments (unless otherwise specified or apparent from the context), refer to any of the constructs or formats known or developed in the art for utilizing the structural and functional characteristics of antibodies in alternative presentations.For example, in some embodiments, antibodies utilized in accordance with the present invention are in a format selected from, but not limited to, intact IgA, IgG, IgE, or IgM antibodies; bispecific or multispecific antibodies (e.g., Zybodies®, etc.); antibody fragments such as Fab fragments, Fab' fragments, F(ab')2 fragments, Fd' fragments, Fd fragments, and isolated CDRs or sets thereof; single-chain Fvs; polypeptide-Fc fusions; single domain antibodies, alternative scaffolds, or antibody mimetics (e.g., anti-cullins, FN3 monobodies, DARPins, affinity antibodies, affilins, affilimers, affitins, alphabodies, avimers, fynomers, Im7, VLRs, VNARs, trimabs, CrossMabs, Tridents); nanobodies, binanobodies, F(ab')2, Fab', di-sdFvs, single domain antibodies, trifunctional antibodies, diabodies, and minibodies, etc. In some embodiments, the relevant format may be or include Adnectins®, Affibodies®, Affilins®, Anticalins®, Avimers®, BiTEs®, cameloid antibodies, Centyrins®, ankyrin repeat proteins or DARPINs®, dual affinity retargeting (DART) agents, Fynomers®, shark single domain antibodies such as IgNARs, immune monoclonal T cell receptors against cancer (ImmTACs), KALBITOR®, MicroProteins, Nanobodies® minibodies, masked antibodies (e.g., Probodies®), Small Modular ImmunoPharmaceuticals ("SMIPs™"), single chain or tandem dibodies (TandAbs®), TCR-like antibodies, Trans-bodies®, TrimerX®, VHHs. In some embodiments, the antibody may lack covalent modifications (eg, glycan attachment) that it would have if produced in nature.In some embodiments, antibodies can contain covalent modifications (e.g., the attachment of a glycan, a payload (e.g., a detectable moiety, a therapeutic moiety, a catalytic moiety, etc.), or other pendant groups (e.g., polyethylene glycol, etc.).

[0091] Antibody agent: As used herein, the term "antibody agent" refers to an agent that specifically binds to a particular antigen. In some embodiments, the term encompasses any polypeptide or polypeptide complex that contains sufficient immunoglobulin structural elements to confer specific binding. Exemplary antibody agents include, but are not limited to, monoclonal or polyclonal antibodies. In some embodiments, an antibody agent may contain one or more constant region sequences characteristic of canine, feline, murine, rabbit, primate, or human antibodies. In some embodiments, an antibody agent may contain one or more sequence elements that are human, humanized, primatized, chimeric, etc., as known in the art. In some embodiments, an antibody agent may contain one or more complementarity-determining regions that are human and / or one or more constant region sequences characteristic of human antibodies. In many embodiments, the term "antibody agent" is used to refer to one or more constructs or formats known or developed in the art for utilizing the structural and functional characteristics of antibodies in alternative presentations.For example, in some embodiments, antibody agents utilized in accordance with the present disclosure include, but are not limited to, intact IgA, IgG, IgE, or IgM antibodies; bispecific or multispecific antibodies (e.g., Zybodies®, etc.); antibody fragments such as Fab fragments, Fab' fragments, F(ab')2 fragments, Fd' fragments, Fd fragments, and isolated CDRs or sets thereof; single chain Fv; polypeptides comprising an antigen-binding specificity fused to an Fc; single domain antibodies (e.g., shark single domain antibodies such as IgNAR or fragments thereof); cameloid antibodies; masked antibodies (e.g., Probodies®, etc.). and KALBITOR®. In some embodiments, the antibody may lack covalent modifications (e.g., glycan attachment) that it would have if produced naturally. In some embodiments, antibodies can contain covalent modifications (e.g., the attachment of glycans, payloads (e.g., detectable moieties, therapeutic moieties, catalytic moieties, etc.), or other pendant groups (e.g., polyethylene glycol, etc.). In many embodiments, antibody agents are or comprise polypeptides whose amino acid sequence includes one or more structural elements recognized by those skilled in the art as complementarity-determining regions (CDRs). In some embodiments, antibody agents are or comprise polypeptides whose amino acid sequence includes at least one CDR (e.g., at least one heavy chain CDR and / or at least one light chain CDR) that is substantially identical to that found in a reference antibody.In some embodiments, the included CDRs are substantially identical to the reference CDRs in that they are sequence identical or contain 1 to 5 amino acid substitutions compared to the reference CDRs. In some embodiments, the included CDRs are substantially identical to the reference CDRs in that they exhibit at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the reference CDRs. In some embodiments, the included CDRs are substantially identical to the reference CDRs in that they exhibit at least 96%, 96%, 97%, 98%, 99%, or 100% sequence identity with the reference CDRs. In some embodiments, the included CDRs are substantially identical to the reference CDRs in that at least one amino acid within the included CDRs has been deleted, added, or substituted relative to the reference CDR, but the included CDRs otherwise have an amino acid sequence that is identical to the amino acid sequence of the reference CDR. In some embodiments, the included CDRs are substantially identical to the reference CDRs in that 1 to 5 amino acids within the included CDRs have been deleted, added, or substituted relative to the reference CDR, but the included CDRs otherwise have an amino acid sequence that is identical to the reference CDR. In some embodiments, the included CDRs are substantially identical to the reference CDRs in that at least one amino acid within the included CDRs has been substituted relative to the reference CDR, but the included CDRs otherwise have an amino acid sequence that is identical to the amino acid sequence of the reference CDR. In some embodiments, the included CDRs are substantially identical to the reference CDRs in that 1 to 5 amino acids within the included CDRs have been deleted, added, or substituted relative to the reference CDR, but the included CDRs otherwise have an amino acid sequence that is identical to the reference CDR. In some embodiments, an antibody agent is or comprises a polypeptide whose amino acid sequence comprises structural elements recognized by those skilled in the art as immunoglobulin variable domains.In some embodiments, an antibody agent is a polypeptide protein having a binding domain that is homologous to an immunoglobulin binding domain or that is largely homologous to an immunoglobulin binding domain.

[0092] Antibody-dependent cellular cytotoxicity: As used herein, the term "antibody-dependent cellular cytotoxicity" or "ADCC" refers to the phenomenon in which target cells bound by an antibody are killed by immune effector cells. Without wishing to be bound by any particular theory, it is observed that ADCC is typically understood to involve the ability of effector cells bearing Fc receptors (FcRs) to recognize and subsequently kill antibody-coated target cells (e.g., cells expressing a specific antigen on their surface to which the antibody is bound). Effector cells that mediate ADCC can include immune cells, including, but not limited to, one or more of natural killer (NK) cells, macrophages, neutrophils, and eosinophils.

[0093] Antibody fragment: As used herein, "antibody fragment" refers to a portion of an antibody or antibody agent as described herein, and typically refers to an antigen-binding portion or portion comprising a variable region thereof. Antibody fragments can be produced by any means. For example, in some embodiments, antibody fragments can be produced enzymatically or chemically by fragmentation of an intact antibody or antibody agent. Alternatively, in some embodiments, antibody fragments can be produced recombinantly (i.e., by expression of an engineered nucleic acid sequence). In some embodiments, antibody fragments can be wholly or partially synthetically produced. In some embodiments, antibody fragments (particularly antigen-binding antibody fragments) are at least about 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or more amino acids in length, and in some embodiments, are at least about 200 amino acids in length.

[0094] Antibody Polypeptide: As used herein, the term "antibody polypeptide" refers to a polypeptide(s) that comprises the characteristic sequence element(s) of an antibody (e.g., one or more CDRs, or a set of CDRs, such as each of CDR1, 2, and 3 found in a reference antibody chain, and / or one or more FR regions and / or a set of FR regions, e.g., the complete variable region of a heavy or light chain of a reference antibody). In many embodiments, an antibody polypeptide comprises sufficient such sequence element(s) that it binds to an epitope (e.g., an epitope bound by a reference antibody comprising the characteristic sequence elements). In some embodiments, an antibody polypeptide is a full-length antibody, or a heavy or light chain thereof. In some embodiments, an antibody polypeptide is or comprises the complete heavy and / or light chain variable region of a reference antibody. In some such embodiments, an antibody polypeptide comprises sufficient specific antibody sequence element(s) to confer specific binding to the relevant epitope, i.e., such that the antibody polypeptide comprises at least one binding site. In some embodiments, an "antibody polypeptide" may comprise a binding domain that is homologous or largely homologous (e.g., exhibits significant sequence homology and / or, in some embodiments, significant sequence identity) to an immunoglobulin binding domain. In some embodiments, an antibody polypeptide exhibits at least 99% identity to an immunoglobulin binding domain. In some embodiments, an "antibody polypeptide" has an immunoglobulin binding domain, e.g., a binding domain that exhibits at least 70%, 80%, 85%, 90%, or 95% identity to a reference immunoglobulin binding domain. In some embodiments, an "antibody polypeptide" may have an amino acid sequence identical to that of an antibody, or a chain or variable region (or combination of variable region(s)) thereof, found in a natural source. In some embodiments, an antibody polypeptide may be prepared, for example, by isolation from a natural source or antibody library, recombinant production in or with a host system, chemical synthesis, etc., or a combination thereof. In some embodiments, an antibody polypeptide is an antibody agent described herein.

[0095] Antigen: As used herein, the term "antigen" refers to an agent that elicits an immune response and / or (ii) an agent that binds to a T cell receptor (e.g., when presented by an MHC molecule) or an antibody. In some embodiments, an antigen elicits a humoral response (e.g., including the production of antigen-specific antibodies). In some embodiments, an antigen elicits a cellular response (e.g., engagement of T cells whose receptors specifically interact with the antigen). In some embodiments, an antigen binds to an antibody and may or may not induce a specific physiological response in an organism. Generally, an antigen can be or include any chemical entity, such as, for example, a small molecule, a nucleic acid, a polypeptide, a carbohydrate, a lipid, a polymer (in some embodiments, other than a biopolymer [e.g., other than a nucleic acid or amino acid polymer]), etc. In some embodiments, an antigen is or includes a polypeptide. In some embodiments, an antigen is or includes a glycan. Those skilled in the art will understand that, generally, antigens may be provided in isolated or pure form, or alternatively, may be provided in crude form (e.g., together with other materials, such as cell extracts or other relatively crude preparations of antigen-containing sources). In some embodiments, antigens utilized in accordance with the present invention are provided in crude form. In some embodiments, the antigen is a recombinant antigen.

[0096] Approximately: As used herein, the term "approximately" or "about," when applied to one or more values ​​of interest, refers to a value similar to a stated reference value. In certain embodiments, the term "approximately" or "about" refers to a range of values ​​that is within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% in either direction (above or below) of the stated reference value, unless otherwise specified or a different meaning is apparent from the context (except where such number would exceed 100% of the possible values).

[0097] Binding: Those skilled in the art will understand that the term "binding," as used herein, typically refers to a non-covalent association between or among two or more entities. "Direct" binding involves physical contact between the entities or moieties, while indirect binding involves a physical interaction due to physical contact through one or more intermediate entities. Binding between two or more entities can typically be assessed in any of a variety of contexts, including when the interacting entities or moieties are studied in isolation or in the context of a more complex system (e.g., in covalent or other association with a carrier entity, and / or in a biological system or cell).

[0098] Cancer: The terms "cancer," "malignancy," "neoplasm," "tumor," and "carcinoma" are used herein to refer to cells that exhibit relatively abnormal, uncontrolled, and / or autonomous growth, resulting in an aberrant growth phenotype characterized by a marked decrease in control of cell proliferation. In some embodiments, tumors may be or include pre-cancerous (e.g., benign), malignant, pre-metastatic, metastatic, and / or non-metastatic cells. The present disclosure specifically identifies particular cancers to which its teachings may be particularly relevant. In some embodiments, the relevant cancers may be characterized as solid tumors. In some embodiments, the relevant cancers may be characterized as hematological tumors. In general, examples of different types of cancer known in the art include, for example, hematopoietic cancers including leukemia, lymphoma (Hodgkin's and non-Hodgkin's), myeloma and myeloproliferative disorders; genitourinary cancers such as sarcoma, melanoma, adenoma, carcinoma of solid tissue, squamous cell carcinoma of the mouth, throat, larynx, lung, liver cancer, prostate cancer, cervical cancer, bladder cancer, uterine cancer, ovarian cancer, endometrial cancer, as well as benign lesions such as renal cell carcinoma, bone cancer, pancreatic cancer, skin cancer, cutaneous or intraocular melanoma, endocrine system cancer, thyroid cancer, parathyroid cancer, head and neck cancer, breast cancer, gastrointestinal cancer and nervous system cancer tumors, papillomas, etc.

[0099] Carrier: As used herein, refers to a diluent, adjuvant, excipient, or vehicle with which a composition is administered. In some exemplary embodiments, the carrier may comprise a sterile liquid, such as water, and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. In some embodiments, the carrier is or comprises one or more solid components.

[0100] CDR: As used herein, refers to a complementarity-determining region within an antibody variable region. There are three CDRs in each of the heavy and light chain variable regions, designated CDR1, CDR2, and CDR3 for each variable region. A "set of CDRs" or "CDR set" refers to a group of three or six CDRs present in either a single variable region capable of binding to an antigen or the CDRs of cognate heavy and light chain variable regions capable of binding to an antigen. Certain systems have been established in the art for defining CDR boundaries (e.g., Kabat, Chothia, etc.), and those of skill in the art will appreciate the differences between these systems and will be able to understand CDR boundaries to the extent necessary to understand and practice the claimed subject matter.

[0101] CDR-grafted antibody: As used herein, a CDR-grafted antibody comprises heavy and light chain variable region sequences from one species but H and / or V L The sequences of one or more of the CDR regions of the mouse V are CDR sequences of another species, for example, a mouse V in which one or more of the mouse CDRs (e.g., CDR3) are replaced with human CDR sequences. H and V L Similarly, a "CDR-grafted antibody" also refers to an antibody in which one or more of the human CDRs (e.g., CDR3) have been replaced with mouse CDR sequences. H and V L It may refer to an antibody having a region.

[0102] Child: As used herein, the term "child" refers to a human between the ages of 1 day and 18 years. In some embodiments, a child can be an infant (e.g., about 12 months, 11 months, 10 months, 9 months, 8 months, 7 months, 6 months, 5 months, 4 months, 3 months, 2 months, or less than 1 month old), and in some embodiments, a child can be older than an infant. In some embodiments, a child can be a toddler (e.g., about 1 to about 3 years old), and in some embodiments, a child can be younger than an toddler or older than an infant. In some embodiments, a child can be a teenager (e.g., about 12 years to about 18 years old), and in some embodiments, a child can be younger than a teenager (and / or younger than an toddler or older than an infant). Weight varies greatly depending on age and the particular child, with a typical range being 4 pounds to 150 pounds.

[0103] Combination therapy: As used herein, the term "combination therapy" refers to a situation in which a subject is exposed to two or more therapeutic regimens (e.g., two or more therapeutic agents) simultaneously. In some embodiments, the two or more regimens may be administered simultaneously. In some embodiments, the regimens may be administered sequentially (e.g., all "doses" of a first regimen are administered before any dose of a second regimen). In some embodiments, the agents are administered in overlapping dosing regimens. In some embodiments, "administration" of a combination therapy may include administering one or more agent(s) or modality(s) in combination to a subject receiving other agent(s) or modality(s). For clarity, combination therapy does not require that the individual agents be administered together in a single composition (or even necessarily simultaneously), although in some embodiments, two or more agents or their active portions may be administered together in a combined composition or even a combined compound (e.g., as part of a single chemical complex or covalent conjugate).

[0104] Equivalent: As used herein, the term "equivalent" refers to two or more agents, entities, circumstances, sets of conditions, etc. that may not be identical to one another, but that are sufficiently similar to permit a comparison between them where one of skill in the art would understand that conclusions can be reasonably drawn based on the observed differences or similarities. In some embodiments, a comparable set of conditions, circumstances, individuals, or populations is characterized by multiple substantially identical characteristics and one or a few different characteristics. Those of skill in the art will understand what degree of identity is required for two or more such agents, entities, circumstances, sets of conditions, etc. to be considered comparable in any given situation, depending on the context. For example, those of skill in the art will understand that sets of circumstances, individuals, or populations are comparable to one another when they are characterized by a sufficient number and type of substantially identical characteristics to warrant a reasonable conclusion that differences in results obtained or phenomena observed under or with different sets of circumstances, individuals, or populations are caused by or indicate variations in those characteristics.

[0105] Composition: Those skilled in the art will understand that the term "composition" can be used to mean a physically discrete entity that includes one or more specified components. Generally, unless otherwise specified, a composition can be in any form, e.g., gas, gel, liquid, solid, etc.

[0106] Comprising: A composition or method described herein as "comprising" one or more named elements or steps is open-ended, meaning that the named elements or steps are essential, but that other elements or steps may be added within the scope of the composition or method. To avoid redundancy, it should also be understood that any composition or method described as "comprising" (or "comprises") one or more named elements or steps also represents a corresponding, more limited composition or method that "consistes essentially of" (or "consists essentially of") the same named elements or steps, meaning that the composition or method includes the named essential elements or steps, and may include additional elements or steps that do not materially affect the basic and novel property(ies) of the composition or method. It should also be understood that any composition or method described herein as "comprising" or "consisting essentially of" one or more named elements or steps also represents a corresponding, more limited, closed-ended composition or method "consisting of" (or "consists of") the named elements or steps, excluding any other elements or steps not named. In any composition or method disclosed herein, known or disclosed equivalents of any named essential element or step may be substituted for that element or step.

[0107] Domain: As used herein, the term "domain" refers to a section or portion of an entity. In some embodiments, a "domain" relates to a particular structural and / or functional characteristic of an entity such that when the domain is physically separated from the remainder of its parent entity, it substantially or completely retains the particular structural and / or functional characteristic. Alternatively or additionally, a domain may be or comprise a portion of an entity that, when separated from its (parent) entity and associated with a different (recipient) entity, substantially retains and / or confers to the recipient entity one or more structural and / or functional characteristics that characterize the parent entity. In some embodiments, a domain is a section or portion of a molecule (e.g., a small molecule, carbohydrate, lipid, nucleic acid, or polypeptide). In some embodiments, a domain is a section of a polypeptide, and in some such embodiments, a domain is characterized by particular structural elements (e.g., particular amino acid sequences or sequence motifs, alpha-helical properties, alpha-sheet properties, coiled-coil properties, random coil properties, etc.) and / or particular functional properties (e.g., binding activity, enzymatic activity, folding activity, signaling activity, etc.).

[0108] Effector function: As used herein, refers to a biochemical event that results from the interaction of an antibody Fc region with an Fc receptor or ligand. Effector functions include, but are not limited to, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and complement-mediated cytotoxicity (CMC). In some embodiments, effector functions operate after antigen binding, independently of antigen binding, or both.

[0109] Effector cell: As used herein, refers to a cell of the immune system that expresses one or more Fc receptors and mediates one or more effector functions. In some embodiments, effector cells may include, but are not limited to, one or more of monocytes, macrophages, neutrophils, dendritic cells, eosinophils, mast cells, platelets, large granular lymphocytes, Langerhans cells, natural killer (NK) cells, T lymphocytes, B lymphocytes, and may be derived from any organism, including, but not limited to, human, mouse, rat, rabbit, and monkey.

[0110] Epitope: As used herein, includes any moiety that is specifically recognized by an immunoglobulin (e.g., antibody or receptor) binding component. In some embodiments, an epitope is composed of multiple chemical atoms or groups on an antigen. In some embodiments, such chemical atoms or groups are surface-exposed when the antigen is in a relevant three-dimensional conformation. In some embodiments, such chemical atoms or groups are physically close to each other in space when the antigen is in such a conformation. In some embodiments, at least some such chemical atoms or groups are physically separated from each other when the antigen adopts an alternative conformation (e.g., linearized).

[0111] Excipient: As used herein, refers to a non-therapeutic agent that may be included in a pharmaceutical composition, for example, to provide or contribute to a desired consistency or stabilizing effect. Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, and the like.

[0112] Framework "or" framework region: As used herein, refers to the sequence of a variable region minus the CDRs. Because CDR sequences can be determined by different systems, framework sequences are likewise subject to correspondingly different interpretations. The six CDRs divide the framework regions on the heavy and light chains into four subregions (FR1, FR2, FR3, and FR4) on each chain, with CDR1 located between FR1 and FR2, CDR2 between FR2 and FR3, and CDR3 between FR3 and FR4. Without identifying specific subregions as FR1, FR2, FR3, and FR4, the framework region, as otherwise referred to, represents the combined FRs within the variable region of a single, naturally occurring immunoglobulin chain. As used herein, FR represents one of the four subregions; for example, FR1 represents the first framework region closest to the amino terminus of the variable region and is 5' with respect to CDR1, and FR represents two or more of the subregions that make up the framework region.

[0113] Functional: As used herein, a "functional" biomolecule is a biomolecule in a form in which it exhibits a property and / or activity by which it is characterized.

[0114] Fragment: A "fragment" of a substance or entity as described herein comprises a distinct portion of the whole, but has a structure that lacks one or more portions found in the whole. In some embodiments, the fragment consists of such a distinct portion. In some embodiments, the fragment consists of or comprises a characteristic structural element or portion found in the whole. In some embodiments, a fragment of a polymer comprises or consists of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500 or more monomer units (e.g., residues) present in the entire polymer. In some embodiments, a polymeric fragment comprises or consists of at least about 5%, 10%, 15%, 20%, 25%, 30%, 25%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more of the monomeric units (e.g., residues) found in the whole polymer. The whole substance or entity may, in some embodiments, be referred to as the "parent" of the fragment.

[0115] High affinity binding: As used herein, the term "high affinity binding" refers to the high tightness with which a particular ligand binds to its partner. Affinity can be measured by any available method, including those known in the art. In some embodiments, in a binding assay, K dis about 500 pM or less (e.g., less than about 400 pM, about 300 pM, about 200 pM, about 100 pM, about 90 pM, about 80 pM, about 70 pM, about 60 pM, about 50 pM, about 40 pM, about 30 pM, about 20 pM, about 10 pM, about 5 pM, about 4 pM, about 3 pM, about 2 pM, etc.). In some embodiments, the affinity is stronger for the polypeptide of interest than for a selected reference polypeptide (e.g., K d In some embodiments, the K of a selected reference polypeptide is low, and the binding is considered to be of high affinity. d K of the polypeptide of interest relative to d Binding is considered to be of high affinity when the ratio of K to a polypeptide of interest is 1:1 or less (e.g., 0.9:1, 0.8:1, 0.7:1, 0.6:1, 0.5:1, 0.4:1, 0.3:1, 0.2:1, 0.1:1, 0.05:1, 0.01:1 or less). d is the K for the selected reference polypeptide d Binding is considered to be high affinity when the affinity is about 100% or less (e.g., about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10%, about 5%, about 4%, about 3%, about 2%, about 1% or less).

[0116] Homology: As used herein, the term "homology" refers to the overall relatedness between polymer molecules, e.g., polypeptide molecules. In some embodiments, polymeric molecules, such as antibodies, are considered to be "homologous" to one another if their sequences are at least 80%, 85%, 90%, 95%, or 99% identical. In some embodiments, polymeric molecules are considered to be "homologous" to one another if their sequences are at least 80%, 85%, 90%, 95%, or 99% similar.

[0117] Human: In some embodiments, the human is an embryo, fetus, infant, child, teenager, adult, or elderly.

[0118] Humanized: As known in the art, the term "humanized" refers to the modification of a V antibody derived from a reference antibody raised in a non-human species (e.g., mouse). H and V L The term "humanized" is generally used to refer to antibodies (or antibody components) that contain variable domain sequences but also contain modifications of these sequences compared to a reference antibody intended to make them more "human-like," i.e., more similar to human germline variable sequences. In some embodiments, a "humanized" antibody (or antibody component) is one that immunospecifically binds to an antigen of interest and has framework (FR) regions having amino acid sequences substantially those of a human antibody and complementarity-determining regions (CDRs) having amino acid sequences substantially those of a non-human antibody. A humanized antibody comprises substantially all of at least one, and typically two, variable domains (Fab, Fab', F(ab')2, FabC, Fv), in which all or substantially all of the CDR regions correspond to the CDR regions of a non-human immunoglobulin (i.e., a donor immunoglobulin) and all or substantially all of the framework regions are those of a human immunoglobulin consensus sequence. In some embodiments, a humanized antibody also comprises at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin constant region. In some embodiments, a humanized antibody contains at least the variable domains of both a light chain and a heavy chain. H 1. Hinge, C H 2. C H 3, and optionally, C of the heavy chain constant region H In some embodiments, the humanized antibody may comprise a humanized V L In some embodiments, the humanized antibody contains only a humanized V region. H In some particular embodiments, the humanized antibody contains only a humanized V region. H and V L Contains the region.

[0119] Identity: As used herein, the term "identity" refers to the overall relatedness between polymeric molecules, e.g., between nucleic acid molecules (e.g., DNA molecules and / or RNA molecules) and / or between polypeptide molecules. In some embodiments, polymeric molecules are considered to be "substantially identical" to one another if their sequences are at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical. For example, calculation of the percent identity of two nucleic acid or polypeptide sequences can be performed by aligning the two sequences for optimal comparison purposes (e.g., gaps can be introduced into one or both of the first and second sequences for optimal alignment, and non-identical sequences can be disregarded for comparison purposes). In certain embodiments, the length of the aligned sequences for comparison purposes is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or substantially 100% of the length of the reference sequence. The nucleotides at corresponding positions are then compared. If a position in the first sequence is occupied by the same residue (e.g., nucleotide or amino acid) as the corresponding position in the second sequence, the molecules are identical at that position. The percent identity between two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps and the length of each gap that needs to be introduced for optimal alignment of the two sequences. Sequence comparison and determination of percent identity between two sequences can be achieved using a mathematical algorithm. For example, the algorithm of Meyers and Miller (CABIOS, 1989, 4:11-17) incorporated into the ALIGN program (version 2.0) can be used to determine the percent identity between two nucleotide sequences. In some exemplary embodiments, comparison of nucleic acid sequences using the ALIGN program uses a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4.The percent identity between two nucleotide sequences can alternatively be determined using the GAP program in the GCG software package using the NWSgapdna.CMP matrix.

[0120] "Improve," "Increase," "Inhibit," or "Decrease": As used herein, the terms "improve," "increase," "inhibit," "decrease," or their grammatical equivalents refer to a value relative to a baseline or other reference measurement. In some embodiments, a suitable reference measurement may be or include a measurement in a particular system (e.g., in a single individual) under otherwise comparable conditions in the absence (e.g., before and / or after) of a particular agent or treatment, or in the presence of a suitable comparable reference agent. In some embodiments, a suitable reference measurement may be or include a measurement in a comparable system known or expected to respond in a particular manner in the presence of the relevant agent or treatment.

[0121] K D: As used herein, refers to the dissociation constant of a binding agent (e.g., an antibody or binding moiety thereof) from a complex with its partner (e.g., the epitope to which the antibody or binding moiety thereof binds).

[0122] Low affinity binding: As used herein, the term "low affinity binding" refers to the low tightness with which a particular ligand binds to its partner. As described herein, affinity can be measured by any available method, including methods known in the art. In some embodiments, K d is about 501 pM or greater (e.g., greater than about 501 pM, 600 pM, 700 pM, 800 pM, 900 pM, 1 nM, 1.1 nM, 1.2 nM, 1.3 nM, 1.4 nM, 1.5 nM, etc.). In some embodiments, the affinity is the same or lower (e.g., K) for the polypeptide of interest than for a selected reference polypeptide. dIn some embodiments, the binding is considered to be of low affinity if the K of the selected reference polypeptide is approximately the same as or higher. d K of the polypeptide of interest relative to d is 1:1 or greater (e.g., 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2:1, 3:1, 4:1, 5:1, 10:1, or greater). In some embodiments, the K of the polypeptide of interest is d is the K of the selected reference polypeptide d Binding is considered to be of low affinity if the affinity is 100% or more (e.g., 100%, 105%, 110%, 115%, 120%, 125%, 130%, 135%, 140%, 145%, 150%, 155%, 160%, 165%, 170%, 175%, 180%, 185%, 190%, 195%, 200%, 300%, 400%, 500%, 1000% or more) of the binding.

[0123] Peptide: As used herein, the term "peptide" refers to a polypeptide that is typically relatively short, e.g., having a length of less than about 100 amino acids, less than about 50 amino acids, less than about 40 amino acids, less than about 30 amino acids, less than about 25 amino acids, less than about 20 amino acids, less than about 15 amino acids, or less than 10 amino acids.

[0124] Pharmaceutical composition: As used herein, the term "pharmaceutical composition" refers to a composition in which an active agent is formulated with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in a unit dose suitable for administration in a treatment regimen that exhibits a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, a pharmaceutical composition may be specially formulated for administration in a particular form (e.g., a solid or liquid form) and / or may be specifically adapted for, for example, oral administration (e.g., specially formulated for buccal, sublingual, or systemic absorption, e.g., as a drench [aqueous or non-aqueous solution or suspension], tablet, capsule, bolus, powder, granules, paste, etc.); parenteral administration (e.g., subcutaneous, intramuscular, intravenous, or epidural injection, e.g., as a sterile solution or suspension, or sustained-release formulation); topical application (e.g., as a cream, ointment, patch, or spray applied, e.g., to the skin, lungs, or buccal cavity); vaginal or rectal administration (e.g., as a pessary, suppository, cream, or foam); intraocular administration; nasal or pulmonary administration, etc.

[0125] Polypeptide: As used herein, refers to a polymeric chain of amino acids. In some embodiments, a polypeptide has a naturally occurring amino acid sequence. In some embodiments, a polypeptide has a non-naturally occurring amino acid sequence. In some embodiments, a polypeptide has an engineered amino acid sequence, in that it is artificially designed and / or created. In some embodiments, a polypeptide can comprise or consist of natural amino acids, unnatural amino acids, or both. In some embodiments, a polypeptide can comprise or consist of only natural amino acids or only unnatural amino acids. In some embodiments, a polypeptide can comprise D-amino acids, L-amino acids, or both. In some embodiments, a polypeptide can comprise only D-amino acids. In some embodiments, a polypeptide can comprise only L-amino acids. In some embodiments, a polypeptide can comprise one or more pendant groups or other modifications, e.g., modification of or attachment to one or more amino acid side chains, at the N-terminus of the polypeptide, the C-terminus of the polypeptide, or any combination thereof. In some embodiments, such pendant groups or modifications can be selected from the group consisting of acetylation, amidation, lipidation, methylation, pegylation, etc., e.g., combinations thereof. In some embodiments, a polypeptide can be cyclic and / or include a cyclic portion. In some embodiments, a polypeptide is not cyclic and / or does not include a cyclic portion. In some embodiments, a polypeptide is linear. In some embodiments, a polypeptide can be or include a stapled polypeptide. In some embodiments, the term "polypeptide" can be appended to the name of a reference polypeptide, activity, or structure, and in such cases, it is used herein to refer to polypeptides that share a related activity or structure and can therefore be considered members of the same class or family of polypeptides. For each such class, the specification provides, and / or one of skill in the art will be aware of, exemplary polypeptides within the class whose amino acid sequence and / or function are known.In some embodiments, such exemplary polypeptides are reference polypeptides of a class or family of polypeptides. In some embodiments, members of a polypeptide class or family exhibit significant sequence homology or identity with the reference polypeptide of the class (and in some embodiments, with all polypeptides in the class), share common sequence motifs (e.g., characteristic sequence elements), and / or share a common activity (in some embodiments, at a similar level or within a specified range). For example, in some embodiments, member polypeptides exhibit an overall degree of sequence homology or identity with the reference polypeptide that is at least about 30-40%, and often greater than about 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more, and / or contain at least one region (e.g., a conserved region that, in some embodiments, is or may include a characteristic sequence element) that exhibits very high sequence identity, often greater than 90%, or even 95%, 96%, 97%, 98%, or 99%. Such conserved regions typically encompass at least 3-4, and often up to 20 or more, amino acids; in some embodiments, the conserved region encompasses at least one stretch of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more contiguous amino acids. In some embodiments, a related polypeptide may comprise or consist of a fragment of a parent polypeptide. In some embodiments, a useful polypeptide may comprise or consist of multiple fragments, each of which is found in the same parent polypeptide in a different spatial arrangement relative to each other than that found in the polypeptide of interest (e.g., a fragment directly linked to the parent may be spatially separated in the polypeptide of interest, or vice versa, and / or the fragments may be present in a different order in the polypeptide of interest than in the parent), and thus the polypeptide of interest is a derivative of that parent polypeptide.

[0126] Reference: As used herein, describes a standard or control against which a comparison is made. For example, in some embodiments, an agent, animal, individual, population, sample, sequence, or value of interest is compared to a reference or control agent, animal, individual, population, sample, sequence, or value. In some embodiments, the reference or control is tested and / or determined substantially contemporaneously with the test or determination of interest. In some embodiments, the reference or control is a historical reference or control, optionally embodied in a tangible medium. Typically, as will be understood by one of skill in the art, a reference or control is determined or analyzed under conditions or circumstances comparable to those being evaluated. One of skill in the art will understand when there is sufficient similarity to justify reliance on and / or comparison to a particular reference or control considered.

[0127] Specific binding: As used herein, the term "specific binding" refers to the ability to distinguish between possible binding partners in the environment in which the binding occurs. A binding agent that interacts with one specific target in the presence of other potential targets is said to "specifically bind" to that interacting target. In some embodiments, specific binding is assessed by detecting or measuring the degree of association between the binding agent and its partner; in some embodiments, specific binding is assessed by detecting or measuring the degree of dissociation of the binding agent-partner complex; in some embodiments, specific binding is assessed by detecting or measuring the ability of a binding agent to compete with an alternative interaction of its partner with another entity. In some embodiments, specific binding is assessed by performing such detection or measurement over a range of concentrations.

[0128] Specific: The term "specific," as used herein with respect to an active agent, is understood by those skilled in the art to mean that the agent discriminates between potential target entities or aspects. For example, in some embodiments, an agent is said to bind "specifically" to a target if it preferentially binds to that target in the presence of one or more competing alternative targets. In many embodiments, the specific interaction depends on the presence of a particular structural feature of the target entity (e.g., an epitope, cleft, binding site). It should be understood that specificity need not be absolute. In some embodiments, specificity can be assessed relative to the specificity of the binding agent for one or more other potential target entities (e.g., competitors). In some embodiments, specificity is assessed relative to that of a reference specific binding agent. In some embodiments, specificity is assessed relative to that of a reference nonspecific binding agent. In some embodiments, an agent or entity does not directly bind to a competing alternative target under conditions in which it binds to its target entity. In some embodiments, a binding agent binds to its target entity with a higher on-rate, a lower off-rate, increased affinity, decreased dissociation, and / or increased stability when compared to competing surrogate target(s).

[0129] Specificity: As known in the art, "specificity" is the degree to which a particular ligand is able to distinguish its binding partner from other potential binding partners.

[0130] Substantially: As used herein, the term "substantially" refers to the qualitative state of exhibiting the entire or nearly entire extent or degree of a desired characteristic or property. Those skilled in the art of biology will understand that biological and chemical phenomena rarely, if ever, proceed to completion and / or perfection or achieve or avoid absolute results. Thus, the term "substantially" is used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.

[0131] Substantial identity: As used herein, refers to a comparison between amino acid or nucleic acid sequences. As will be understood by those skilled in the art, two sequences are generally considered to be "substantially identical" if they contain identical residues at corresponding positions. As is well known in the art, amino acid or nucleic acid sequences can be compared using any of a variety of algorithms, including those available in commercially available computer programs, such as BLASTN for nucleotide sequences, BLASTP for amino acid sequences, gapped BLAST, and PSI-BLAST. Exemplary such programs are described in Altschul et al., Basic local alignment search tool, J. Mol. Biol., 215(3):403-410, 1990, Altschul et al., Methods in Enzymology, Altschul et al., Nucleic Acids Res. 25:3389-3402, 1997, Baxevanis et al., Bioinformatics: A Practical Guide to the Analysis of Genes and Proteins, Wiley, 1998, and Misener, et al. (eds.), Bioinformatics Methods and Protocols (Methods in Molecular Biology, Vol. 132), Humana Press, 1999. In addition to identifying identical sequences, the above programs typically provide an indication of the degree of identity. In some embodiments, two sequences are considered to be substantially identical if at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more of their corresponding residues are identical over the relevant stretch of residues, which in some embodiments is the complete sequence.In some embodiments, the relevant extension is at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, or more residues. In the context of CDRs, references to "substantial identity" typically refer to CDRs that have no more than a small number (e.g., 3, 2, or 1) of amino acid sequence changes compared to the amino acid sequence of the reference CDR. In some embodiments, a CDR that is substantially identical to a reference CDR differs from the reference CDR by one or more amino acid changes at the ends of the reference CDR. In some such embodiments, the relevant CDR is identical to the reference CDR except at one or both ends. As is known in the art, CDR elements typically have lengths ranging from a few amino acids (e.g., 3, 4, 5, 6, or 7) to about 20 or 30 amino acids (see, e.g., Collis et al. J. Mol. Biol. 325:337, 2003, incorporated herein by reference). Thus, in some embodiments, a CDR may be considered substantially identical to a reference CDR when it shares at least about 80% (or less for shorter CDRs), at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100% identity with the reference CDR.

[0132] Substantial sequence homology: The phrase "substantial homology" is used herein to refer to a comparison between amino acid or nucleic acid sequences. As will be understood by those skilled in the art, two sequences are generally considered to be "substantially homologous" if they contain homologous residues at corresponding positions. Homologous residues may be identical residues. Alternatively, homologous residues may be non-identical residues, with appropriately similar structural and / or functional properties. For example, as is well known to those skilled in the art, certain amino acids are typically classified as "hydrophobic" or "hydrophilic" amino acids and / or as having "polar" or "non-polar" side chains. Substitution of one amino acid for another amino acid of the same type can often be considered a "homologous" substitution. Typical amino acid classifications are summarized below. [Table 16] [Table 17] As is well known in the art, amino acid or nucleic acid sequences can be compared using any of a variety of algorithms, including those available in commercially available computer programs, such as BLASTN for nucleotide sequences, BLASTP for amino acid sequences, Gapped BLAST, and PSI-BLAST. Exemplary such programs are described in Altschul et al., Basic local alignment search tool, J. Mol. Biol., 215(3):403-410, 1990; Altschul, et al., Methods in Enzymology; Altschul, et al., "Gapped BLAST and PSI-BLAST: a new generation of protein database search programs", Nucleic Acids Res. 25:3389-3402, 1997; Baxevanis, et al., Bioinformatics: A Practical Guide to the Analysis of Genes and Proteins, Wiley, 1998; and Misener, et al., (eds.), Bioinformatics Methods and Protocols (Methods in Molecular Biology, Vol. 132), Humana Press, 1999. In addition to identifying homologous sequences, the above programs typically provide an indication of the degree of homology. In some embodiments, two sequences are considered to be substantially homologous if at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or more of their corresponding residues are homologous over the relevant stretch of residues. In some embodiments, the relevant stretch is the complete sequence.In some embodiments the relevant extension is at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, at least 100, at least 125, at least 150, at least 175, at least 200, at least 225, at least 250, at least 275, at least 300, at least 325, at least 350, at least 375, at least 400, at least 425, at least 450, at least 475, at least 500 or more residues.

[0133] Treat: As used herein, the terms "treat," "treatment," or "treating" are used to refer to one or more of the partial or complete alleviation, amelioration, palliation, inhibition, prevention, delay in onset, reduction in severity, and / or reduction in frequency (e.g., incidence) of one or more symptoms or characteristics of a disease, disorder, and / or condition. In some embodiments, treatment may be prophylactic, e.g., administered to a subject who does not exhibit signs of a disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject who exhibits only early signs of a disease, disorder, and / or condition, e.g., reduced risk of developing pathology associated with the disease, disorder, and / or condition, and / or delayed onset of one or more characteristics of the disease, disorder, and / or condition, and / or reduced rate of onset or worsening of one or more characteristics of the disease, disorder, and / or condition.

[0134] Treatment: As used herein, the term "treatment" (also "treat" or "treating") refers to the administration of a therapy that partially or completely alleviates, ameliorates, palliates, inhibits, delays the onset of, reduces the severity of, and / or reduces the incidence of one or more symptoms, characteristics, and / or causes of a particular disease, disorder, and / or condition. In some embodiments, such treatment may be of a subject who does not exhibit symptoms of the associated disease, disorder, and / or condition and / or who exhibits only early signs of the disease, disorder, and / or condition. Alternatively or additionally, such treatment may be of a subject who exhibits one or more symptoms of the associated disease, disorder, and / or condition. In some embodiments, treatment may be of a subject who has been diagnosed as suffering from the associated disease, disorder, and / or condition. In some embodiments, treatment may be of a subject who is known to have one or more susceptibility factors, e.g., susceptibility factors that statistically correlate with an increased risk of developing the associated disease, disorder, and / or condition. Thus, in some embodiments, treatment may be prophylactic. In some embodiments, treatment may be therapeutic.

[0135] Variant: As used herein, the term "variant" refers to a molecule or entity (e.g., a nucleic acid, protein, or small molecule, e.g., a molecule or entity that exhibits significant structural identity with a reference molecule or entity, but that is structurally different from the reference molecule or entity, e.g., in the presence or absence, or level, of one or more chemical moieties compared to the reference molecule or entity. In some embodiments, a variant also differs functionally from its reference molecule or entity. In many embodiments, whether a particular molecule or entity is properly considered a "variant" of a reference is based on the degree of structural identity with the reference molecule. As will be understood by those skilled in the art, biological or chemical reference molecules are typically characterized by certain characteristic structural elements. A variant, by definition, is a distinct molecule or entity that shares one or more such characteristic structural elements but differs from the reference molecule or entity in at least one aspect. To give a few examples, a polypeptide may have characteristic sequence elements composed of multiple amino acids that have designated positions relative to each other in linear or three-dimensional space and / or contribute to a particular structural motif and / or biological function, and a nucleic acid may have characteristic sequence elements composed of multiple nucleotide residues that have designated positions relative to each other in linear or three-dimensional space. In some embodiments, a variant polypeptide or nucleic acid may differ from a reference polypeptide or nucleic acid as a result of one or more differences in amino acid or nucleotide sequence and / or one or more differences in chemical moieties (e.g., carbohydrates, lipids, phosphate groups) that are covalent components of the polypeptide or nucleic acid (e.g., to which the polypeptide or nucleic acid backbone is attached). In some embodiments, a variant polypeptide or nucleic acid exhibits an overall sequence identity with a reference polypeptide or nucleic acid that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, or 99%. In some embodiments, a variant polypeptide or nucleic acid does not share at least one characteristic sequence element with a reference polypeptide or nucleic acid.In some embodiments, a reference polypeptide or nucleic acid has one or more biological activities. In some embodiments, a variant polypeptide or nucleic acid shares one or more of the biological activities of the reference polypeptide or nucleic acid. In some embodiments, a variant polypeptide or nucleic acid lacks one or more of the biological activities of the reference polypeptide or nucleic acid. In some embodiments, a variant polypeptide or nucleic acid exhibits a reduced level of one or more biological activities compared to a reference polypeptide or nucleic acid. In some embodiments, a polypeptide or nucleic acid of interest is considered to be a "variant" of a reference polypeptide or nucleic acid if the amino acid or nucleotide sequence of the reference polypeptide or nucleic acid is identical to the reference amino acid or nucleotide sequence but has a small number of sequence changes at specific positions. Typically, less than about 20%, about 15%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, or about 2% of the residues in the variant are substituted, inserted, or deleted compared to the reference. In some embodiments, a variant polypeptide or nucleic acid contains about 10, about 9, about 8, about 7, about 6, about 5, about 4, about 3, about 2, or about 1 substituted residues compared to the reference. Often, a variant polypeptide or nucleic acid contains very few (e.g., less than about 5, about 4, about 3, about 2, or about 1) functional residues (i.e., residues responsible for a particular biological activity) substituted, inserted, or deleted compared to the reference. In some embodiments, a variant polypeptide or nucleic acid contains no more than about 5, about 4, about 3, about 2, or about 1 additions or deletions compared to the reference, and in some embodiments, no additions or deletions compared to the reference. In some embodiments, the variant polypeptide or nucleic acid comprises fewer than about 25, about 20, about 19, about 18, about 17, about 16, about 15, about 14, about 13, about 10, about 9, about 8, about 7, about 6, and fewer than about 5, about 4, about 3, or about 2 additions or deletions compared to the reference. In some embodiments, the reference polypeptide or nucleic acid is one that occurs in nature. In some embodiments, the reference polypeptide or nucleic acid is a human polypeptide or nucleic acid.

[0136] MODE FOR CARRYING OUT THE INVENTION The present disclosure provides, inter alia, novel activin A antibody agents that have improved binding kinetics, binding affinity, pharmacokinetics, and / or function, e.g., compared to a suitable reference anti-activin A antibody. In some embodiments, the activin A antibody agents disclosed herein bind to activin A with high affinity and / or high specificity. For example, in some embodiments, the activin A antibody agents have a K of about 5 pM to about 1000 pM (e.g., about 6.17 pM to about 960 pM) as assessed, e.g., in an assay that measures antibody binding affinity, e.g., a surface plasmon resonance assay (Biacore). D binds to activin A.

[0137] In some embodiments, provided activin A antibody agents may exhibit preferential binding to activin A compared to one or more TGF beta family members other than activin A. In some such embodiments, preferential binding may be assessed, for example, by simultaneously contacting the activin A antibody agent with activin A and one or more other TGF beta family members. Alternatively, or additionally, in some embodiments, preferential binding may be assessed in comparison to a suitable reference activin A antibody agent and may reflect, for example, a higher level of binding to activin A compared to one or more other TGF beta family members than observed with the reference antibody. In some embodiments, an activin A antibody agent does not bind to one or more TGF beta family members other than activin A. In some embodiments, an activin A antibody agent disclosed herein binds to activin A and also binds to one or more other TGF beta family members. For example, in some embodiments, provided activin A antibody agents bind to activin A and activin B or GDF11, or both.

[0138] In some embodiments, the activin A antibody agents disclosed herein inhibit the activity of activin A and / or reduce activin A levels (reducing activin A levels in blood, plasma, serum, and / or urine) when administered to a cell, tissue, or subject. In some embodiments, the activin A antibody agents disclosed herein can be used to treat a condition or disease associated with increased activin A. In some embodiments, the activin A antibody agents disclosed herein can be used to treat symptoms of a condition or disease associated with increased activin A. In some embodiments, the symptoms include any one, all, or a combination of mass loss, loss of appetite, fatigue, muscle mass loss, fat mass loss, lean mass loss, lean mass atrophy, functional muscle mass loss, muscle strength loss, bone loss, anemia, or fibrosis. Also provided herein are compositions comprising the activin A antibody agents disclosed herein, as well as methods for making and using the same.

[0139] Activin A Activin A is a roughly 25 kDa protein that forms homodimers with other activin A proteins via disulfide bridges and is a member of the transforming growth factor beta (TGF-beta) superfamily (Morianos I. et al. (2019) Journal of Autoimmunity, Volume 104). Activin A protein is synthesized as a precursor polypeptide containing an amino-terminal prodomain and a carboxy-terminal mature domain with 250–350 residues (Bloise E. et al. (2018) Physiological Reviews, 99(1)). The precursor polypeptide is cleaved by a furin-like protease, which releases the biologically active mature protein (see Bloise E et al. (2018)).

[0140] The human activin A polypeptide sequence is provided herein as SEQ ID NO: 215:

[0141] MPLLWLRGFLLASCWIIVRSSTPPGSEGHSAAPDCPSCALAALPKDVPNSQPEMVEAVKKHILNMLHLKKRPDVTQPVPKAALLNAIRKLHVGKVGENGYVEIEDD IGRRAEMNELMEQTSEIITFAESGTARKTLHFEISKEGSDLSVVERAEVWLFLKVPKANRTRTKVTIRLFQQQKHPQGSLDTGEEAEEVGLKGERSELLLSEKVVDA RKSTWHVFPVSSSIQRLLDQGKSSLDVRIACEQCQESGASLVLLGKKKKEEEGEGKKKGGGEGGAGADEEKEQSHRPFLMLQARQSEDHPHRRRRRGLECDGKVN ICCKKQFFVSFKDIGWNDWIIAPSGYHANYCEGECPSHIAGTSGSSLSFHSTVINHYRMRGHSPFANLKSCCVPTKLRPMSMLYYDDGQNIIKKDIQNMIVEECGCS The amino acid sequence of human activin A (SEQ ID NO: 215) includes a signal peptide (residues 1-20) and the mature activin A sequence (residues 311-426).

[0142] Human activin A signal peptide: MPLLWLRGFLLASCWIIVRS (SEQ ID NO: 217)

[0143] Mature human activin A sequence: GLECDGKVNICCKKQFFVSFKDIGWNDWIIAPSGYHANYCEGECPSHIAGTSGSSLSFHSTVINHYRMRGHSPFANLKSCCVPTKLRPMSMLYYDDGQNIIKKDIQNMIVEECGCS (SEQ ID NO: 218)

[0144] Human activin A can be encoded by the following nucleic acid sequence from the INHBA gene (SEQ ID NO: 216): 1 agtacagtat aaaacttcac agtgccaata ccatgaagag gagctcagac agctcttacc 61 acatgataca agagccggct ggtggaagg tgggaccag aagagaatt tgctgaagag 121 gagagaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaacc 181 tgcgcgtgag gggggaggaa aagcagggcc ttttaaaag gcaatcacacaa siactttgc 241 tgccaggatg cccttgctt ggctgagagg atttcttg gcaagttgct ggattatagt 301 gaggagttcc cccacccag gatccgaggg gcacagcgcg gccccgact gtccgtccctg 361 tgcgctggcc gcccccaa aggatgtacc caacctcag ccagagatgg tggaggccgt 421 caagaagcac attackaaca tgctgcactt gagagaga cccgatgtca cccagccggt 481 acccaggcg gcgcttctga acgcgatcag aaagctcat gtgggcaag tcgggagaa 541 cgggtagtg gagatagagg atgacattgg aaggaggca gaatgaatg aacttatgga 601 gcagacctcg gagatcatca cgtttgccga gtcaggaaca gccaggaaga cgctgcactt 661 cgagatttcc aaggaaggca gtgacctgtc agtggtggag cgtgcagaag tctggctct 721 cctaaagtc cccaaggcca acaggaccag gaccaagctc accatccgcc tctccagca 781 gcagaagcac ccgcagggca gcttggacac aggggagag gccgaggag tgggcttaaa 841 gggggagagg agtgaactgt tgctctctga aaaagtagta gacgctcgga agagcacctg 901 gcatgtcttc cctgtctcca gcagcatcca gcggttgctg gcagggca agagctccct 961 ggacgttcgg attgcctgtg agcagtgcca ggagagtggc gccagcttgg ttctcctggg 1021 caagaagaag aagaagaag aggagggga aggaaaag aagggcggag gtgaaggtgg 1081 ggcaggagca gatgaggaa aggagcagtc gcacagacct ttcctcatgc tgcaggcccg 1141 gcagtctgaa gaccaccctc atcgccggcg tcggcggggc ttggagtgtg atggcaaggt 1201 caacatctgc tgtaagaaac agttctttgt cagtttcaag gacatcggct ggaatgactg 1261 gatcattgct ccctctggct atcatgccaa ctactgcgag ggtgagtgcc cgagccatat 1321 agcaggcacg tccgggtcct cactgtcctt ccactcaaca gtcatcaacc actaccgcat 1381 gcggggccat agcccctttg ccaacctcaa atcgtgctgt gtgcccacca agctgagacc 1441 catgtccatg ttgtactatg atgatggtca aaacatcatc aaaaaggaca ttcagaacat 1501 gatcgtggag gagtgtgggt gctcatagag ttgcccagcc caggggaaa gggagcaaga 1561 gttgtccaga gagacagtg gcaaatgaa gaattttta agttttctga gttaaccaga 1621 aaatagaaaaaaaaaaaaaaaaaaaaaaaag 1681 aaaaacctg atgaacaga tgaagaga tgtggaaaa atccttagcc agggctcaga 1741 gatgaagcag tgaagagac aggaattggg agggaaggg agatggtgt accctttatt 1801 tttctgaa tcatgat catcagtt gtttaacgg gttattgtcc ttcccct 1861 tgaggttccc tgtgagcct tgaatcacc atatctatct gcagtagtgt ggactagac 1921 aaccaata gcatctagaa agccatgagt ttgaagggc ccatcacagg cactttccta 1981 cccaattacc caggtcataa gtatgtctg tgtgacactt atctctgtgt atatcagcat 2041 acacacac acacacac acacacac acacacat tccacacat tacatatata 2101 cacatactgg taaagaaca atcgtgtgca gtgtcaca cttcctttt ctgtaccact 2161 ttgcaaaaaaaaaaaaaaattgaga acagtatgg aagaatgaa 2221 agatcaagga aaaaagaata ccaagttaca tttcgttaag gtgcttatga tcttagaact 2281 atgcaaccta ataggtttga aactgtttac ctgagagaga acaaaaagag agacttttttt 2341 gtattggaag taatctgatt aatttttatt ttcttcaagg agagatactt gaaaggaata 2401 tgtttgtcca tctgttggat ccaaacattt ctatattttg taaatgttgt tgttgttttt 2461 ttttaatcg tttactattt gcactacaat ggtgtttgac ctgtctaatc cttatttaac 2521 aagtattttc tttggttggg ggtgggggtg gggtttaaga gctgcactta atgtgagcta 2581 taaaagaact gctacagcac acaaatagc tatttttatt attataatta taattattat 2641 tattattttg taccttaaaa atagacaca tacaccaaag acatttgtgt gagcctttaa 2701 acagtctgtc tgtggttggt atcattcacc atcaatgagt caggggttgg gattcaaggt 2761 tgagtagtgt ggattgtgtt caggcttaaa agacctgaga agttggtttt ttgactcctt 2821 ttacatccat gaaacaggac atttcatact ggatgtacag tagttgtaca ctgttggata 2881 tcaagttcaa tcaaattcat ggaactacat gcttgtatgt gtatatatac attgcttgtg 2941 catatgcata tctgtatgta tatatacatg tattgtacca tgtccataca cattttaagc 3001 acttcaggct gtcattttt aatgttctta aagcaatgaa tgtttgtgtg caaaacacag 3061 tatttttaag aaggataggc tatagttttt gcttttactc tgaactaggt gggcgcattt 3121 caaaaattcg gatgggaaaa agcctggaaa ttccagtgaa tattcagcaa ggcccttt 3181 cattgtacag ggatcaaatt tcctcctcttt ttttgtgccc cctcccactt ctacaagtta 3241 tcccctgtgg ggaaaacagg atgataatca aaactctggg ctgatgtttt tccaacttag 3301 tgtctattgg aatcaatctt aaatcagaag ctttttcaga aaaataatat ttaggccaga 3361 attagagttg agtgtatttt ttaaaaatga ttaaggcttg gttgtgagaa atattacctg 3421 taccagctgg gaaaaatat gtcatcacta actaaaagat aattaatttg agagaaagtg 3481 ttaagagagg gagagtaagg aagagaacag ttaagaggag gcagaggtga gggcagtagt 3541 aaaaatctct aaaattttaa tttacagcca aaattcttca tgtgtaaatt tgtattgatt 3601 cagatgcaga aatgaaaaaa aaacaccttt gttttataaa tatcaaagta catgcttaaa 3661 gccaagtttt tatctagttt attctagtac ttagcttgcc tggaatagct aataaattat 3721 tcatgtatgt gcttttgaaa atccagagcc ctatttttac acacttgtgt gaagttggca 3781 aacatttga aaaatggaaa aaagtttcta ataattggga acaattacat taattaataat 3841 tttgtaaaat attgaagctt ttagccctat gtcaatttgt agattaaaat aaattaatta 3901 taggaaagga agataacagt gagaaaccaa acattacaaa aggtggttta gctctccttg 3961 aaaatac tagttggta tactataaca cttggctata tgtaggcaat gtcactactg 4021 ggcaaataca cttactgtgt tctagaggca gccctttctt atgcagaaaa tacaatacgc 4081 actgcatgag aagcttgaga gtggattcta atccaggtct gtcgaccttg gatatcatgc 4141 atgtgggaag gtgggtgtgg tgagaaaagt tttaaggcaa gagtagatgg ccatgttcaa 4201 ctttacaaaa tttcttggaa aactggcagt atttgaact gcatcttctt tggtaccgga 4261 acctgcagaa acagtgtgag aaattaagtc ctggttcact gcgcagtagc aaagatggtc 4321 aaggccatgg aaaaagcaga aatttaccaa gaaagctgat acccatgtat agttcccact 4381 catctcaat acatctgcta tcttttag ctaagtccta gatatcgg ggatacatg 4441 ggggttgatt agtgaccaca gttatcagaa gcagagaaat gtaattccat attttatttg 4501 aaacttattc catattttaa ttggatattg agtgatgggg ttcaaca cccacaact 4561 ttaatttgt taaatttata tggctttgaa atagaagtat aagttgctac catttttga 4621 taacattgaa agatagtatt tacatctt ggaaataca agtcctgtga 4681 acaaccactc ttcacctag cagcatgagg ccaaagtaa aggctttaaa ttatacata 4741 tgggattt agtagtatgt ttttcttg aaactcagtg gcttatcta accttactat 4801 ctcctacactc tttctctaag actaactct aggcttta aaatctcccc accaccact 4861 tagtaacct gaaaagaatt tgtctttaaa tatcttta tagtacatg tattttgg 4921 accaattga cattttcgac tattttcc aaaaagtca ggtgaatttc agcacactga 4981 gttgggaatt tcttatccca gagaccaac caatttcata tttatttaag attgattcca 5041 tactccgttt tcaggagaa tccctgcagt ctccttaaag gtagacaaa tactttctat 5101 tttttttca cattgtggg attggacttt aagaggtgac tctaaaaaaa cagagaacaa 5161 atatgtctca gttgtattaa gcacggaccc atattatcat attcacttaa aaaaatgatt 5221 tcctgtgcac cttttggcaa cttctctttt caatgtaggg aaaaacttag tcaccctgaa 5281 aacccacaaa ataaataaaa cttgtagatg tgggcagaag gtttgggggt ggacattgta 5341 tgtgtttaaa ttaaaccctg tatcactgag aagctgttgt atgggtcaga gaaaatgaat 5401 gcttagaagc tgttcacatc ttcaagagca gaagcaaacc acatgtctca gctatattat 5461 tatttatttt tttgcataa agtgaatcat ttcttctgta ttaatttcca aagggtttta 5521 ccctctattt aaatgctttg aaaacagtg cattgacaat gggttgatat ttttctttaa 5581 aagaaaata taattatgaa agccaagata atctgaagcc tgttttattt taaaactttt 5641 tatgttctgt ggttgatgtt gttgtgtgt ttgtttctat tttgttggtt tttactttg 5701 ttttttgttt tgttttgttt tgttttgcat actacatgca gttctttaac caatgtctgt 5761 ttggctaatg taattaaagt tgttaattta tatgagtgca tttcaactat gtcaatggtt 5821 tcttaatatt tattgtgtag aagtactggt aattttttta tttacaatat gtttaaagag 5881 ataacagttt gatatgtttt catgtgttta tagcagaagt tatttatttc tatggcattc 5941 cagcggatat tttggtgttt gcgaggcatg cagtcaatat tttgtacagt tagtggacag 6001 tattcagcaa cgcctgatag cttctttggc cttatgttaa ataaaaagac ctgtttggga 6061 tgtaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaa

[0145] Activin A can bind to type I receptor or type II receptor. Activin A's binding to type II receptor, such as ActRIIA or AcRIIB, recruits and phosphorylates type I receptor (such as ActRI or ALK4). Upon activation of type I receptor, Smad2 and Smad3 proteins are phosphorylated, activating appropriate downstream signal cascades. Furthermore, activation of type I receptor can also result in the activation of pathways such as p38 MAPK pathway, ERK1 / 2 pathway, and JNK pathway.

[0146] Without wishing to be bound by any particular theory, in some embodiments, the activin A antibody agents disclosed herein bind to activin A and inhibit the binding of endogenous activin A (e.g., active activin A) to an activin A receptor (e.g., a type II receptor [e.g., ACTRIIA or ACTRIIB] and / or a type I receptor [e.g., ActRI or ALK4]), thus preventing activation of the type I and / or type I receptor and / or one or more downstream signaling pathways. In some embodiments, modulation of the activin A receptor by the activin A antibody agents disclosed herein allows for the treatment of conditions, diseases, or disorders associated with (e.g., mediated by) activin A.

[0147] Furthermore, without wishing to be bound by any particular theory, in some embodiments, the activin A antibody agents disclosed herein bind to activin A and inhibit the binding of endogenous activin A to a receptor, e.g., a receptor that binds to activin A, e.g., an activin A receptor (e.g., a type II receptor [e.g., ACTRIIA or ACTRIIB] and / or a type I receptor [e.g., ActRI or ALK4]). In some embodiments, the activin A receptor is accessible to, e.g., an antibody agent as disclosed herein.

[0148] While certain anti-activin A antibodies have been previously developed (see, e.g., WO2015017576), none of the antibodies known in the art have previously been demonstrated as a viable therapeutic option for preventing and treating conditions, diseases, or disorders associated with (e.g., mediated by) elevated levels of activin A, or symptoms thereof, and further, none teach or suggest the specific antibodies or antibody agents described herein, which exhibit surprising and unexpected properties, including those described herein. In some embodiments, the elevated level of activin A is greater than or equal to about 500 pg / ml, e.g., as assessed in a sample from a subject, e.g., a blood, plasma, serum, or urine sample. In some embodiments, provided antibody agents block and / or reverse weight loss, even in dramatic weight loss contexts (e.g., models), involving, for example, strong and / or complete blockage of functional signaling through activin A receptors; alternatively or additionally, in some embodiments, provided antibody agents prevent or reverse mass loss (e.g., muscle mass loss, lean mass loss, fat mass loss, and / or bone mass loss), mass loss, aging, liver damage, kidney damage, or cancer. Thus, the present disclosure provides novel activin A antibody agents that can be used to fill the unmet need for the treatment and / or prevention of conditions, diseases or disorders associated with elevated activin A, or symptoms thereof.

[0149] Activin A antibody Disclosed herein are activin A antibody agents that bind, e.g., specifically bind, e.g., with high affinity, to activin A. The anti-activin A antibodies disclosed herein can be effective in plasma and / or multiple tissue compartments, and activin A can act on its target cells, e.g., cells that express a receptor that binds to activin A.

[0150] In some embodiments, activin A target cells are or include cells expressing an activin A receptor (e.g., a type II receptor [e.g., ACTRIIA or ACTRIIB] and / or a type I receptor [e.g., ActRI or ALK4]). In some embodiments, an activin A antibody agent can modulate the activin A receptor pathway to inhibit one or more activities of activin A or reduce the level of activin A, e.g., reduce the level of free and / or active activin A in blood, plasma, serum, and / or urine. In some embodiments, an activin A antibody agent disclosed herein binds to activin A and inhibits the activity of activin A and / or reduces the level of activin A, e.g., reduce the level of free and / or active activin A in blood, plasma, serum, and / or urine. In some embodiments, the activin A antibody agents disclosed herein bind to activin A and prevent activin A from binding to an activin A receptor (e.g., a type II receptor [e.g., ACTRIIA or ACTRIIB] and / or a type I receptor [e.g., ActRI or ALK4]). In some embodiments, the binding of the activin A antibody agent to activin A prevents activation of the activin A receptor (e.g., a type II receptor [e.g., ACTRIIA or ACTRIIB] and / or a type I receptor [e.g., ActRI or ALK4]).

[0151] In some embodiments, activin A target cells are or include cells that express an activin A receptor. In some embodiments, activin A antibody agents disclosed herein bind to activin A and inhibit the activity of activin A and / or reduce the level of activin A, e.g., reduce the level of free and / or active activin A. In some embodiments, activin A antibody agents disclosed herein bind to activin A and prevent the binding of activin A to an activin A receptor (e.g., type II receptor [e.g., ACTRIIA or ACTRIIB] and / or type I receptor [e.g., ActRI or ALK4]).

[0152] In some embodiments, the activin A antibody agents disclosed herein bind to any or all forms of activin A, e.g., homodimeric activin A, monomeric activin A, intracellular activin A, soluble activin A, ECM-bound activin A, mature activin A, proprotein activin A (e.g., preprocessed) and / or active activin A.

[0153] In some embodiments, the activin A binding agent specifically binds to activin A and reduces levels of activin A (e.g., free and / or active activin A). In some embodiments, levels of homodimeric activin A are reduced. In some embodiments, levels of circulating activin A are reduced. In some embodiments, levels of free and / or active activin A are reduced. In some embodiments, levels of free and active activin A are reduced.

[0154] In some embodiments, the level of activin A (e.g., free and / or active activin A) is reduced compared to a comparator agent. In some embodiments, the comparator agent comprises cells, tissues, or subjects that have not been contacted with an activin A antibody agent disclosed herein.

[0155] In some embodiments, the level of activin A (e.g., free and / or active activin A) is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100%. In some embodiments, the level of activin A (e.g., free and / or active activin A) is reduced by about 5% to about 100%, about 10% to about 100%, about 15% to about 100%, about 20% to about 100%, about 25% to about 100%, about 30% to about 100%, about 35% to about 100%, about 40% to about 100%, about 45% to about 100%, about 50% to about 100%, about 55% to about 100%, about 60% to about 100%, about 65% to about 100%, about 70% to about 100%, about 75% to about 100%, about 80% to about 100%, about 90% to about 100%, or about 95% to about 100%.

[0156] In some embodiments, the level of activin A (e.g., free and / or active activin A) is reduced by about 5% to about 100%, about 5% to about 95%, about 5% to about 90%, about 5% to about 85%, about 5% to about 80%, about 5% to about 75%, about 5% to about 70%, about 5% to about 65%, about 5% to about 60%, about 5% to about 55%, about 5% to about 50%, about 5% to about 45%, about 5% to about 40%, about 5% to about 35%, about 5% to about 30%, about 5% to about 25%, about 5% to about 20%, about 5% to about 15%, or about 5% to about 10%.

[0157] In some embodiments, activin A activity comprises the activity of an activin receptor. In some embodiments, activin A activity comprises the activity of one or more signal transduction pathways activated by an activin receptor. In some embodiments, the activin receptor-mediated signal transduction pathway comprises one or more of: (i) the SMAD pathway, (ii) the ERK / MAPK pathway, (iii) the p38 MAPK pathway, (iv) NOX-2-dependent signal transduction, or (v) a Snail- and / or Slug-mediated pathway.

[0158] Disclosed herein are activin A antibody agents that can modulate the activity of activin A. In some embodiments, the activin A antibody agents specifically bind to activin A and modulate one or more, or all, or any combination of detectable activin A activities, such that the antibody agents modulate activin A receptor activity, modulate the SMAD pathway, modulate the ERK / MAPK pathway, modulate the p38MAPK pathway, modulate NOX-2-dependent signaling, modulate Snail- and / or Slug-mediated pathways, or modulate a combination thereof.

[0159] Those skilled in the art will appreciate that in some embodiments, for example, as described herein, activin A activity can be assessed using one or more artisan-recognized assays. For example, activin 2B receptor / SMAD reporter assays can be used to assess activin A activity, as disclosed in Example 2 herein.

[0160] The human activin A protein sequence is highly conserved in primates, rodents, domestic mammals, birds, and other species such as pandas, seals, sloths, and whales. Table 15 provides a summary of the sequence homology between human activin A and activin A in various species. The list provided in Table 15 is an exemplary list of species with activin A that is highly conserved compared to human activin A. In addition to those disclosed in Table 15, many other animals and birds have activin A protein sequences that are highly homologous (e.g., >95%) to human activin A. Upon reading this disclosure, one skilled in the art will understand that known methods for determining sequence homology can be used to distinguish activin A from other species that share high sequence homology with human activin A, for example, as described herein.

[0161] [Table 15-1] [Table 15-2]

[0162] Based on the high homology between human activin A and activin A from other species, as shown in Table 14, one skilled in the art will understand that the activin A antibody agents disclosed herein will bind to one or more of the species shown in Table 14.

[0163] In some embodiments, the activin A antibody agents disclosed herein specifically bind to human activin A. In some embodiments, the activin A antibody agents disclosed herein specifically bind to primate activin A. In some embodiments, the activin A antibody agents disclosed herein specifically bind to domestic mammal activin A. In some embodiments, the domestic mammal is selected from a dog, cat, ferret, horse, sheep, pig, Bactrian camel, and yak.

[0164] In some embodiments, provided activin A antibody agents may exhibit preferential binding to activin A relative to one or more TGF beta family members other than activin A. In some such embodiments, preferential binding may be assessed, for example, by contacting the activin A antibody agent with activin A and one or more other TGF beta family members simultaneously. Alternatively, or additionally, in some embodiments, preferential binding may be assessed in comparison to a suitable reference activin A antibody agent (e.g., as described in WO2015017576) and may reflect, for example, a higher level of binding to activin A relative to one or more other TGF beta family members than observed with the reference antibody.

[0165] In some embodiments, the activin A antibody agents disclosed herein preferentially bind to activin A. In some embodiments, the activin A antibody agents disclosed herein do not bind to one or more members of the TGF beta superfamily other than activin A. In some embodiments, the activin A antibody agents disclosed herein do not bind to GDNF, GDF8, GDF10, GDF11, BMP9, BMP10, activin B, or a combination thereof.

[0166] In some embodiments, an activin A antibody agent disclosed herein preferentially binds to activin A. In some embodiments, an activin A antibody agent disclosed herein binds to one or more members of the TGF-beta superfamily in addition to activin A. In some embodiments, an activin A antibody agent disclosed herein binds to activin A and activin B, or GDF11, or both. In some embodiments, an activin A antibody agent disclosed herein binds to activin A and activin B. In some embodiments, an activin A antibody agent disclosed herein binds to activin A and GDF11. In some embodiments, an activin A antibody agent disclosed herein binds to activin A, activin B, and GDF11.

[0167] In some embodiments, an activin A binding agent that binds to activin A and activin B does not modulate activin B activity and / or levels, for example, when characterized in an assay that assesses activin B activity and / or levels.

[0168] In some embodiments, an activin A binding agent that binds to activin A and GDF11 does not modulate GDF11 activity and / or levels, for example, when characterized in an assay that assesses GDF11 activity and / or levels.

[0169] Those skilled in the art will understand that in some embodiments, for example, as described herein, the activity of activin B or GDF11 can be assessed using one or more artisan-recognized assays. For example, as disclosed in Example 2 herein, an assay using cells expressing an activin 2B receptor / SMAD reporter can be used to assess the activity of activin B or GDF11. Several assays can be used to measure activation of the activin 2B receptor and induction of SMAD signaling following stimulation with activin B or GDF11, for example, a luciferase-based reporter system.

[0170] Without wishing to be bound by theory, the provided activin A antibody agents can bind to activin A and one or more members of the TGF beta superfamily, but the regulatory effect of the provided activin A antibody agents on activin A may be independent of binding to one or more TGF beta superfamily members.

[0171] Those skilled in the art reading this disclosure will understand that, in some embodiments, antibody agents provided by the present disclosure include (i) intact IgA, IgG, IgD, IgE, or IgM antibodies, (ii) antibody fragments (e.g., antibody variable regions containing both heavy and light chain sequences, e.g., Fab), (iii) single domain antibodies (e.g., light chain antibodies or heavy chain antibodies), (iv) single chain antibodies (e.g., single chain Fv, camelid antibodies, etc.), (v) antibody-drug conjugates, (vi) bispecific or other multispecific antibodies, (vii) polypeptides comprising an antigen-binding specificity fused to an Fc region, etc.

[0172] Those of skill in the art reading this disclosure will further appreciate if the contributions provided are not limited to intact antibodies or fragments thereof (eg, including both heavy and light chain sequences).

[0173] For example, one of skill in the art will understand that individual light chains and / or individual heavy chains, or their variable region sequences (e.g., as exemplified herein, e.g., as presented in Table 1), described herein may be useful in combination with other light chains and / or heavy chains. In some embodiments, a single light chain (or its variable region sequence) described herein may be utilized with two (or more) different heavy chains (e.g., which may be or include heavy chains exemplified herein), or their variable region sequences, in a "common light chain" bispecific format. In some embodiments, exemplary light and heavy chains (e.g., their variable region sequences) may be "mixed and matched" with each other in antibody agents provided by the present disclosure (e.g., antibody agents that specifically bind to activin A and / or have one or more other structural and / or functional properties described herein).

[0174] Furthermore, one of skill in the art will appreciate that the present disclosure provides useful heavy and light chain antibody sequences, specifically including useful variable region sequences, including, for example, useful CDR and / or framework (FR) sequences.

[0175] In some embodiments, the present disclosure provides polypeptides (e.g., which may be or may be included in an antibody agent that specifically binds to activin A) that comprise one or more CDR and / or FR sequences set forth in Table 1 or 2. In some embodiments, the present disclosure provides polypeptides that comprise two or more CDR elements from Table 1 or 2, and in particular, the present disclosure provides polypeptides that comprise three or six CDR elements from Table 1 or 2.

[0176] In some embodiments, the present disclosure provides a polypeptide (e.g., which may be or be included in an antibody agent that specifically binds to activin A) that includes one LC CDR1, one LC CDR2, and one LC CDR3 from Table 1. In some such embodiments, two or three CDRs are from the same LC of Table 1.

[0177] In some embodiments, the present disclosure provides a polypeptide (e.g., which may be or may be included in an antibody agent that specifically binds to activin A) that includes one HC CDR1, one HC CDR2, and one HC CDR3 from Table 2. In some such embodiments, two or three CDRs are from the same HC in Table 2.

[0178] In some embodiments, the present disclosure provides a polypeptide (e.g., which may be or be included in an antibody agent that specifically binds to activin A) comprising one each of an LC CDR1, an LC CDR2, an LC CDR3, an HC CDR1, an HC CDR2, and an HC CDR3 from Table 1 or 2. In some such embodiments, two or more CDRs, and in some embodiments, all of the LC CDRs, all of the HC CDRs, or both, are derived from the same antibody of Table 1 or 2.

[0179] Those of skill in the art will further understand that, in some embodiments, useful polypeptides described herein comprising one or more CDRs from Table 1 or 2 may comprise a heavy or light chain CDR set (i.e., each of CDR1, CDR2, and CDR3) comprising one or two CDRs from a first antibody chain (i.e., LC or HC) in Table 1 or 2 and at least one from a second antibody chain (e.g., of the same type) in Table 1 or 2. Alternatively, or additionally, those of skill in the art will understand that, in some embodiments, useful polypeptides described herein comprising one or more CDRs from Table 1 or 2 may comprise a heavy or light chain CDR set (i.e., each of CDR1, CDR2, and CDR3) comprising at least one CDR from a first antibody chain (i.e., LC or HC) in Table 1 or 2 and at least one other CDR that differs from its corresponding CDR in the relevant chain in Table 1 or 2. In some such embodiments, the different CDR(s) will differ from the corresponding CDR(s) at no more than 3, no more than 2, or no more than 1 position; alternatively or additionally, in some such embodiments, the different CDR(s) will differ from the corresponding CDR(s) only at the terminal residue(s).

[0180] In some embodiments, an activin A antibody agent disclosed herein that binds to activin A comprises LC CDR1, LC CDR2, and LC CDR3 as provided in Table 1. In some embodiments, the presence of LC CDR1, LC CDR2, and LC CDR3 is sufficient to confer binding and / or otherwise useful in an antibody agent disclosed herein (i.e., specifically binds to activin A). In some embodiments, an antibody agent comprising LC CDR1, LC CDR2, and LC CDR3 can be in any format disclosed herein. For example, in some embodiments, an antibody agent comprising LC CDR1, LC CDR2, and LC CDR3 can be a single-chain antibody and can bind to activin A.

[0181] In some embodiments, an activin A antibody agent disclosed herein that binds to activin A comprises HC CDR1, HC CDR2, and HC CDR3 and is sufficient to confer binding to activin A and / or is otherwise useful in the antibody agents disclosed herein. In some embodiments, an antibody agent comprising HC CDR1, HC CDR2, and HC CDR3 can be in any format disclosed herein. For example, in some embodiments, an antibody agent comprising HC CDR1, HC CDR2, and HC CDR3 can be a single chain antibody and can bind to activin A.

[0182] In some embodiments, an activin A antibody agent disclosed herein that binds to activin A comprises any set of three LC CDRs (e.g., LC CDR1, LC CDR2, and LC CDR3) provided in Table 1, and any set of three HC CDRs (e.g., HC CDR1, HC CDR2, and HC CDR3) provided in Table 2. In some embodiments, the presence of any set of three LC CDRs and any set of three HC CDRs is sufficient to confer binding of any antibody agent disclosed herein to activin A. In some embodiments, such an activin A antibody agent can be a fragment (e.g., scFv, Fab, or other fragment), or an intact antibody, or a polypeptide comprising the antigen-binding specificity fused to Fc.

[0183] In some embodiments, disclosed herein are activin A antibody agents that compete (e.g., when tested in a standard competition assay) for binding to human activin A with a different activin A antibody agent, such as an activin A antibody agent disclosed in WO2015017576. In some embodiments, an activin A antibody agent disclosed herein competes for binding to human activin A with a different activin A antibody agent when evaluated at two or more concentrations (e.g., over a concentration range of at least 2-fold, 4-fold, 6-fold, 8-fold, 10-fold or more).

[0184] In some embodiments, disclosed herein are activin A antibody agents that do not compete (e.g., when tested in a standard competition assay) for binding to human activin A with a different activin A antibody agent, e.g., an activin A antibody agent disclosed in WO2015017576.

[0185] In some embodiments, disclosed herein are activin A antibody agents that bind to sterically overlapping (e.g., partially or completely overlapping) epitopes as the activin A antibody agents disclosed in WO2015017576.

[0186] Light chain (e.g., light chain variable region) polypeptide (LC polypeptide) The present disclosure provides polypeptides comprising light chain (LC) sequences (e.g., light chain variable region sequence(s)) that may be useful, for example, in the antibody agents described herein that target activin A. In some such embodiments, such provided polypeptides are useful and / or included in such antibody agents described herein. In some embodiments, the LC polypeptide comprises at least one LC CDR provided in Table 1 or a sequence having at least 85% identity thereto. In some embodiments, the LC polypeptide comprises one, two, or three LC CDRs (e.g., LC CDR1, LC CDR2, and / or LC CDR3). In some embodiments, the LC polypeptide comprises an LC CDR1. In some embodiments, the LC polypeptide comprises an LC CDR2. In some embodiments, the LC polypeptide comprises an LC CDR3. In some embodiments, the LC polypeptide comprises an LC CDR1, an LC CDR2, and an LC CDR3.

[0187] In some embodiments, for example, in an activin A antibody agent, an LC polypeptide having LC CDR1, LC CDR2, and LC CDR3 can bind (eg, specifically bind) to activin A.

[0188] In some embodiments, the LC polypeptide further comprises one or more framework regions and / or constant regions.

[0189] In some embodiments, the LC polypeptide comprises a light chain constant region and / or a heavy chain constant region, hi some embodiments, the LC polypeptide comprises a light chain constant region or a portion thereof (e.g., a lambda light chain constant region or a variant or portion thereof, or a kappa light chain constant region or a variant or portion thereof).

[0190] In some embodiments, the light chain kappa constant region comprises the sequence of SEQ ID NO:102, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:102.

[0191] RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 102, light chain kappa)

[0192] In some embodiments, the LC polypeptide comprises the sequence of SEQ ID NO: 102, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 102.

[0193] In some embodiments, the LC polypeptide disclosed herein further comprises a half-life extender. In some embodiments, the half-life extender is or comprises albumin, such as human serum albumin. In some embodiments, the half-life extender comprises a modification that increases binding to neonatal Fc receptor (FcRn).

[0194] In some embodiments, the LC polypeptide comprises (i) an LC CDR1 sequence provided in Table 1, e.g., any one of SEQ ID NOs: 1, 11, 28, 53, 68, 85, or 93; (ii) a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity to an LC CDR1 sequence provided in Table 1, e.g., any one of SEQ ID NOs: 1, 11, 28, 53, 68, 85, or 93; or (iii) a sequence having at least 5, 10, or 20 substitutions to an LC CDR1 sequence provided in Table 1, e.g., any one of SEQ ID NOs: 1, 11, 28, 53, 68, 85, or 93.

[0195] In some embodiments, the LC polypeptide comprises (i) an LC CDR2 sequence provided in Table 1, e.g., any one of SEQ ID NOs: 2, 16, 29, 43, 48, 54, 61, 69, 86, or 94; (ii) a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity to an LC CDR2 sequence provided in Table 1, e.g., any one of SEQ ID NOs: 2, 16, 29, 43, 48, 54, 61, 69, 86, or 94; or (iii) a sequence having at least 5, 10, or 20 substitutions to an LC CDR2 sequence provided in Table 1, e.g., any one of SEQ ID NOs: 2, 16, 29, 43, 48, 54, 61, 69, 86, or 94.

[0196] In some embodiments, the LC polypeptide is (i) a LC CDR3 sequence provided in Table 1, e.g., any one of SEQ ID NOs: 3, 12, 17, 21, 30, 36, 44, 49, 55, 62, 70, 80, 87, or 95; (ii) a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity to a LC CDR3 sequence provided in Table 1, e.g., any one of SEQ ID NOs: 3, 12, 17, 21, 30, 36, 44, 49, 55, 62, 70, 80, 87, or 95; or (iii) a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity to a LC CDR3 sequence provided in Table 1, e.g., any one of SEQ ID NOs: 3, 12, 17, 21, 30, 36, 44, 49, 55, 62, 70, 80, 87, or 95. CDR3 sequences, for example, sequences having at least 5, 10, or 20 substitutions relative to any one of SEQ ID NOs: 3, 12, 17, 21, 30, 36, 44, 49, 55, 62, 70, 80, 87, or 95.

[0197] In some embodiments, an antibody agent comprising LC CDR1, LC CDR2, and / or LC CDR3 can specifically bind to activin A.

[0198] In some embodiments, the LC polypeptide comprises (i) the LC CDR1, LC CDR2, and LC CDR3 sequences provided in Table 1, (ii) a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity to the LC CDR1, LC CDR2, and LC CDR3 sequences provided in Table 1, or (iii) a sequence having at least 5, 10, or 20 substitutions to the LC CDR1, LC CDR2, and LC CDR3 sequences provided in Table 1.

[0199] In some embodiments, the LC polypeptide comprises (i) an LC CDR1 of SEQ ID NO: 1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 1; (ii) an LC CDR2 of SEQ ID NO: 2, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 2; and / or (iii) an LC CDR3 of SEQ ID NO: 3. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:3.

[0200] In some embodiments, the LC polypeptide comprises (i) an LC CDR1 of SEQ ID NO: 11, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 11; (ii) an LC CDR2 of SEQ ID NO: 2, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 2; and / or (iii) an LC CDR3 of SEQ ID NO: 12. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 12.

[0201] In some embodiments, the LC polypeptide comprises (i) an LC CDR1 of SEQ ID NO: 11, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 11; (ii) an LC CDR2 of SEQ ID NO: 16, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 16; and / or (iii) an LC CDR3 of SEQ ID NO: 17. CDR3 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 17.

[0202] In some embodiments, the LC polypeptide comprises (i) an LC CDR1 of SEQ ID NO: 11, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 11; (ii) an LC CDR2 of SEQ ID NO: 2, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 2; and / or (iii) an LC CDR3 of SEQ ID NO: 21. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:21.

[0203] In some embodiments, the LC polypeptide comprises (i) an LC CDR1 of SEQ ID NO: 28, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 28; (ii) an LC CDR2 of SEQ ID NO: 29, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 29; and / or (iii) an LC CDR3 of SEQ ID NO: 30. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 30.

[0204] In some embodiments, the LC polypeptide comprises (i) an LC CDR1 of SEQ ID NO: 1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 1; (ii) an LC CDR2 of SEQ ID NO: 2, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 2; and / or (iii) an LC CDR3 of SEQ ID NO: 36. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 36.

[0205] In some embodiments, the LC polypeptide comprises (i) an LC CDR1 of SEQ ID NO: 11, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 11; (ii) an LC CDR2 of SEQ ID NO: 43, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 43; and / or (iii) an LC CDR3 of SEQ ID NO: 44. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:44.

[0206] In some embodiments, the LC polypeptide comprises (i) an LC CDR1 of SEQ ID NO: 11, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 11; (ii) an LC CDR2 of SEQ ID NO: 48, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 48; and / or (iii) an LC CDR3 of SEQ ID NO: 49. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:49.

[0207] In some embodiments, the LC polypeptide comprises (i) an LC CDR1 of SEQ ID NO: 53, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 53; (ii) an LC CDR2 of SEQ ID NO: 54, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 54; and / or (iii) an LC CDR3 of SEQ ID NO: 55. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 55.

[0208] In some embodiments, the LC polypeptide comprises (i) an LC CDR1 of SEQ ID NO: 28, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 28; (ii) an LC CDR2 of SEQ ID NO: 61, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 61; and / or (iii) an LC CDR3 of SEQ ID NO: 62. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 62.

[0209] In some embodiments, the LC polypeptide comprises (i) an LC CDR1 of SEQ ID NO: 68, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 68; (ii) an LC CDR2 of SEQ ID NO: 69, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 69; and / or (iii) an LC CDR3 of SEQ ID NO: 70. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 70.

[0210] In some embodiments, the LC polypeptide comprises (i) an LC CDR1 of SEQ ID NO: 28, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 28; (ii) an LC CDR2 of SEQ ID NO: 61, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 61; and / or (iii) an LC CDR3 of SEQ ID NO: 80. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 80.

[0211] In some embodiments, the LC polypeptide comprises (i) an LC CDR1 of SEQ ID NO: 85, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 85; (ii) an LC CDR2 of SEQ ID NO: 86, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 86; and / or (iii) an LC CDR3 of SEQ ID NO: 87. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 87.

[0212] In some embodiments, the LC polypeptide comprises (i) an LC CDR1 of SEQ ID NO: 93, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 93; (ii) an LC CDR2 of SEQ ID NO: 94, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 94; and / or (iii) an LC CDR3 of SEQ ID NO: 95. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 95.

[0213] In some embodiments, the LC polypeptide further comprises one or more framework regions (FRs), e.g., as described herein. In some embodiments, the LC polypeptide comprises one, two, three, or four FRs, e.g., as described herein. In some embodiments, the FRs comprise LC FRs derived from a human mature antibody, a human germline sequence, a non-human framework (e.g., a rodent framework); or a non-human framework that has been modified, e.g., immunodepleted or partially humanized, e.g., to remove antigenic or cytotoxic determinants, or a sequence having at least 85% sequence identity to the LC FR sequences described herein, or a sequence having at least 5, 10, or 20 changes relative to the LC FR sequences described herein.

[0214] In some embodiments, the LC polypeptide comprises (i) a FR sequence provided in Table 1, (ii) a sequence having at least 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a FR sequence provided in Table 1, or (iii) a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) compared to a FR sequence provided in Table 1.

[0215] In some embodiments, the LC polypeptide comprises an LC FR1 provided in Table 1; a sequence having at least 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to an LC FR1 sequence provided in Table 1; or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) compared to an LC FR1 sequence provided in Table 1.

[0216] In some embodiments, the LC polypeptide comprises an LC FR2 provided in Table 1; a sequence having at least 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to an LC FR2 sequence provided in Table 1; or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) compared to an LC FR2 sequence provided in Table 1.

[0217] In some embodiments, the LC polypeptide comprises an LC FR3 provided in Table 1; a sequence having at least 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to an LC FR3 sequence provided in Table 1; or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) compared to an LC FR3 sequence provided in Table 1.

[0218] In some embodiments, the LC polypeptide comprises an LC FR4 provided in Table 1; a sequence having at least 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to an LC FR4 sequence provided in Table 1; or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) compared to an LC FR4 sequence provided in Table 1.

[0219] In some embodiments, the LC polypeptide comprises LC CDR1, LC CDR2, and LC CDR3 provided in Table 1, or a sequence having at least 85% identity thereto, and LC FR1, LC FR2, LC FR3, and LC FR4 provided in Table 1, or a sequence having at least 92% identity thereto.

[0220] In some embodiments, the LC polypeptide comprises the sequence of SEQ ID NO: 8, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 8.

[0221] In some embodiments, the LC polypeptide comprises the sequence of SEQ ID NO: 13, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 13.

[0222] In some embodiments, the LC polypeptide comprises the sequence of SEQ ID NO: 18, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 18.

[0223] In some embodiments, the LC polypeptide comprises the sequence of SEQ ID NO:22, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:22.

[0224] In some embodiments, the LC polypeptide comprises the sequence of SEQ ID NO: 33, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 33.

[0225] In some embodiments, the LC polypeptide comprises the sequence of SEQ ID NO: 37, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 37.

[0226] In some embodiments, the LC polypeptide comprises the sequence of SEQ ID NO:45, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:45.

[0227] In some embodiments, the LC polypeptide comprises the sequence of SEQ ID NO:50, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:50.

[0228] In some embodiments, the LC polypeptide comprises the sequence of SEQ ID NO:58, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:58.

[0229] In some embodiments, the LC polypeptide comprises the sequence of SEQ ID NO: 65, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 65.

[0230] In some embodiments, the LC polypeptide comprises the sequence of SEQ ID NO:74, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:74.

[0231] In some embodiments, the LC polypeptide comprises the sequence of SEQ ID NO: 82, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 82.

[0232] In some embodiments, the LC polypeptide comprises the sequence of SEQ ID NO: 90, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 90.

[0233] In some embodiments, the LC polypeptide comprises the sequence of SEQ ID NO:99, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:99.

[0234] In some embodiments, the LC polypeptide comprises an LC sequence provided in Table 1, e.g., any one of SEQ ID NOs: 9, 14, 19, 23, 34, 38, 41, 46, 51, 59, 66, 75, 83, 91, 100; or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity thereto; or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) relative to any one of SEQ ID NOs: 9, 14, 19, 23, 34, 38, 41, 46, 51, 59, 66, 75, 83, 91, 100.

[0235] Exemplary useful LC polypeptides that can be included in the activin A antibody agents disclosed herein are disclosed in Table 1 below.

[0236] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18]

[0237] Heavy chain (e.g., heavy chain variable region) polypeptide (HC polypeptide) The present disclosure provides polypeptides comprising heavy chain (HC) sequences (e.g., heavy chain variable region sequence(s)) that may be useful, for example, in the antibody agents described herein that target activin A. In some such embodiments, such provided polypeptides are useful and / or included in such antibody agents described herein. In some embodiments, the HC polypeptide comprises at least one HC CDR of an activin A antibody agent provided in Table 2, or a sequence having at least 85% identity thereto. In some embodiments, the HC polypeptide comprises one, two, or three HC CDRs (e.g., HC CDR1, HC CDR2, and / or HC CDR3). In some embodiments, the HC polypeptide comprises HC CDR1. In some embodiments, the HC polypeptide comprises HC CDR2. In some embodiments, the HC polypeptide comprises HC CDR3. In some embodiments, the HC polypeptide comprises HC CDR1, HC CDR2, and HC CDR3.

[0238] In some embodiments, an HC polypeptide comprising HC CDR1, HC CDR2, and HC CDR3 can bind (eg, specifically bind) to activin A.

[0239] In some embodiments, the HC polypeptide further comprises one or more framework regions, and / or a heavy chain constant region, or portion or variant thereof (e.g., CH1, CH2, and / or CH3 regions). In some embodiments, the HC polypeptide comprises a CH1, CH2, or CH3, or a combination thereof. In some embodiments, the HC polypeptide comprises a CH2 and a CH3, e.g., an Fc domain.

[0240] In some embodiments, the Fc domain comprises a mammalian Fc domain. In some embodiments, the Fc domain comprises a dog, cat, mouse, rat, rabbit, primate, bovine, equine, ovine, or human Fc domain. In some embodiments, the Fc domain comprises a human Fc domain. In some embodiments, the Fc domain comprises a dog Fc domain. In some embodiments, the Fc domain comprises a feline Fc domain. In some embodiments, the Fc domain is selected from Fc domains of immunoglobulin isotypes. In some embodiments, the immunoglobulin isotypes include IgA, IgD, IgG, IgM, or IgE. In some embodiments, the Fc domain comprises the Fc domain of an IgG, e.g., a human IgG. In some embodiments, the IgG is or comprises an IgG1, IgG2, IgG3, or IgG4.

[0241] In some embodiments, the Fc region is a wild-type Fc region, e.g., a wild-type human Fc region. In some embodiments, the Fc region comprises a variant, e.g., an Fc region, comprising an addition, substitution, or deletion of at least one amino acid residue within the Fc region, which, e.g., results in reduced or ablated affinity for at least one Fc receptor.

[0242] The Fc region of an antibody interacts with a number of receptors or ligands, including Fc receptors (e.g., FcyRI, FcyRIIA, FcyRIIIA), complement protein Clq, and other molecules such as proteins A and G. These interactions are essential for a variety of effector functions and downstream signaling events, including antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC).

[0243] In some embodiments, an HC polypeptide comprising a variant Fc region has one or more of the following properties: (1) reduced effector function (e.g., reduced ADCC, ADCP, and / or CDC), (2) reduced binding to one or more Fc receptors, and / or (3) reduced binding to Clq complement. In some embodiments, the reduction in any one or all of properties (1)-(3) is compared to an otherwise similar antibody having a wild-type Fc region. In some embodiments, an activin A antibody agent comprising a variant Fc region has reduced affinity for human Fc receptors, e.g., FcγRI, FcγRII, and / or FcγRIII. Exemplary Fc region variants are disclosed in Saunders KO, (2019) Frontiers in Immunology; vol. 10, Article 296, the entire contents of which are incorporated herein by reference. For example, the Fc region variant is or includes the modifications provided in Table 3 of Saunders KO (2019). In some embodiments, the Fc region variant comprises a Leu234Ala / Leu235Ala (LALA) mutation, a Leu235Glu (LE) mutation, a Ser228Pro / Leu235Glu (SPLE) mutation, a Leu234Ala / Leu235Ala / Pro239Gly (LALA-PG) mutation, a Pro331Ser / Leu234Glu / Leu235Phe (TM) mutation, an Asp265Ala (DA) mutation, a Leu235Ala / Gly237Ala (LAGA) mutation, or a combination thereof.

[0244] In some embodiments, the HC polypeptides disclosed herein comprise a Leu234Ala / Leu235Ala (LALA) mutation.

[0245] In some embodiments, the HC polypeptides disclosed herein comprise Leu235Ala / Gly237Ala (LAGA) mutations.

[0246] In some embodiments, the Fc region variant comprises mutations relative to a wild-type Fc region, e.g., an IgG1 FcR wild-type region. In some embodiments, the hinge and CH2 sequence of the IgG1 FcR wild-type region comprises the following sequence: CPPCPAPELLGGPSVFLFPPK (SEQ ID NO: 222).

[0247] In some embodiments, the Fc region variant is, for example, SEQ ID NO: 223: [ka] In some embodiments, the HC polypeptide comprises an Fc region with a LAGA mutation, for example, as provided in SEQ ID NO: 223.

[0248] In some embodiments, the Fc region variant is, for example, SEQ ID NO: 224: [ka] In some embodiments, the HC polypeptide comprises an Fc region with a FEGG mutation, for example, as provided in SEQ ID NO: 224.

[0249] In some embodiments, the Fc region variant is, for example, SEQ ID NO: 225: [ka] In some embodiments, the HC polypeptide comprises an Fc region with an AAGG mutation, for example, as provided in SEQ ID NO: 225.

[0250] In some embodiments, the Fc region variant is, for example, SEQ ID NO: 226: [ka] In some embodiments, the HC polypeptide comprises an Fc region with an AAGA mutation, for example, as provided in SEQ ID NO: 226.

[0251] In some embodiments, Fc region variants comprising Fc mutations (e.g., as described herein) have reduced (e.g., no) binding to the neonatal Fc receptor (FcRn), e.g., when compared to an otherwise similar Fc region without the associated Fc mutations. In some embodiments, activin A antibody agents comprising an Fc region with Fc mutations (e.g., as described herein) have reduced (e.g., no) binding to FcRn and reduced placental transfer, when compared to an otherwise similar activin A antibody agent having an Fc region without the associated Fc mutations.

[0252] In some embodiments, Fc region variants comprising LAGA, FEGG, AAGG, AAGA, LALA mutations, or combinations thereof, exhibit reduced (e.g., no) binding to the neonatal Fc receptor (FcRn), e.g., compared to an otherwise similar Fc region without the relevant mutation (e.g., LAGA, FEGG, AAGG, AAGA, LALA mutation, or combinations thereof). In some embodiments, GDF15 antibody agents comprising an Fc region with LAGA, FEGG, AAGG, AAGA, LALA mutations, or combinations thereof, exhibit reduced (e.g., no) binding to FcRn and reduced placental transfer, compared to an otherwise similar activin A antibody agent having an Fc region without the relevant mutation (e.g., LAGA, FEGG, AAGG, AAGA, LALA mutation, or combinations thereof). In some embodiments, Fc region variants comprising an I253A mutation, an H310A mutation, an H435R mutation, an H435A mutation, or a combination thereof, exhibit reduced (e.g., no) binding to the neonatal Fc receptor (FcRn), e.g., compared to an otherwise similar Fc region without the relevant mutation (e.g., the relevant I253A mutation, an H310A mutation, an H435R mutation, an H435A mutation, or a combination thereof). In some embodiments, activin A antibody agents comprising an Fc region with an I253A mutation, an H310A mutation, an H435R mutation, an H435A mutation, or a combination thereof exhibit reduced (e.g., no) binding to FcRn and reduced placental transfer, compared to an otherwise similar activin A antibody agent having an Fc region without the relevant mutation (e.g., the relevant I253A mutation, an H310A mutation, an H435R mutation, an H435A mutation, or a combination thereof).

[0253] In some embodiments, the HC polypeptide disclosed herein further comprises a half-life extender.In some embodiments, the half-life extender is or comprises albumin, such as human serum albumin.In some embodiments, the half-life extender comprises a modification that increases binding to neonatal Fc receptor (FcRn).

[0254] In some embodiments, the HC polypeptide comprises a CH3 domain or a variant thereof. In some embodiments, the CH3 variant is characterized in that, when introduced into the HC polypeptide, the half-life of the HC polypeptide is extended without reducing one or more other desirable characteristics, such as neutralizing potency, effector function, and / or generability. In some embodiments, the HC polypeptide having a CH3 variant has an extended half-life compared to other similar HC polypeptides without the associated CH3 variant.

[0255] In some embodiments, a CH3 variant has at least one amino acid residue addition, substitution, or deletion compared to a reference CH3 domain, eg, a wild-type CH3 domain.

[0256] In some embodiments, a CH3 variant has an amino acid residue at position 428 that differs from a reference CH3 domain, e.g., a wild-type CH3 domain. In some embodiments, a CH3 variant has an amino acid residue at position 434 that differs from a reference CH3 domain, e.g., a wild-type CH3 domain. In some embodiments, a CH3 variant has amino acid residues at positions 428 and 434 that differ from a reference CH3 domain, e.g., a wild-type CH3 domain.

[0257] In some embodiments, the CH3 variant has a leucine at position 428.

[0258] In some embodiments, the CH3 variant has an alanine at position 434.

[0259] In some embodiments, the CH3 variant has a leucine at position 428 and an alanine at position 434.

[0260] In some embodiments, an HC polypeptide comprising a CH3 variant is characterized in that, when administered to a subject, increased antibody-dependent cellular cytotoxicity (ADCC) and / or antibody-dependent cellular phagocytosis (ADCP) is observed compared to that observed when an HC polypeptide without the associated CH3 variant is administered to a comparable subject. In some embodiments, the increased ADCC is characterized by one or more of increased surface expression of CD107α on natural killer (NK) cells, increased interferon-γ (IFNγ) production by NK cells, or increased tumor necrosis factor-α (TNFα) production by NK cells. In some embodiments, the increased ADCP is characterized by one or more of co-localization of target cells and macrophages using microscopy or flow cytometry, and inclusion of a pH-sensitive dye to distinguish between cell-associated and internalized target cells.

[0261] In some embodiments, a HC polypeptide comprising a CH3 variant has improved generativity compared to a HC polypeptide that does not contain the related CH3 variant. In some embodiments, improving the generativity of a HC polypeptide comprising a CH3 variant comprises increasing expression, increasing solubility, increasing covalent bond integrity, increasing conformational stability, increasing colloidal stability, decreasing polyspecificity, and / or decreasing immunogenicity of a HC polypeptide comprising a CH3 variant compared to a HC polypeptide that does not contain the related CH3 variant.

[0262] In some embodiments, disclosed herein are preparations of antibody agents comprising a human constant region comprising a variant CH3 domain, wherein the antibody agent is characterized by a neutralizing potency and / or effector function of the antibody agent that is comparable to that of an antibody agent comprising a parent CH3 domain, and / or wherein the antibody agent is characterized by an increased developability of the antibody agent compared to that of an antibody agent comprising a reference (e.g., parent) CH3 domain, wherein the variant CH3 domain differs from the parent CH3 domain at positions 428 and 434, wherein the variant CH3 domain comprises a leucine at position 428 and an alanine at position 434. In some embodiments, the developability of the antibody agent comprises high-level expression, high solubility, covalent integrity, conformational stability, colloidal stability, reduced polyspecificity, and / or reduced immunogenicity.

[0263] According to IMGT, the CH3 domain is amino acid positions (or simply referred to herein as "positions") 341-446 (EU numbering). The term "CH3 domain" is used broadly herein to refer to a heavy chain region comprising at least seven consecutive amino acid positions from heavy chain positions 341-446 (EU numbering). A CH3 domain reference sequence corresponding to amino acid positions 341-446 according to EU numbering is provided herein as SEQ ID NO: 227, which is an exemplary amino acid sequence of a wild-type (WT) CH3 domain.

[0264] Exemplary CH3 domain reference sequences:

[0265] GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 227).

[0266] In some embodiments, the HC polypeptide is selected from the group consisting of (i) a HC CDR1 sequence provided in Table 2, e.g., any one of SEQ ID NOs: 103, 113, 120, 125, 129, 134, 140, 149, 157, 163, 169, 179, 190, 196, 202, or 209; (ii) a HC CDR1 sequence provided in Table 2; or (iii) a sequence having at least 5, 10, or 20 substitutions compared to a CDR1 sequence provided in Table 2, e.g., a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity to any one of SEQ ID NOs: 103, 113, 120, 125, 129, 134, 140, 149, 157, 163, 169, 179, 190, 196, 202, or 209.

[0267] In some embodiments, the HC polypeptide comprises (i) a HC CDR2 sequence provided in Table 2, e.g., any one of SEQ ID NOs: 104, 114, 121, 130, 135, 141, 145, 150, 158, 164, 170, 180, 186, 191, 197, 203, or 210; (ii) a HC CDR2 sequence provided in Table 2; (iii) a CDR2 sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity to any one of SEQ ID NOs: 104, 114, 121, 130, 135, 141, 145, 150, 158, 164, 170, 180, 186, 191, 197, 203, or 210; or (iv) a CDR2 sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity to any one of SEQ ID NOs: 104, 114, 121, 130, 135, 141, 145, 150, 158, 164, 170, 180, 186, 191, 197, 203, or 210. CDR2 sequences, such as sequences having at least 5, 10, or 20 substitutions compared to any one of SEQ ID NOs: 104, 114, 121, 130, 135, 141, 145, 150, 158, 164, 170, 180, 186, 191, 197, 203, or 210.

[0268] In some embodiments, the HC polypeptide is (i) a HC CDR3 sequence provided in Table 2, e.g., any one of SEQ ID NOs: 105, 115, 151, 165, 171, 181, 192, 198, or 204; (ii) a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity to a HC CDR3 sequence provided in Table 2, e.g., any one of SEQ ID NOs: 105, 115, 151, 165, 171, 181, 192, 198, or 204; or (iii) a HC CDR3 sequence provided in Table 2. CDR3 sequences, for example, sequences having at least 5, 10, or 20 substitutions compared to any one of SEQ ID NOs: 105, 115, 151, 165, 171, 181, 192, 198, or 204.

[0269] In some embodiments, the HC polypeptide comprising HC CDR1, HC CDR2, and / or HC CDR3 is capable of specifically binding to activin A.

[0270] In some embodiments, the HC polypeptide comprises (i) the HC CDR1, HC CDR2, and HC CDR3 sequences provided in Table 2, (ii) a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the HC CDR1, HC CDR2, and HC CDR3 sequences provided in Table 2, or (iii) a sequence having at least 5, 10, or 20 substitutions relative to the HC CDR1, HC CDR2, and HC CDR3 sequences provided in Table 2.

[0271] In some embodiments, the HC polypeptide comprises (i) the HC CDR1 of SEQ ID NO: 103, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 103, (ii) the HC CDR2 of SEQ ID NO: 104, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 104; and / or (iii) the HC CDR1 of SEQ ID NO: 105. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 105.

[0272] In some embodiments, the HC polypeptide comprises (i) the HC CDR1 of SEQ ID NO: 113, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 113; (ii) the HC CDR2 of SEQ ID NO: 114, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 114; and / or (iii) the HC CDR1 of SEQ ID NO: 115. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 115.

[0273] In some embodiments, the HC polypeptide comprises (i) the HC CDR1 of SEQ ID NO: 120, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 120; (ii) the HC CDR2 of SEQ ID NO: 121, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 121; and / or (iii) the HC CDR1 of SEQ ID NO: 115. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 115.

[0274] In some embodiments, the HC polypeptide comprises (i) the HC CDR1 of SEQ ID NO: 125, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 125; (ii) the HC CDR2 of SEQ ID NO: 121, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 121; and / or (iii) the HC CDR1 of SEQ ID NO: 115. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 115.

[0275] In some embodiments, the HC polypeptide comprises (i) the HC CDR1 of SEQ ID NO: 129, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 129; (ii) the HC CDR2 of SEQ ID NO: 130, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 130; and / or (iii) the HC CDR1 of SEQ ID NO: 105. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 105.

[0276] In some embodiments, the HC polypeptide comprises (i) the HC CDR1 of SEQ ID NO: 134, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 134; (ii) the HC CDR2 of SEQ ID NO: 135, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 135; and / or (iii) the HC CDR2 of SEQ ID NO: 115. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 115.

[0277] In some embodiments, the HC polypeptide comprises (i) the HC CDR1 of SEQ ID NO: 140, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 140; (ii) the HC CDR2 of SEQ ID NO: 141, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 141; and / or (iii) the HC CDR2 of SEQ ID NO: 105. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 105.

[0278] In some embodiments, the HC polypeptide comprises (i) the HC CDR1 of SEQ ID NO: 134, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 134; (ii) the HC CDR2 of SEQ ID NO: 145, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 145; and / or (iii) the HC CDR1 of SEQ ID NO: 105. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 105.

[0279] In some embodiments, the HC polypeptide comprises (i) the HC CDR1 of SEQ ID NO: 149, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 149; (ii) the HC CDR2 of SEQ ID NO: 150, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 150; and / or (iii) the HC CDR1 of SEQ ID NO: 151. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 151.

[0280] In some embodiments, the HC polypeptide comprises (i) the HC CDR1 of SEQ ID NO: 157, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 157; (ii) the HC CDR2 of SEQ ID NO: 158, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 158; and / or (iii) the HC CDR2 of SEQ ID NO: 151. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 151.

[0281] In some embodiments, the HC polypeptide comprises (i) the HC CDR1 of SEQ ID NO: 163, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 163; (ii) the HC CDR2 of SEQ ID NO: 164, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 164; and / or (iii) the HC CDR1 of SEQ ID NO: 165. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 165.

[0282] In some embodiments, the HC polypeptide comprises (i) the HC CDR1 of SEQ ID NO: 169, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 169; (ii) the HC CDR2 of SEQ ID NO: 170, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 170; and / or (iii) the HC CDR1 of SEQ ID NO: 171. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 171.

[0283] In some embodiments, the HC polypeptide comprises (i) the HC CDR1 of SEQ ID NO: 179, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 179; (ii) the HC CDR2 of SEQ ID NO: 180, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 180; and / or (iii) the HC CDR1 of SEQ ID NO: 181. CDR3 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 181.

[0284] In some embodiments, the HC polypeptide comprises (i) the HC CDR1 of SEQ ID NO: 179, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 179; (ii) the HC CDR2 of SEQ ID NO: 186, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 186; and / or (iii) the HC CDR2 of SEQ ID NO: 181. CDR3 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 181.

[0285] In some embodiments, the HC polypeptide comprises (i) the HC CDR1 of SEQ ID NO: 190, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 190; (ii) the HC CDR2 of SEQ ID NO: 191, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 191; and / or (iii) the HC CDR2 of SEQ ID NO: 192. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 192.

[0286] In some embodiments, the HC polypeptide comprises (i) the HC CDR1 of SEQ ID NO: 196, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 196; (ii) the HC CDR2 of SEQ ID NO: 197, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 197; and / or (iii) the HC CDR1 of SEQ ID NO: 198. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 198.

[0287] In some embodiments, the HC polypeptide comprises (i) the HC CDR1 of SEQ ID NO:202, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:202; (ii) the HC CDR2 of SEQ ID NO:203, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:203; and / or (iii) the HC CDR1 of SEQ ID NO:204. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 204.

[0288] In some embodiments, the HC polypeptide comprises (i) the HC CDR1 of SEQ ID NO:209, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:209; (ii) the HC CDR2 of SEQ ID NO:210, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:210; and / or (iii) the HC CDR1 of SEQ ID NO:204. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 204.

[0289] In some embodiments, the HC polypeptide further comprises one or more framework regions (FRs), e.g., as described herein. In some embodiments, such HC polypeptides comprise one, two, three, or four FRs, e.g., as described herein. In some embodiments, the FRs comprise HC FRs derived from a human mature antibody, a human germline sequence, a non-human framework (e.g., a rodent framework); or a non-human framework that has been modified, e.g., immunodepleted or partially humanized, e.g., to remove antigenic or cytotoxic determinants, or a sequence having at least 85% sequence identity to the HC FR sequences described herein, or a sequence having at least 5, 10, or 20 changes relative to the HC FR sequences described herein.

[0290] In some embodiments, the HC polypeptide comprises (i) a FR sequence provided in Table 2, (ii) a sequence having at least 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a FR sequence provided in Table 2, or (iii) a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) compared to a FR sequence provided in Table 2.

[0291] In some embodiments, the HC polypeptide comprises an HC FR1 provided in Table 2; a sequence having at least 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to an HC FR1 sequence provided in Table 2; or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) compared to an HC FR1 sequence provided in Table 2.

[0292] In some embodiments, the HC polypeptide comprises an HC FR2 provided in Table 2; a sequence having at least 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to an HC FR2 sequence provided in Table 2; or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) compared to an HC FR2 sequence provided in Table 2.

[0293] In some embodiments, the HC polypeptide comprises an HC FR3 provided in Table 2; a sequence having at least 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to an HC FR3 sequence provided in Table 2; or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) compared to an HC FR3 sequence provided in Table 2.

[0294] In some embodiments, the HC polypeptide comprises an HC FR4 provided in Table 2; a sequence having at least 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to an HC FR4 sequence provided in Table 2; or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) compared to an HC FR4 sequence provided in Table 2.

[0295] In some embodiments, the HC polypeptide comprises HC CDR1, HC CDR2, and HC CDR3 provided in Table 2, or a sequence having at least 85% identity thereto, and HC FR1, HC FR2, HCFR3, and HC FR4 provided in Table 2, or a sequence having at least 92% identity thereto.

[0296] In some embodiments, the HC polypeptide comprises the sequence of SEQ ID NO:110, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:110.

[0297] In some embodiments, the HC polypeptide comprises the sequence of SEQ ID NO:117, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:117.

[0298] In some embodiments, the HC polypeptide comprises the sequence of SEQ ID NO:122, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:122.

[0299] In some embodiments, the HC polypeptide comprises the sequence of SEQ ID NO: 126, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 126.

[0300] In some embodiments, the HC polypeptide comprises the sequence of SEQ ID NO:131, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:131.

[0301] In some embodiments, the HC polypeptide comprises the sequence of SEQ ID NO: 137, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 137.

[0302] In some embodiments, the HC polypeptide comprises the sequence of SEQ ID NO: 142, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 142.

[0303] In some embodiments, the HC polypeptide comprises the sequence of SEQ ID NO: 146, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 146.

[0304] In some embodiments, the HC polypeptide comprises the sequence of SEQ ID NO: 154, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 154.

[0305] In some embodiments, the HC polypeptide comprises the sequence of SEQ ID NO: 160, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 160.

[0306] In some embodiments, the HC polypeptide comprises the sequence of SEQ ID NO: 166, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 166.

[0307] In some embodiments, the HC polypeptide comprises the sequence of SEQ ID NO: 176, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 176.

[0308] In some embodiments, the HC polypeptide comprises the sequence of SEQ ID NO: 183, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 183.

[0309] In some embodiments, the HC polypeptide comprises the sequence of SEQ ID NO: 187, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 187.

[0310] In some embodiments, the HC polypeptide comprises the sequence of SEQ ID NO: 193, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 193.

[0311] In some embodiments, the HC polypeptide comprises the sequence of SEQ ID NO:199, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:199.

[0312] In some embodiments, the HC polypeptide comprises the sequence of SEQ ID NO:206, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:206.

[0313] In some embodiments, the HC polypeptide comprises the sequence of SEQ ID NO:211, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:211.

[0314] In some embodiments, the HC polypeptide has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 123, 127, 132, 138, 143, 147, 155, 161, 167, 177, 184, 188, 194, 200, 207, 212, or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 109%, 109%, 1109, 1200, 1210, 1220, 1230, 1240, 1250, 1260, 1270, 1280, 1300, 1310, 1320, 1330, 1340, 1350, 1360, 1370, 1380, 1390, 1410, 1420, 1430, 1440, 1450, 1460, 1470, 1480, 1490, 1510, 1520, 1530, Sequences having 4%, 95%, 96%, 97%, 98%, or 99% identity, or sequences having at least 5, 10, or 20 substitutions to any one of the HC amino acid sequences provided in Table 2, e.g., SEQ ID NOs: 111, 118, 123, 127, 132, 138, 143, 147, 155, 161, 167, 177, 184, 188, 194, 200, 207, 212.

[0315] In some embodiments, the HC polypeptides disclosed herein comprise a terminal lysine, for example, as provided in Table 2. In some embodiments, the HC polypeptides disclosed herein do not comprise a terminal lysine.

[0316] Exemplary useful HC polypeptides that can be included in the activin A antibody agents disclosed herein are disclosed in Table 2 below.

[0317]

Table 2-1

Table 2-2

Table 2-3

Table 2-4

Table 2-5

Table 2-6

Table 2-7

Table 2-8

Table 2-9

Table 2-10

Table 2-11

Table 2-12

Table 2-13

Table 2-14

Table 2-15

Table 2-16

Table 2-17

[0318] IgG (SEQ ID NO: 214)

[0319] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0320] In some embodiments, the HC polypeptide disclosed herein comprises the IgG sequence of SEQ ID NO: 214 or a sequence having at least 85% identity thereto.

[0321] Activin A antibody preparation containing a light chain polypeptide and a heavy chain polypeptide In some embodiments, an activin A antibody agent disclosed herein, e.g., an activin A antibody agent polypeptide, comprises a light chain comprising a variable region comprising one, two, or three LC CDRs, and a heavy chain comprising a variable region comprising one, two, or three HC CDRs. In some embodiments, an activin A antibody agent comprises a light chain comprising an LC CDR1, an LC CDR2, and an LC CDR3, and a heavy chain comprising an HC CDR1, an HC CDR2, and an HC CDR3.

[0322] In some embodiments, an activin A antibody agent comprising LC CDR1, LC CDR2 and LC CDR3, and a heavy chain comprising HC CDR1, HC CDR2 and HC CDR3, can specifically bind to activin A, e.g., human, primate, or domestic mammalian activin A (e.g., dog, cat, horse, sheep, cow, yak, and / or camel).

[0323] In some embodiments, the activin A antibody agent comprises one, two, or three LC CDRs provided in Table 1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, and one, two, or three HC CDRs provided in Table 2, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto.

[0324] In some embodiments, the activin A antibody agent is selected from the group consisting of (a) (i) an LC CDR1 provided in Table 1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto, (ii) an LC CDR2 provided in Table 1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto, and / or (iii) an LC CDR3 provided in Table 1. a light chain comprising (i) an HC CDR1 provided in Table 2 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; and (b) (i) an HC CDR1 provided in Table 2 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; and / or (iii) a heavy chain comprising an HC CDR2 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to an HC CDR2 provided in Table 2; and / or (iv) an HC CDR3 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to an HC CDR3 provided in Table 2.

[0325] In some embodiments, the activin A antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 1; an LC CDR2 of SEQ ID NO: 2, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 2; and an LC CDR3 of SEQ ID NO: 3. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 3; and (ii) HC CDR1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 103; ...2, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 104; CDR2 of SEQ ID NO: 104 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 104; and HC CDR3 of SEQ ID NO: 105 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 105.

[0326] In some embodiments, the activin A antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 11, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 11; an LC CDR2 of SEQ ID NO: 2, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 2; and an LC CDR3 of SEQ ID NO: 12. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 12, and (ii) HC CDR1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 113; ...2, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 114; CDR2 of SEQ ID NO: 114 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 114; and HC CDR3 of SEQ ID NO: 115 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 115.

[0327] In some embodiments, the activin A antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 11, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 11; an LC CDR2 of SEQ ID NO: 16, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 16; and an LC CDR3 of SEQ ID NO: 17. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 17, and (ii) the HC CDR1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 120; the HC CDR1 of SEQ ID NO: 121. CDR2 of SEQ ID NO: 121 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 121; and HC CDR3 of SEQ ID NO: 115 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 115.

[0328] In some embodiments, the activin A antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 11, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 11; an LC CDR2 of SEQ ID NO: 2, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 2; and an LC CDR3 of SEQ ID NO: 21. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 21, and (ii) HC CDR1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 125; HC CDR1 of SEQ ID NO: 121 CDR2 of SEQ ID NO: 121 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 121; and HC CDR3 of SEQ ID NO: 115 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 115.

[0329] In some embodiments, the activin A antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 1; an LC CDR2 of SEQ ID NO: 2, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 2; and an LC CDR3 of SEQ ID NO: 3. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 3; and (ii) HC CDR1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 129; HC CDR1 of SEQ ID NO: 130. CDR2 of SEQ ID NO: 130, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 130; and HC CDR3 of SEQ ID NO: 105, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 105.

[0330] In some embodiments, the activin A antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 28, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 28; an LC CDR2 of SEQ ID NO: 29, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 29; and an LC CDR3 of SEQ ID NO: 30. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 30, and (ii) HC CDR1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 134; HC CDR1 of SEQ ID NO: 135. CDR2 of SEQ ID NO: 135 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 135; and HC CDR3 of SEQ ID NO: 115 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 115.

[0331] In some embodiments, the activin A antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 1; an LC CDR2 of SEQ ID NO: 2, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 2; and an LC CDR3 of SEQ ID NO: 36. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 36, and (ii) HC CDR1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 140; HC CDR1 of SEQ ID NO: 141. CDR2 of SEQ ID NO: 141 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 141; and HC CDR3 of SEQ ID NO: 105 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 105.

[0332] In some embodiments, the activin A antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 1; an LC CDR2 of SEQ ID NO: 2, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 2; and an LC CDR3 of SEQ ID NO: 36. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 36, and (ii) HC CDR1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 134; HC CDR1 of SEQ ID NO: 145 CDR2 of SEQ ID NO: 145 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 145; and HC CDR3 of SEQ ID NO: 105 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 105.

[0333] In some embodiments, the activin A antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 11, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 11; an LC CDR2 of SEQ ID NO: 43, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 43; and an LC CDR3 of SEQ ID NO: 44. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 44, and (ii) HC CDR1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 149; HC CDR1 of SEQ ID NO: 150 CDR2 of SEQ ID NO: 150, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 150; and HC CDR3 of SEQ ID NO: 151, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 151.

[0334] In some embodiments, the activin A antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 11, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 11; an LC CDR2 of SEQ ID NO: 48, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 48; and an LC CDR3 of SEQ ID NO: 49. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 49, and (ii) HC CDR1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 157; ...2, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 158; CDR2 of SEQ ID NO: 158, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 158; and HC CDR3 of SEQ ID NO: 151, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 151.

[0335] In some embodiments, the activin A antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 53, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 53; an LC CDR2 of SEQ ID NO: 54, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 54; and an LC CDR3 of SEQ ID NO: 55. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 55, and (ii) HC CDR1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 163; ... CDR2 of SEQ ID NO: 164 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 164; and HC CDR3 of SEQ ID NO: 165 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 165.

[0336] In some embodiments, the activin A antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 28, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 28; an LC CDR2 of SEQ ID NO: 61, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 61; and an LC CDR3 of SEQ ID NO: 62. CDR3 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 62, and (ii) C CDR1 of SEQ ID NO: 169 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 169; HC of SEQ ID NO: 170 CDR2 of SEQ ID NO: 170, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 170; and HC CDR3 of SEQ ID NO: 171, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 171.

[0337] In some embodiments, the activin A antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 68, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 68; an LC CDR2 of SEQ ID NO: 69, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 69; and an LC CDR3 of SEQ ID NO: 70. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 70, and (ii) HC CDR1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 179; ... CDR2 of SEQ ID NO: 180, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 180; and HC CDR3 of SEQ ID NO: 181, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 181.

[0338] In some embodiments, the activin A antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 68, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 68; an LC CDR2 of SEQ ID NO: 69, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 69; and an LC CDR3 of SEQ ID NO: 70. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 70, and (ii) HC CDR1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 179; HC CDR1 of SEQ ID NO: 186 CDR2 of SEQ ID NO: 181 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 186; and HC CDR3 of SEQ ID NO: 181 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 181.

[0339] In some embodiments, the activin A antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 28, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 28; an LC CDR2 of SEQ ID NO: 61, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 61; and an LC CDR3 of SEQ ID NO: 80. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 80, and (ii) HC CDR1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 190; ... CDR2 of SEQ ID NO: 191 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 191; and HC CDR3 of SEQ ID NO: 192 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 192.

[0340] In some embodiments, the activin A antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 85, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 85; an LC CDR2 of SEQ ID NO: 86, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 86; and an LC CDR3 of SEQ ID NO: 87. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 87; and (ii) HC CDR1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 196; ... CDR2 of SEQ ID NO: 198 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 197; and HC CDR3 of SEQ ID NO: 198 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 198.

[0341] In some embodiments, the activin A antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 93, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 93; an LC CDR2 of SEQ ID NO: 94, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 94; and an LC CDR3 of SEQ ID NO: 95. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 95; and (ii) HC CDR1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 202; HC CDR1 of SEQ ID NO: 203. CDR2 of SEQ ID NO: 204 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 203; and HC CDR3 of SEQ ID NO: 204 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 204.

[0342] In some embodiments, the activin A antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 93, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 93; an LC CDR2 of SEQ ID NO: 94, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 94; and an LC CDR3 of SEQ ID NO: 95. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 95, and (ii) HC CDR1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 209; HC CDR1 of SEQ ID NO: 210 CDR2 of SEQ ID NO: 210, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 210; and HC CDR3 of SEQ ID NO: 204, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 204.

[0343] In some embodiments, the activin A antibody agent comprises a light chain polypeptide (LC polypeptide) described herein.

[0344] In some embodiments, the activin A antibody agent comprises a heavy chain polypeptide (HC polypeptide) described herein. In some embodiments, the HC polypeptide in the activin A antibody agent does not contain a terminal lysine.

[0345] In some embodiments, the activin A antibody agent comprises a light chain polypeptide (LC polypeptide) described herein and a heavy chain polypeptide (HC polypeptide) described herein. In some embodiments, the HC polypeptide in the activin A antibody agent does not contain a terminal lysine.

[0346] In some embodiments, the activin A antibody agent comprises a light chain (VL) comprising a variable region comprising three LC CDRs and one or more framework regions (e.g., as described herein), and a heavy chain (VH) comprising a variable region comprising three HC CDRs and one or more framework regions (e.g., as described herein).

[0347] In some embodiments, the VL and / or VH of the activin A antibody agent further comprise one or more framework regions (FRs), e.g., as described herein. In some embodiments, the VL and / or VH of the activin A antibody agent comprise one, two, three, or four FRs, e.g., as described herein. In some embodiments, the FRs comprise FRs derived from a human mature antibody, a human germline sequence, a non-human framework (e.g., a rodent framework); or a non-human framework that has been modified, e.g., immunodepleted or partially humanized, e.g., to remove antigenic or cytotoxic determinants, or a sequence having at least 85% sequence identity to the LC FR sequences described herein, or a sequence having at least 5, 10, or 20 changes relative to the LC FR sequences described herein.

[0348] In some embodiments, the VL and / or VH of the activin A antibody agent comprises (i) an FR sequence provided in Table 1 or Table 2, (ii) an sequence having at least 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the FR sequence provided in Table 1 or 2, or (iii) an sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) compared to the FR sequence provided in Table 1 or 2.

[0349] In some embodiments, the VL and / or VH of the activin A antibody agent comprises an FR1 provided in Table 1 or 2, a sequence having at least 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the FR1 sequence provided in Table 1 or 2, or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) compared to the FR1 sequence provided in Table 1 or 2.

[0350] In some embodiments, the VL and / or VH of the activin A antibody agent comprises an FR2 provided in Table 1 or 2, a sequence having at least 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the FR2 sequence provided in Table 1 or 2, or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) compared to the FR2 sequence provided in Table 1 or 2.

[0351] In some embodiments, the VL and / or VH of the activin A antibody agent comprises an FR3 provided in Table 1 or 2, a sequence having at least 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the FR3 sequence provided in Table 1 or 2, or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) compared to the FR3 sequence provided in Table 1 or 2.

[0352] In some embodiments, the VL and / or VH of the activin A antibody agent comprises an FR4 provided in Table 1 or 2, a sequence having at least 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the FR4 sequence provided in Table 1 or 2, or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) compared to the FR4 sequence provided in Table 1 or 2.

[0353] In some embodiments, the activin A antibody agent comprises a VL comprising the three LC CDRs and LC FR1, LC FR2, LCFR3, and LC FR4 of an activin A antibody agent provided in Table 1, or a sequence having at least 92% identity thereto; and / or a VH comprising the three HC CDRs and HC FR1, HC FR2, HC FR3, and HC FR4 of an activin A antibody agent provided in Table 2, or a sequence having at least 92% identity thereto.

[0354] In some embodiments, the activin A antibody agent comprises a VL sequence provided in Table 1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto, and a VH sequence provided in Table 2, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto.

[0355] In some embodiments, the activin A antibody agent comprises the sequence of SEQ ID NO: 8, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; and the sequence of SEQ ID NO: 110, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto.

[0356] In some embodiments, the activin A antibody agent comprises the sequence of SEQ ID NO: 13, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; and the sequence of SEQ ID NO: 117, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto.

[0357] In some embodiments, the activin A antibody agent comprises the sequence of SEQ ID NO: 18, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; and the sequence of SEQ ID NO: 122, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto.

[0358] In some embodiments, the activin A antibody agent comprises the sequence of SEQ ID NO: 22, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; and the sequence of SEQ ID NO: 126, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto.

[0359] In some embodiments, the activin A antibody agent comprises the sequence of SEQ ID NO: 8, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; and the sequence of SEQ ID NO: 131, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto.

[0360] In some embodiments, the activin A antibody agent comprises the sequence of SEQ ID NO: 33, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; and the sequence of SEQ ID NO: 137, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto.

[0361] In some embodiments, the activin A antibody agent comprises the sequence of SEQ ID NO: 37, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; and the sequence of SEQ ID NO: 142, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto.

[0362] In some embodiments, the activin A antibody agent comprises the sequence of SEQ ID NO: 37, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; and the sequence of SEQ ID NO: 146, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto.

[0363] In some embodiments, the activin A antibody agent comprises the sequence of SEQ ID NO: 45, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; and the sequence of SEQ ID NO: 154, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto.

[0364] In some embodiments, the activin A antibody agent comprises the sequence of SEQ ID NO: 50, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; and the sequence of SEQ ID NO: 160, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto.

[0365] In some embodiments, the activin A antibody agent comprises the sequence of SEQ ID NO: 58, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; and the sequence of SEQ ID NO: 166, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto.

[0366] In some embodiments, the activin A antibody agent comprises the sequence of SEQ ID NO: 65, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; and the sequence of SEQ ID NO: 176, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto.

[0367] In some embodiments, the activin A antibody agent comprises the sequence of SEQ ID NO: 74, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; and the sequence of SEQ ID NO: 183, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto.

[0368] In some embodiments, the activin A antibody agent comprises the sequence of SEQ ID NO: 74, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; and the sequence of SEQ ID NO: 187, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto.

[0369] In some embodiments, the activin A antibody agent comprises the sequence of SEQ ID NO: 82, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; and the sequence of SEQ ID NO: 193, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto.

[0370] In some embodiments, the activin A antibody agent comprises the sequence of SEQ ID NO: 90, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; and the sequence of SEQ ID NO: 199, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto.

[0371] In some embodiments, the activin A antibody agent comprises the sequence of SEQ ID NO: 99, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto, and the sequence of SEQ ID NO: 206, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto.

[0372] In some embodiments, the activin A antibody agent comprises the sequence of SEQ ID NO: 99, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto, and the sequence of SEQ ID NO: 211, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence...

Claims

1. A light chain comprising a light chain variable region (VL) comprising a light chain complementarity determining region 1 (LC CDR1), a LC CDR2, and a LC CDR3 as provided in Table 1; and a heavy chain comprising a heavy chain variable region (VH) comprising heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and HC CDR3 as provided in Table 2; An antibody agent comprising a polypeptide that binds to activin A.

2. The antibody agent is (i) intact IgA, IgG, IgD, IgE or IgM antibodies; (ii) antibody fragment, (iii) a single chain Fv, or (iv) a polypeptide comprising an antigen-binding domain fused to an Fc domain,

3. The antibody agent described in claim 1, which is capable of specifically binding to activin A.

4. The antibody agent is (A)(i) an LC CDR1 of SEQ ID NO: 1, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 1; an LC CDR2 of SEQ ID NO: 2, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 2; and an LC CDR3 of SEQ ID NO: 3, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 3; (ii) a HC CDR1 of SEQ ID NO: 103, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 103; a HC CDR2 of SEQ ID NO: 104, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 104; and a HC CDR3 of SEQ ID NO: 105, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 105; (B)(i) an LC CDR1 of SEQ ID NO: 11, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 11; an LC CDR2 of SEQ ID NO: 2, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 2; and an LC CDR3 of SEQ ID NO: 12, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 12; (ii) a HC CDR1 of SEQ ID NO: 113, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 113; a HC CDR2 of SEQ ID NO: 114, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 114; and a HC CDR3 of SEQ ID NO: 115, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 115; (C)(i) an LC CDR1 of SEQ ID NO: 11, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 11; an LC CDR2 of SEQ ID NO: 16, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 16; and an LC CDR3 of SEQ ID NO: 17, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 17; (ii) a HC CDR1 of SEQ ID NO: 120, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 120; a HC CDR2 of SEQ ID NO: 121, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 121; and a HC CDR3 of SEQ ID NO: 115, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 115; (D)(i) an LC CDR1 of SEQ ID NO: 11, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 11; an LC CDR2 of SEQ ID NO: 2, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 2; and an LC CDR3 of SEQ ID NO: 21, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 21; (ii) a HC CDR1 of SEQ ID NO: 125, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 125; a HC CDR2 of SEQ ID NO: 121, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 121; and a HC CDR3 of SEQ ID NO: 115, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 115; (E)(i) an LC CDR1 of SEQ ID NO: 1, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 1; an LC CDR2 of SEQ ID NO: 2, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 2; and an LC CDR3 of SEQ ID NO: 3, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 3; (ii) an HC CDR1 of SEQ ID NO: 129, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 129; an HC CDR2 of SEQ ID NO: 130, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 130; and an HC CDR3 of SEQ ID NO: 105, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 105; (F)(i) an LC CDR1 of SEQ ID NO:28, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO:28; an LC CDR2 of SEQ ID NO:29, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO:29; and an LC CDR3 of SEQ ID NO:30, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO:

30. (ii) a HC CDR1 of SEQ ID NO: 134, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 134; a HC CDR2 of SEQ ID NO: 135, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 135; and a HC CDR3 of SEQ ID NO: 115, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 115; (G)(i) an LC CDR1 of SEQ ID NO: 1, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 1; an LC CDR2 of SEQ ID NO: 2, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 2; and an LC CDR3 of SEQ ID NO: 36, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 36; (ii) a HC CDR1 of SEQ ID NO: 140, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 140; a HC CDR2 of SEQ ID NO: 141, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 141; and a HC CDR3 of SEQ ID NO: 105, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 105; (H)(i) an LC CDR1 of SEQ ID NO: 1, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 1; an LC CDR2 of SEQ ID NO: 2, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 2; and an LC CDR3 of SEQ ID NO: 36, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 36; (ii) a HC CDR1 of SEQ ID NO: 134, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 134; a HC CDR2 of SEQ ID NO: 145, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 145; and a HC CDR3 of SEQ ID NO: 105, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 105; (I) (i) an LC CDR1 of SEQ ID NO: 11, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 11; an LC CDR2 of SEQ ID NO: 43, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 43; and an LC CDR3 of SEQ ID NO: 44, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 44; (ii) a HC CDR1 of SEQ ID NO: 149, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 149; a HC CDR2 of SEQ ID NO: 150, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 150; and a HC CDR3 of SEQ ID NO: 151, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 151; (J)(i) an LC CDR1 of SEQ ID NO: 11, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 11; an LC CDR2 of SEQ ID NO: 48, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 48; and an LC CDR3 of SEQ ID NO: 49, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 49; (ii) a HC CDR1 of SEQ ID NO: 157, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 157; a HC CDR2 of SEQ ID NO: 158, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 158; and a HC CDR3 of SEQ ID NO: 151, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 151; (K)(i) an LC CDR1 of SEQ ID NO: 53, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 53; an LC CDR2 of SEQ ID NO: 54, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 54; and an LC CDR3 of SEQ ID NO: 55, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 55; (ii) a HC CDR1 of SEQ ID NO: 163, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 163; a HC CDR2 of SEQ ID NO: 164, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 164; and a HC CDR3 of SEQ ID NO: 165, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 165; (L)(i) an LC CDR1 of SEQ ID NO:28, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO:28; an LC CDR2 of SEQ ID NO:61, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO:61; and an LC CDR3 of SEQ ID NO:62, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO:62; (ii) a HC CDR1 of SEQ ID NO: 169, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 169; a HC CDR2 of SEQ ID NO: 170, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 170; and a HC CDR3 of SEQ ID NO: 171, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 171; (M) (i) an LC CDR1 of SEQ ID NO: 68, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 68; an LC CDR2 of SEQ ID NO: 69, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 69; and an LC CDR3 of SEQ ID NO: 70, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 70; (ii) a HC CDR1 of SEQ ID NO: 179, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 179; a HC CDR2 of SEQ ID NO: 180, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 180; and a HC CDR3 of SEQ ID NO: 181, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 181; (N)(i) an LC CDR1 of SEQ ID NO: 68, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 68; an LC CDR2 of SEQ ID NO: 69, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 69; and an LC CDR3 of SEQ ID NO: 70, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 70; (ii) a HC CDR1 of SEQ ID NO: 179, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 179; a HC CDR2 of SEQ ID NO: 186, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 186; and a HC CDR3 of SEQ ID NO: 181, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 181; (O)(i) an LC CDR1 of SEQ ID NO:28, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO:28; an LC CDR2 of SEQ ID NO:61, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO:61; and an LC CDR3 of SEQ ID NO:80, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO:80; (ii) a HC CDR1 of SEQ ID NO: 190, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 190; a HC CDR2 of SEQ ID NO: 191, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 191; and a HC CDR3 of SEQ ID NO: 192, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 192; (P)(i) an LC CDR1 of SEQ ID NO: 85, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 85; an LC CDR2 of SEQ ID NO: 86, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 86; and an LC CDR3 of SEQ ID NO: 87, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 87; (ii) a HC CDR1 of SEQ ID NO: 196, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 196; a HC CDR2 of SEQ ID NO: 197, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 197; and a HC CDR3 of SEQ ID NO: 198, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 198; (Q)(i) an LC CDR1 of SEQ ID NO: 93, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 93; an LC CDR2 of SEQ ID NO: 94, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 94; and an LC CDR3 of SEQ ID NO: 95, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 95; (ii) a HC CDR1 of SEQ ID NO: 202, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 202; a HC CDR2 of SEQ ID NO: 203, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 203; and a HC CDR3 of SEQ ID NO: 204, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 204; or (R)(i) an LC CDR1 of SEQ ID NO: 93, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 93; an LC CDR2 of SEQ ID NO: 94, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 94; and an LC CDR3 of SEQ ID NO: 95, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 95; (ii) a HC CDR1 of SEQ ID NO: 209, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 209; a HC CDR2 of SEQ ID NO: 210, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 210; and a HC CDR3 of SEQ ID NO: 204, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO:

204. The antibody agent according to claim 1.

5. The antibody agent of claim 1, wherein the heavy chain further comprises the sequence of at least one constant region (CH), the at least one constant region comprising an Fc domain, and the Fc domain comprises one or more modifications that modulate one or more properties of the antibody agent.

6. the one or more modifications being (i) a LAGA mutation, a FEGG mutation, an AAGG mutation, an AAGA mutation, a LALA mutation, or any combination thereof; (ii) an I253A mutation, an H310A mutation, an H435R mutation, an H435A mutation, or any combination thereof; (iii) a CH3 variant, optionally comprising a leucine at position 428 and / or an alanine at position 434; and / or (iv) The antibody agent according to claim 5, comprising any combination or all of (i) to (iii).

7. The antibody agent is (i) the sequence of SEQ ID NO: 8, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 8; and the sequence of SEQ ID NO: 110, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 110; (ii) the sequence of SEQ ID NO: 13, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 13; and the sequence of SEQ ID NO: 117, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 117; (iii) the sequence of SEQ ID NO: 18, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 18; and the sequence of SEQ ID NO: 122, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 122; (iv) the sequence of SEQ ID NO: 22, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 22; and the sequence of SEQ ID NO: 126, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 126; (v) the sequence of SEQ ID NO: 8, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 8; and the sequence of SEQ ID NO: 131, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 131; (vi) the sequence of SEQ ID NO: 33, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 33; and the sequence of SEQ ID NO: 137, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 137; (vii) the sequence of SEQ ID NO: 37, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 37; and the sequence of SEQ ID NO: 142, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 142; (viii) the sequence of SEQ ID NO: 37, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 37; and the sequence of SEQ ID NO: 146, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 146; (ix) the sequence of SEQ ID NO: 45, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 45; and the sequence of SEQ ID NO: 154, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 154; (x) the sequence of SEQ ID NO: 50, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 50; and the sequence of SEQ ID NO: 160, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 160; (xi) the sequence of SEQ ID NO: 58, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 58; and the sequence of SEQ ID NO: 166, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 166; (xii) the sequence of SEQ ID NO: 65, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 65; and the sequence of SEQ ID NO: 176, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 176; (xiii) the sequence of SEQ ID NO: 74, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 74; and the sequence of SEQ ID NO: 183, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 183; (xiv) the sequence of SEQ ID NO: 74, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 74; and the sequence of SEQ ID NO: 187, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 187; (xv) the sequence of SEQ ID NO: 82, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 82; and the sequence of SEQ ID NO: 193, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 193; (xvi) the sequence of SEQ ID NO: 90, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 90; and the sequence of SEQ ID NO: 199, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 199; (xvii) the sequence of SEQ ID NO: 99, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions with respect to SEQ ID NO: 99, and the sequence of SEQ ID NO: 206, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions with respect to SEQ ID NO: 206; or (xviii) The antibody agent according to any one of claims 1 to 6, comprising the sequence of SEQ ID NO: 99, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions with respect to SEQ ID NO: 99; and the sequence of SEQ ID NO: 211, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions with respect to SEQ ID NO:

211.

8. The antibody agent is (i) the sequence of SEQ ID NO: 9, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 9; and the sequence of SEQ ID NO: 111, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 111; (ii) the sequence of SEQ ID NO: 14, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 14; and the sequence of SEQ ID NO: 118, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 118; (iii) the sequence of SEQ ID NO: 19, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 19; and the sequence of SEQ ID NO: 123, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 123; (iv) the sequence of SEQ ID NO: 23, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 23; and the sequence of SEQ ID NO: 127, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 127; (v) the sequence of SEQ ID NO: 9, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 9; and the sequence of SEQ ID NO: 132, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 132; (vi) the sequence of SEQ ID NO: 34, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 34; and the sequence of SEQ ID NO: 138, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 138; (vii) the sequence of SEQ ID NO: 38, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 38; and the sequence of SEQ ID NO: 143, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 143; (viii) the sequence of SEQ ID NO: 38, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 38; and the sequence of SEQ ID NO: 147, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 147; (ix) the sequence of SEQ ID NO: 46, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 46; and the sequence of SEQ ID NO: 155, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 155; (x) the sequence of SEQ ID NO: 51, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 51; and the sequence of SEQ ID NO: 161, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 161; (xi) the sequence of SEQ ID NO: 59, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 59; and the sequence of SEQ ID NO: 167, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 167; (xii) the sequence of SEQ ID NO: 66, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 66; and the sequence of SEQ ID NO: 177, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 177; (xiii) the sequence of SEQ ID NO: 75, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 75; and the sequence of SEQ ID NO: 184, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 184; (xiv) the sequence of SEQ ID NO: 75, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 75; and the sequence of SEQ ID NO: 188, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 188; (xv) the sequence of SEQ ID NO: 83, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 83; and the sequence of SEQ ID NO: 194, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 194; (xvi) the sequence of SEQ ID NO: 91, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 91; and the sequence of SEQ ID NO: 200, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 200; (xvii) the sequence of SEQ ID NO: 100, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 100; and the sequence of SEQ ID NO: 207, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions relative to SEQ ID NO: 207; or (xviii) The antibody agent according to any one of claims 1 to 6, comprising the sequence of SEQ ID NO: 100, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions with respect to SEQ ID NO: 100; and the sequence of SEQ ID NO: 212, or a sequence having at least 85% identity thereto, or a sequence having at least 5 substitutions with respect to SEQ ID NO:

212.

9. The antibody agent has a binding affinity (K Ｄ The antibody agent according to any one of claims 1 to 6, which binds to human activin A at the nucleotide sequence (SEQ ID NO: 1).

10. (i) the antibody agent reduces plasma, blood, serum, and / or urine levels of activin A to less than about 500 pg / mL; (ii) the antibody agent prevents an increase in activin A levels in plasma, blood, serum, and / or urine above about 500 pg / mL; and / or (iii) The antibody agent of any one of claims 1 to 6, wherein the antibody agent reduces activin A activity by about 5%.

11. The antibody agent of any one of claims 1 to 6, wherein the antibody agent does not bind to or has minimal binding affinity to one or more TGF beta superfamily members other than activin A.

12. The antibody agent according to any one of claims 1 to 6, wherein the antibody agent is produced in a bacterial cell, a yeast cell, or a mammalian cell.

13. An isolated nucleic acid encoding the antibody agent of any one of claims 1 to 6.

14. 1. An isolated nucleic acid comprising a sequence encoding an activin A antibody agent, said nucleic acid comprising: (a) a variable heavy (VH) sequence comprising SEQ ID NO:112, SEQ ID NO:119, SEQ ID NO:124, SEQ ID NO:128, SEQ ID NO:133, SEQ ID NO:139, SEQ ID NO:144, SEQ ID NO:148, SEQ ID NO:156, SEQ ID NO:162, SEQ ID NO:168, SEQ ID NO:178, SEQ ID NO:185, SEQ ID NO:189, SEQ ID NO:195, SEQ ID NO:201, SEQ ID NO:208, SEQ ID NO:213, or a sequence having at least 85% identity to any of the foregoing; and / or (b) a variable light chain (VL) sequence comprising SEQ ID NO:10, SEQ ID NO:15, SEQ ID NO:20, or SEQ ID NO:24, SEQ ID NO:35, SEQ ID NO:39, SEQ ID NO:47, SEQ ID NO:52, SEQ ID NO:60, SEQ ID NO:67, SEQ ID NO:76, SEQ ID NO:84, SEQ ID NO:92, SEQ ID NO:101, or a sequence having at least 85% identity to any of the foregoing.

15. A vector comprising the nucleic acid of claim 13.

16. A host cell comprising the vector of claim 15.

17. A method for producing an antibody agent that binds to activin A, comprising culturing a host cell described in claim 16 under conditions in which the activin A antibody agent is expressed by the host cell.

18. A composition comprising the activin A antibody polypeptide of any one of claims 1 to 6.

19. A pharmaceutical composition comprising the activin A antibody polypeptide of any one of claims 1 to 6 and an excipient.

20. The pharmaceutical composition of claim 19 for use in a method, wherein the method comprises: contacting the pharmaceutical composition with a cell, tissue, or subject, thereby inhibiting activin A in the cell, tissue, or subject; the subject has a condition or disorder associated with increased activin A. Pharmaceutical compositions for use.

21. 21. The pharmaceutical composition for use according to claim 20, wherein contacting comprises administering the activin A pharmaceutical composition to the cell, the tissue, or the subject.

22. the condition or disorder is (i) Disorders of the hypothalamic pituitary gonadal axis; (ii) fibrodysplasia ossificans progressiva (FOP); (iii) pulmonary arterial hypertension and / or hypertension; (iv) anorexia-cachectic disorders associated with chronic diseases such as cancer, chronic kidney disease, chronic heart failure, COPD, elderly and muscular immobility, ICU patients; (v) anemia; (vi) metabolic diseases; (vii) inflammatory diseases; (viii) autoimmune disorders; (ix) fibrotic diseases; (x) cancer; (xi) cancer treatment-related toxicity; (xii) aging; or (xiii) Chemotherapy resistance 21. The pharmaceutical composition for use according to claim 20, comprising:

23. 21. The pharmaceutical composition for use according to claim 20, wherein the condition or disorder is cachexia, mass loss, weight loss, aging, liver damage, kidney damage, cancer, cancer metastasis, chemotherapy-induced toxicity, chemotherapy resistance, hypertension, or any combination thereof.

24. the method improves symptoms of the disorder in a subject; 21. The pharmaceutical composition for use according to claim 20, wherein the symptom is weight loss, loss of appetite, fatigue, muscle mass loss, fat mass loss, lean mass loss, lean mass atrophy, bone loss, anemia, fibrosis, or any combination thereof.

25. Inhibition of activin A (a) reducing the activity, level, and / or stability of activin A; and / or 21. The pharmaceutical composition for use according to claim 20, comprising (b) preventing an increase in the level of activin A.

26. The use, (a) Use for preventing and / or reversing mass loss, or both; (b) use for preventing and / or reversing weight loss; (c) Use for preventing and / or reversing aging; (d) use for preventing and / or reversing liver damage; (e) Use for promoting liver regeneration; (f) Use for preventing recurrence of metastasis in the liver in a subject with cancer; (g) Use for reducing and / or preventing chemotherapy resistance; (h) Use for preventing and / or reversing kidney damage; (i) Use for preventing and / or treating SARS-CoV-2 infection; (j) Use for preventing and / or treating cachexia; (k) Use for preventing and / or treating cancer; (l) Use for preventing, reducing, and / or treating metastasis; or (m) Use of any combination of (a) to (l), 21. A pharmaceutical composition for use according to claim 20.

27. The object is (a) undergoing, having undergone, or about to undergo partial hepatectomy; and / or 27. The pharmaceutical composition for use according to claim 26, wherein (b) the subject has liver damage, has cancer, is an aging subject, or any combination thereof.

28. 27. The pharmaceutical composition for use according to claim 26, wherein the chemotherapy resistance is induced by a therapy administered to the subject to treat the cancer.

29. 27. The pharmaceutical composition for use according to claim 26, wherein the subject has a cancer with a TP53 mutation, a SMAD4 mutation, or both.

30. 27. The pharmaceutical composition for use according to claim 26, wherein the cancer comprises colorectal cancer, colon cancer, gastric cancer, sarcoma, lymphoma, leukemia, head and neck cancer, thymic cancer, epithelial cancer, salivary cancer, liver cancer, stomach cancer, thyroid cancer, lung cancer, ovarian cancer, breast cancer, prostate cancer, esophageal cancer, pancreatic cancer, glioma, leukemia, lymphoma, multiple myeloma, renal cell carcinoma, bladder cancer, cervical cancer, choriocarcinoma, oral cancer, skin cancer, melanoma, endometrial cancer, myelofibrosis, bone cancer or brain cancer.

31. A pharmaceutical composition for use in a method, said method comprising: (a) assessing the level and / or activity of activin A in a sample from the subject; and / or (b) administering the pharmaceutical composition to the subject if the level of activin A is higher than a comparator drug.

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