Activin receptor-binding proteins type II (ACTRII), their method of production and use, nucleic acid molecule or set of nucleic acid molecules, vector, host cell, pharmaceutical composition and use.

Abstract

The present invention relates to actrii-binding proteins, such as anti-actriia and anti-actriib antibodies, and compositions and methods for producing actrii-binding proteins. In certain respects, actrii-binding proteins inhibit or antagonize actrii activity. Furthermore, the disclosure provides compositions and methods for the diagnosis and treatment of diseases and conditions associated with muscle wasting; a fibrotic condition; inflammatory, cardiovascular, pulmonary, musculoskeletal, neurological, ocular, skeletal, autoimmune or metabolic disease or condition; wound healing; and cancer and other actrii-mediated diseases and conditions.

Description

[0001] The content of the sequence listing sent electronically in the ASCII text file 3174_003PC01_SeqListing.txt (Size: 177 kilobytes; and Creation Date: March 10, 2017) filed with the application is incorporated herein by reference in its entirety. BACKGROUND OF THE INVENTION

[0002] The transforming growth factor beta (TGF-beta) family contains a variety of growth factors that are known to exert biological effects on a wide variety of cell types in both vertebrates and invertebrates. Members of the TGF-beta family play important roles during embryonic development in the formation of tissue patterns and specification and can influence a variety of differentiation processes, including adipogenesis, myogenesis, chondrogenesis, cardiogenesis, hematopoiesis, neurogenesis, and epithelial cell differentiation. The family includes proteins that are described as growth and differentiation factors (GDFs), bone morphogenetic proteins (BMPs), activins, and inhibins.

[0003] Members of the TGF-beta family transduce signals through a mechanism that includes a multi-step process in which the TGF-beta family member binds to a type II serine / threonine kinase receptor expressed on the cell surface, the type II receptor forms a heteromeric complex with a type I cognate receptor and activates the Petition 870260053005, dated 01 / 06 / 2026, p. 8 / 649 2 / 304 type I receptor through phosphorylation, the activated type I receptor phosphorylates and activates Smad proteins that transduce the signal from the cytoplasm to the nucleus, and the nuclear Smad oligomers bind to DNA and associate with transcription factors to regulate the expression of target genes.

[0004] Two members of the related type II TGF-beta receptor family, ActRIIB and ActRIIA, have been identified as type II receptors for activin A and activin B, and other members of the TGFbeta family including BMP7, BMP9, BMP10, GDF1, GDF3, GDF8 (myostatin), GDF11 and Nodal (Yamashita et al., J. Cell Biol. 130: 217-226 (1995); Lee et al., PNAS 98: 9306-9311 (2001); Yeo et al., Mol. Cell 7: 949-957 (2001); and oh et al., Genes Dev. ALK4 and ALK7 are the main receptors of the type I TGF-beta receptor family member for activin A and B, respectively.

[0005] It has been proposed that alterations in the expression and activity of members of the TGF-beta ligand and receptor families are associated with a variety of disorders and conditions including muscular, bone, neurological and metabolic disorders and conditions and cancer. It is an objective of this description to provide ActRII antagonists and their uses in the diagnosis and treatment, prevention and / or improvement of a disease or condition associated with ActRII and / or ActRII ligands. SUMMARY

[0006] The description provides activin receptor type II (ActRII) binding proteins and modes of use of ActRII binding proteins. In particular aspects, ActRII binding proteins are able to inhibit or block the binding of ActRII to one or more cognate ActRII ligands and / or one or more cognate ActRII receptors. In some aspects, ActRII binding proteins are able to inhibit or block the binding of ActRII to an ActRII ligand. Petition 870260053005, dated 01 / 06 / 2026, page 9 / 649 3 / 304 (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10). The description also provides methods for using ActRIl-binding proteins for the diagnosis or treatment, prevention, and / or improvement of a disease or condition associated with elevated ActRIl expression and / or ActRIl-mediated signaling. Such diseases or conditions include, but are not limited to, muscle disorders such as degenerative muscle disease, muscular dystrophy, muscle atrophy, or muscle wasting disorders; a fibrotic condition; an inflammatory, autoimmune, cardiovascular, pulmonary, musculoskeletal, skeletal, ocular, neurological, or metabolic disease or condition; obesity; wound healing; and cancer.

[0007] In some respects, the ActRIl-binding protein binds specifically to ActRHB. In more respects, the supplied ActRIl-binding protein binds specifically to ActRHB and has at least one selected feature from the group consisting of: (a) competing with an ActRIl ligand (e.g., Union A, Union B, GDF1, GDF3, GDF8 (Myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRHB; (b) decreasing the phosphorylation of ALK4 and / or ALK7 in cells expressing ActRHB and ALK4 and / or ALK7 in the presence of an ActRHB ligand (e.g., activin A and / or GDF8 (Myostatin)); (c) decreases the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRHB in the presence of an ActRHB ligand (e.g., activin A and / or GDF8); and (d) binds to ActRHB with a Kd 1 nM and > 1 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRHB-binding protein possesses 2, 3, or 4 of the above characteristics.In some respects, the ActRHB-binding protein has at least 2 or at least 3 of the above characteristics. In other respects, the ActRHB-binding protein competes for binding to... Petition 870260053005, dated 01 / 06 / 2026, p. 10 / 649 4 / 304 ActRIIB is an antibody with a VH and VL pair of ActRIIB-binding proteins disclosed here. In other respects, the ActRIIB-binding protein is either an anti-ActRIIB antibody or a fragment of an ActRIIB-binding antibody.

[0008] In some respects, the ActRII-binding protein binds specifically to ActRIIB and ActRIIA. In more respects, the supplied ActRII-binding protein binds specifically to ActRIIB and ActRIIA and has at least one selected feature from the group consisting of: (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (Myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB and / or ActRIIA; (b) decreasing ALK4 and / or ALK7 phosphorylation in cells expressing ActRIIB and / or ActRIIA and ALK4 and / or ALK7 in the presence of an ActRIIB and / or ActRIIA ligand (e.g., activin A and / or GDF8 (Myostatin)); (c) decreases the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB and / or ActRIIA in the presence of an ActRIIB and / or ActRIIA ligand (e.g., activin A and / or GDF8); and (d) binds to ActRIIB with a Kd < 1 nM and >1 pM (e.g., as determined by BIACORE® analysis).In some respects, the ActRIIB- and ActRIIA-binding protein possesses 2, 3, or 4 of the above characteristics. In some respects, the ActRIIB- and ActRIIA-binding protein has at least 2 or at least 3 of the above characteristics. In other respects, the ActRIIB- and ActRIIA-binding protein competes for binding to ActRIIB and ActRIIA with an antibody with a VH and VL pair of ActRIIB- and ActRIIA-binding antibodies disclosed herein. In other respects, the ActRIIB- and ActRIIA-binding protein is an anti-ActRIIB and ActRIIB antibody or an ActRIIB and ActRIIA-binding antibody fragment.

[0009] In some respects, the ActRII-binding protein binds specifically to ActRIIA. In more respects, the binding protein Petition 870260053005, dated 01 / 06 / 2026, p. 11 / 649 5 / 304 to the supplied ActRII binds to ActRIIA specifically and has at least one selected feature from the group consisting of: (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (Myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIA; (b) decreasing the phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIA and ALK4 and / or ALK7 in the presence of an ActRIIA ligand (e.g., activin A and / or GDF8 (Myostatin)); (c) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIA in the presence of an ActRIIA ligand (e.g., activin A and / or GDF8); (d) binds to ActRIIA with a Kd < 1 nM and > 1 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRIIA-binding protein possesses 2, 3, or 4 of the above characteristics. In some respects, the ActRIIA-binding protein has at least 2 or at least 3 of the above characteristics.In other respects, the ActRIIA-binding protein competes for binding to ActRIIA with an antibody containing a VH and VL ActRIIA-binding pair disclosed here. In other respects, the ActRIIA-binding protein is either an anti-ActRIIA antibody or an ActRIIA-binding antibody fragment.

[0010] In some respects, the ActRII-binding protein comprises a set of complementary determinant regions (CDRs): variable heavy chain (VH) region -CDR1, VH-CDR2, VHCDR3, variable light chain (VL) region -CDR1, VL-CDR2 and VLCDR3, wherein the CDRs are present in a variable heavy chain (VH) region and a variable light chain (VL) region pair disclosed in Table 1. In some respects, the ActRII-binding protein comprises a set of CDRs present in a VH pair and a VL pair selected from the group consisting of: (a) a VH sequence of SEQ ID NO: 2, 16, 22, 28, 34 or 40, and a VL sequence of SEQ ID NO: 9 wherein the protein binds to ActRIIB, (b) a Petition 870260053005, dated 01 / 06 / 2026, page 12 / 649 6 / 304 VH sequence of SEQ ID NO: 63 or 77, and a VL sequence with the amino acid sequence of SEQ ID NO: 70 and in which the protein binds to ActRIIB; (c) a VH sequence of SEQ ID NO: 45 or 57 and a VL sequence of SEQ ID NO: 50, and in which the protein binds to ActRIIB; (d) a VH sequence of SEQ ID NO: 84, 98, 105, 112 or 119, and a VL sequence of SEQ ID NO: 91, and in which the protein binds to ActRIIB and activin receptor type IIA (ActRIIA); and (e) a VH sequence of SEQ ID NO: 125 and a VL sequence of SEQ ID NO: 132, and in which the protein binds to ActRIIA.

[0011] In some respects, the ActRII-binding protein comprises a set of CDRs present in a VH with the amino acid sequence of SEQ ID NO: 144 and a VL with the amino acid sequence of SEQ ID NO: 151 and in which the protein binds to ActRIIB.

[0012] In some respects, the ActRII-binding protein comprises a set of CDRs present in a VH with the amino acid sequence of SEQ ID NO: 165 and a VL with the amino acid sequence of SEQ ID NO: 172, and in which the protein binds to ActRIIA and ActRIIB.

[0013] In additional aspects, the ActRII-binding protein binds specifically to ActRII and comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2 and VL-CDR3, wherein the set of CDRs is identical to or has a total of one, two, three, four, five, six, seven, eight, nine, ten or fewer than ten amino acid substitutions, deletions and / or insertions from a reference set of CDRs wherein: (a) (i) VH-CDR1 has the amino acid sequence SEQ ID NO: 3, 17, 23, 29, 35 or 41; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO: 4, 18, 24, 30 or 36; (iii) VHCDR3 has the amino acid sequence SEQ ID NO: 5; (iv) VLCDR1 has the amino acid sequence SEQ ID NO: 10; (v) VL Petition 870260053005, dated 01 / 06 / 2026, p. 13 / 649 7 / 304 (a) (i) VH-CDR2 has the amino acid sequence SEQ ID NO: 11; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO: 12; and wherein the protein binds to ActRIIB; (b) (i) VH-CDR1 has the amino acid sequence SEQ ID NO: 64 or 78; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO: 65 or 79; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO: 66 or 80; (iv) VLCDR1 has the amino acid sequence SEQ ID NO: 71; (v) VLCDR2 has the amino acid sequence SEQ ID NO: 72; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO: 73; and wherein the protein binds to ActRIIB; (c) (i) VH-CDR1 has the amino acid sequence SEQ ID NO: 3 or 58; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO: 4 or 59; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO: 46; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO: 51; (v) VL-CDR2 has the amino acid sequence SEQ ID NO: 52;(vi) VL-CDR3 has the amino acid sequence SEQ ID NO: 53; and in which the protein binds to ActRIIB; (d) (i) VH-CDR1 has the amino acid sequence SEQ ID NO: 85, 99, 106 or 113; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO: 86, 100, 107, 114 or 120; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO: 87, 101, 108, 115 or 121; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO: 92; (v) VL-CDR2 has the amino acid sequence SEQ ID NO: 93; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO: 94; and in which the protein binds to ActRIIB and ActRIIA; or (e) (i) VH-CDR1 has the amino acid sequence SEQ ID NO: 126; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO: 127; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO: 128; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO: 133; (v) VL-CDR2 has the amino acid sequence SEQ ID NO: 134;and (vi) the VL-CDR3 has the; Petition 870260053005, dated 01 / 06 / 2026, p. 14 / 649 8 / 304 amino acid sequence of SEQ ID NO: 135; and where the protein binds to ActRIIA.

[0014] In additional aspects, the ActRII-binding protein specifically binds to ActRIIB and comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2 and VL-CDR3, wherein the set of CDRs is identical to or has a total of one, two, three, four, five, six, seven, eight, nine, ten or fewer than ten amino acid substitutions, deletions and / or insertions from a reference set of CDRs in which (i) VH-CDR1 has the amino acid sequence SEQ ID NO: 145; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO: 146; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO: 147; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO: 152; (v) VL-CDR2 has the amino acid sequence SEQ ID NO: 153; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO: 154.

[0015] In additional aspects, the ActRII-binding protein specifically binds to ActIIRA and ActRIIB and comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2 and VLCDR3, wherein the set of CDRs is identical to or has a total of one, two, three, four, five, six, seven, eight, nine, ten or fewer than ten amino acid substitutions, deletions and / or insertions from a reference set of CDRs wherein (i) VH-CDR1 has the amino acid sequence SEQ ID NO: 166; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO: 167; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO: 168; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO: 173; (v) VL-CDR2 has the amino acid sequence SEQ ID NO: 174; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO: 175.

[0016] In some respects, the ActRII-binding protein binds specifically to ActRII and comprises a set of CDRs in which: Petition 870260053005, dated 01 / 06 / 2026, p. 15 / 649 9 / 304 (a) (i) VH-CDR1 has the amino acid sequence SEQ ID NO: 3, 17, 23, 29, 35 or 41; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO: 4, 18, 24, 30 or 36; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO: 5; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO: 10; (v) VL-CDR2 has the amino acid sequence SEQ ID NO: 11; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO: 12; and wherein the protein binds to ActRIIB; (b) (i) VH-CDR1 has the amino acid sequence SEQ ID NO: 64 or 78; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO: 65 or 79; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO: 66 or 80; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO: 71; (v) VL-CDR2 has the amino acid sequence SEQ ID NO: 72; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO: 73; and wherein the protein binds to ActRIIB;(c) (i) VH-CDR1 has the amino acid sequence SEQ ID NO: 3 or 58; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO: 4 or 59; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO: 46; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO: 51; (v) VL-CDR2 has the amino acid sequence SEQ ID NO: 52; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO: 53; and wherein the protein binds to ActRIIB; (d) (i) VH-CDR1 has the amino acid sequence SEQ ID NO: 85, 99, 106 or 113; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO: 86, 100, 107, 114, or 120; (iii) VHCDR3 has the amino acid sequence SEQ ID NO: 87, 101, 108, 115, or 121; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO: 92; (v) VL-CDR2 has the amino acid sequence SEQ ID NO: 93; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO: 94; and wherein the protein binds to ActRIIB and ActRIIA;or (e) (i) VH-CDR1 has the amino acid sequence of SEQ ID; Petition 870260053005, dated 01 / 06 / 2026, p. 16 / 649 10 / 304 NO: 126; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO: 127; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO: 128; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO: 133; (v) VL-CDR2 has the amino acid sequence SEQ ID NO: 134; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO: 135; and where the protein binds to ActRIIA.

[0017] In some respects, the ActRII-binding protein binds specifically to ActRIIB and comprises a set of CDRs wherein (i) VH-CDR1 has the amino acid sequence SEQ ID NO: 145; (ii) VH-CDR2 has the amino acid sequence SEQ IDNO: 146; (iii) VH-CDR3 has the amino acid sequence of SEQ IDNO: 147; (iv) VL-CDR1 has the amino acid sequence of SEQ IDNO: 152; (v) VL-CDR2 has the amino acid sequence of SEQ IDNO: 153; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO: 154.

[0018] In some respects, the ActRII-binding protein binds specifically to ActIIRA and ActRIIB and comprises a set of CDRs wherein (i) VH-CDR1 has the amino acid sequence SEQ ID NO: 166; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO: 167; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO: 168; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO: 173; (v) VL-CDR2 has the amino acid sequence SEQ ID NO: 174; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO: 175.

[0019] In some respects, the ActRII-binding protein binds specifically to ActRII and comprises a set of CDRs that has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than ten, or zero amino acid substitutions, deletions, and / or insertions—a reference set of CDRs in which: (a)(i) VHCDR1 has the amino acid sequence of SEQ ID NO: 3; (ii) VHPetion 870260053005, dated 01 / 06 / 2026, page 17 / 649 11 / 304 (a) CDR2 has the amino acid sequence SEQ ID NO: 4; (iii) VHCDR3 has the amino acid sequence SEQ ID NO: 5; (iv) VLCDR1 has the amino acid sequence SEQ ID NO: 10; (v) VLCDR2 has the amino acid sequence SEQ ID NO: 11; and (vi) VLCDR3 has the amino acid sequence SEQ ID NO: 12; and wherein the protein binds to ActRIIB; (b)(i) VH-CDR1 has the amino acid sequence SEQ ID NO: 17; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO: 18; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO: 5; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO: 10; (v) VL-CDR2 has the amino acid sequence SEQ ID NO: 11; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO:12; and in which the protein binds to ActRIIB; (c)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:23; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:24; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:5;(iv) VL-CDR1 has the amino acid sequence SEQ ID NO:10; (v) VLCDR2 has the amino acid sequence SEQ ID NO:11; and (vi) VLCDR3 has the amino acid sequence SEQ ID NO:12; and wherein the protein binds to ActRIIB; (d)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:29; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:30; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:5; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO:10; (v) VL-CDR2 has the amino acid sequence SEQ ID NO:11; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO:12; and wherein the protein binds to ActRIIB; (e)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:35; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:36; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:5; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO:10; (v) VLCDR2 has the amino acid sequence SEQ ID NO:11; and (vi) VL; Petition 870260053005, dated 01 / 06 / 2026, p. 18 / 649 12 / 304 CDR3 has the amino acid sequence SEQ ID NO:12; and where the protein binds to ActRIIB; (f)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:41; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:18; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:5; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO:10; (v) VL-CDR2 has the amino acid sequence SEQ ID NO:11; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO:12; and where the protein binds to ActRIIB; (g)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:64; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:65; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:66 or 80; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO:71; (v) VL-CDR2 has the amino acid sequence SEQ ID NO:72; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO:73; and wherein the protein binds to ActRIIB;and (h)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:78; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:79; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:80; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO:71; (v) VL-CDR2 has the amino acid sequence SEQ ID NO:72; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO:73; and wherein the protein binds to ActRIIB; (i)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:3; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:4; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:46; (iv) VLCDR1 has the amino acid sequence SEQ ID NO:51; (v) VLCDR2 has the amino acid sequence SEQ ID NO:52; and (vi) VLCDR3 has the amino acid sequence SEQ ID NO:53; and wherein the protein binds to ActRIIB; (j)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:58; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:59;(iii) VH-CDR3 has the sequence of; Petition 870260053005, dated 01 / 06 / 2026, p. 19 / 649 13 / 304 amino acids of SEQ ID NO:46; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:51; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO:52; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:53; and wherein the protein binds to ActRIIB; (k)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO:85; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:86; (iii) VHCDR3 has the amino acid sequence of SEQ ID NO:87; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:92; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO:93; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:94; and in which the protein binds to ActRIIB and ActRIIA; (l)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:99; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:100; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:101; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO:92;(v) VL-CDR2 has the amino acid sequence SEQ ID NO:93; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO:94; and in which the protein binds to ActRIIB and ActRIIA; (m)(i) VH-CDR1 has the amino acid sequence of; SEQ ID NO:106; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:107, (iii) VH-CDR3 has the amino acid sequence of SEq ID NO 108; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:92; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO:93; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:94; and in which the protein binds to ActRIIB and ActRIIA; (n)(i)a VH-CDR1 has the amino acid sequence SEQ ID NO:113; (ii)a VH-CDR2 has the amino acid sequence SEQ ID NO:114; (iii)a VH-CDR3 has the amino acid sequence SEQ ID NO:115; (iv)a VL-CDR1 has the amino acid sequence SEQ ID NO:92; (v) VLCDR2 has the amino acid sequence SEQ ID NO:93; and (vi) VLCDR3 has the amino acid sequence SEQ ID NO:94; and wherein the Petition 870260053005, dated 01 / 06 / 2026, p. 20 / 649 14 / 304 protein binds to ActRIIB and ActRIIA; (o)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:113; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:120; (iii) the amino acid sequence of the VH-CDR3 theme SEQ ID NO:121; (iv) the amino acid sequence of the VL-CDR1 theme SEQ ID NO:92; (v) VL-CDR2 has the amino acid sequence SEQ ID NO:93; and (vi) the amino acid sequence of the VL-CDR3 theme SEQ ID NO:94; and in which the protein binds to ActRIIB and ActRIIA; or (p)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:126; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:127; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:128; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO:133; (v) VL-CDR2 has the amino acid sequence SEQ ID NO:134; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO:135; and in which the protein binds to ActRIIA.

[0020] In some respects, the ActRII-binding protein binds specifically to ActRIIB and comprises a set of CDRs that has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than ten, or zero amino acid substitutions, deletions, and / or insertions from a reference set of CDRs wherein (i) VHCDR1 has the amino acid sequence of SEQ ID NO: 145; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO: 146; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO: 147; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO: 152; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO: 153; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO: 154.

[0021] In some respects, the ActRII-binding protein binds specifically to ActIIRA and ActRIIB and comprises a set of CDRs that have a total of one, two, three, four, five, six, seven, eight, nine, ten, less than ten, or zero substitutions, deletions, and / or Petition 870260053005, dated 01 / 06 / 2026, p. 21 / 649 15 / 304 amino acid insertions from a reference set of CDRs where (i) VH-CDR1 has the amino acid sequence SEQ ID NO: 166; (ii) VH-CDR2 has the amino acid sequence SEQ IDNO: 167; (iii) VH-CDR3 has the amino acid sequence of SEQ IDNO: 168; (iv) VL-CDR1 has the amino acid sequence of SEQ IDNO: 173; (v) VL-CDR2 has the amino acid sequence of SEQ IDNO: 174; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO: 175.

[0022] In some respects, the ActRII-binding protein binds specifically to ActRII and comprises a VH and VL pair selected from the group consisting of: (a)(i) a VH with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:2, 16, 22, 28, 34 or 40, and (ii) a VL with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:9, and wherein the protein binds to ActRIIB; (b)(i) a VH with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:45 or 57, and (ii) a VL with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:50, and in which the protein binds to ActRIIB; (c)(i) a VH with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:63 or 77, and (ii) a VL with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:70, and in which the protein binds to ActRIIB;(d)(i) a VH with the amino acid sequence of SEQ ID NO:84, 98, 105, 112 or 119, and (ii) a VL with the amino acid sequence of SEQ ID NO:91, and in which the protein binds to ActRIIB and ActRIIA; and (e)(i) a VH with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:125, and (ii) a VL with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:132, and in which the protein binds to ActRIIA.; Petition 870260053005, dated 01 / 06 / 2026, p. 22 / 649 16 / 304

[0023] In some respects, the ActRII-binding protein binds specifically to ActRIIB and comprises a VH with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO: 144 and a VL with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO: 151.

[0024] In some respects, the ActRII-binding protein binds specifically to ActIIRA and ActRIIB and comprises a VH with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO: 165 and a VL with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO: 172.

[0025] In another aspect, the ActRII-binding protein comprises a VH and VL pair selected from the group consisting of: (a) a VH sequence of SEQ ID NO: 2, 16, 22, 28, 34 or 40, and a VL sequence of SEQ ID NO: 9; wherein the protein binds to ActRIIB; (b) a VH sequence of SEQ ID NO: 45 or 57, and a VL sequence of SEQ ID NO: 50; wherein the protein binds to ActRIIB; (c) a VH sequence of SEQ ID NO: 63 or 77, and a VL sequence of SEQ ID NO: 70; wherein the protein binds to ActRIIB; (d) a VH sequence of SEQ ID NO: 84, 98, 105, 112 or 119, and a VL sequence of SEQ ID NO: 91; and in which the protein binds to ActRIIB and ActRIIA; and (e) a VH sequence with SEQ ID NO: 125 and a VL sequence with SEQ ID NO: 132 in which the protein binds to ActRIIA.

[0026] In additional aspects, an ActRII-binding protein competes for binding to ActRII with an antibody comprising a pair of VH and VL sequences described herein. In some aspects, an ActRII-binding protein binds to the same epitope as an ActRII-binding protein disclosed herein.

[0027] In some respects, the ActRII-binding protein binds to a polypeptide selected from the group consisting of: (a) NANWELERT amino acid residues (SEQ ID NO: 157) of ActRIIB; (b) Petition 870260053005, dated 01 / 06 / 2026, p. 23 / 649 17 / 304 amino acid residues CCEGNFCNER (SEQ ID NO: 159) from ActRIIB; (c) amino acid residues CCEGNMCNEK (SEQ ID NO: 161) from ActRIIA; and (d) amino acid residues ECLFFNANWEKD (SEQ ID NO: 162) from ActRIIA.

[0028] In another aspect, the ActRII-binding protein comprises a VH sequence of SEQ ID NO: 144 and a VL sequence of SEQ ID NO: 151; and the protein binds to ActRIIB.

[0029] In another aspect, the ActRII-binding protein comprises a VH sequence of SEQ ID NO: 165 and a VL sequence of SEQ ID NO: 172; and the protein binds to ActIIRA and ActRIIB.

[0030] In another aspect, the ActRII-binding protein comprises a VH and VL pair selected from the group consisting of: (a) a VH sequence from SEQ ID NO:2 and a VL sequence from SEQ ID NO:9; (b) a VH sequence from SEQ ID NO:16 and a VL sequence from SEQ ID NO:9; (c) a VH sequence from SEQ ID NO:22 and a VL sequence from SEQ ID NO:9; (d) a VH sequence from SEQ ID NO:28 and a VL sequence from SEQ ID NO:9; (e) a VH sequence from SEQ ID NO:34 and a VL sequence from SEQ ID NO:9; (f) a VH sequence from SEQ ID NO:40 and a VL sequence from SEQ ID NO:9; (g) a VH sequence from SEQ ID NO:45 and a VL sequence from SEQ ID NO:50; (h) a VH sequence from SEQ ID NO:57 and a VL sequence from SEQ ID NO:50; (i) a VH sequence from SEQ ID NO:63 and a VL sequence from SEQ ID NO:70; (j) a VH sequence from SEQ ID NO:77 and a VL sequence from SEQ ID NO:70; (k) a VH sequence from SEQ ID NO:84 and a VL sequence from SEQ ID NO:91; (l) a VH sequence from SEQ ID NO:98 and a VL sequence from SEQ ID NO:91;(m) a VH sequence from SEQ ID NO:105 and a VL sequence from SEQ ID NO:91; (n) a VH sequence from SEQ ID NO:112 and a VL sequence from SEQ ID NO:91; (o) a VH sequence from SEQ ID NO:119 and a VL sequence from SEQ ID NO:91; and (p) a VH sequence from SEQ ID; Petition 870260053005, dated 01 / 06 / 2026, page 24 / 649 18 / 304 In one aspect, the ActRII binding protein comprises a VH with a sequence from SEQ ID NO:125 and a VL with a sequence from SEQ ID NO:132. In another aspect, the ActRII binding protein comprises a VH with a sequence from SEQ ID NO:144 and a VL with a sequence from SEQ ID NO:151. In another aspect, the ActRII binding protein comprises a VH with a sequence from SEQ ID NO:165 and a VL with a sequence from SEQ ID NO:172.

[0031] In some respects, the ActRII binding protein comprises a VH and VL pair selected from the group consisting of: (a)(i) a VH sequence with a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen or zero substitutions, deletions and / or insertions of a reference VH sequence selected from the group consisting of SEQ ID NO:2, 16, 22, 28, 34 or 40, and (ii) a VL sequence with a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen or zero amino acid substitutions, deletions and / or insertions of a reference VL sequence of SEQ ID NO:9, and wherein the protein binds to ActRIIB;(b)(i) a VH sequence with a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO:45 or 57, and (ii) a VL sequence with a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO:50, and in which the protein binds to ActRIIB; (c)(i) a VH sequence with a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO:63 or 77, and (ii) a VL sequence with a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a VL sequence of; Petition 870260053005, dated 01 / 06 / 2026, p. 25 / 649 19 / 304 reference of SEQ ID NO:70, and in which the protein binds to ActRIIB; (d)(i) a VH sequence with a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO:84, 98, 105, 112, or 119, and (ii) a VL sequence with a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO:91, and in which the protein binds to ActRIIB and ActRIIA;(e)(i) a VH sequence with a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO:125, and (ii) a VL sequence with a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO:132, and in which the protein binds to ActRIIA.;

[0032] In some respects, the ActRII binding protein comprises a VH sequence with a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero, amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 144 and a VL sequence with a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 151, and the protein binds to ActRIIB.

[0033] In some respects, the ActRII binding protein comprises a VH sequence with a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions of a Petition 870260053005, dated 01 / 06 / 2026, p. 26 / 649 20 / 304 reference VH sequence of SEQ ID NO: 165 and a VL sequence with a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen or zero amino acid substitutions, deletions and / or insertions from a reference VL sequence of SEQ ID NO: 172 and the protein binds to ActIIRA and ActRIIB.

[0034] In another aspect, the ActRII-binding protein comprises a VH and VL pair wherein: (a) the VH sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen or zero amino acid substitutions, deletions and / or insertions from a reference VH sequence of SEQ ID NO:2; the VL sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen or zero amino acid substitutions, deletions and / or insertions from a reference VL sequence of SEQ ID NO:9; and wherein the protein binds to ActRIIB; (b) the VH sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen or zero amino acid substitutions, deletions and / or insertions from a reference VH sequence of SEQ ID NO:16;(a) the VL sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO:9; and in which the protein binds to ActRIIB; (b) the VH sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO:22; the VL sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO:9; and in which the protein binds to ActRIIB; (d) the sequence VH has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen or zero substitutions, deletions and / or insertions; Petition 870260053005, dated 01 / 06 / 2026, p. 27 / 649 21 / 304 amino acids from a reference VH sequence of SEQ ID NO:28; the VL sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO:9; and in which the protein binds to ActRIIB; (e) the VH sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO:34; the VL sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO:9; and in which the protein binds to ActRIIB;(f) the VH sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO:40; the VL sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO:9; and in which the protein binds to ActRIIB; (g) the sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO:45; the VL sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO:50; where the protein binds to ActRIIB;(h) the VH sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen or zero amino acid substitutions, deletions and / or insertions from a reference VH sequence of SEQ ID NO:57; the VL sequence has a total of one, two, three, four, five, six,; Petition 870260053005, dated 01 / 06 / 2026, p. 28 / 649 22 / 304 seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO:50; wherein the protein binds to ActRIIB; (i) the VH sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO:63; the VL sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO:70; and wherein the protein binds to ActRIIB; (j) the VH sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen or zero amino acid substitutions, deletions and / or insertions from a reference VH sequence of SEQ ID NO:77;(k) the VL sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO:70; and in which the protein binds to ActRIIB; (k) the sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO:84; the VL sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO:91; in which the protein binds to ActRIIB and ActRIIA; (l) the VH sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen or zero amino acid substitutions, deletions and / or insertions from a reference VH sequence of SEQ ID NO:98;The VL sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions of a VL sequence; Petition 870260053005, dated 01 / 06 / 2026, p. 29 / 649 23 / 304 reference of SEQ ID NO:91; wherein the protein binds to ActRIIB and ActRIIA; (m) the VH sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO:105; the VL sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO:91; and wherein the protein binds to ActRIIB and ActRIIA; (n) the VH sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO:112;(a) the VL sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO:91; and in which the protein binds to ActRIIB and ActRIIA; (b) the VH sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO:119; the VL sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO:91; and in which the protein binds to ActRIIB and ActRIIA;or (p) the VH sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO:125; the VL sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO:132; and wherein the protein is; Petition 870260053005, dated 01 / 06 / 2026, p. 30 / 649 24 / 304 calls ActRIIA.

[0035] In another aspect, the ActRII-binding protein comprises a VH and VL pair, wherein the VH sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero, amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 144 and the VL sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 151, and the protein binds to ActRIIB.

[0036] In another aspect, the ActRII-binding protein comprises a VH and VL pair, wherein the VH sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen or zero amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 165 and the VL sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen or zero amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 172 and the protein binds to ActRIIA and ActRIIB.

[0037] In some respects, the ActRII-binding protein is an antibody that binds specifically to ActRII. In further respects, the antibody is a monoclonal antibody, a recombinant antibody, a human antibody, a humanized antibody, a chimeric antibody, a bispecific antibody, or a multispecific antibody. In some respects, the ActRII-binding protein is the ActRII-binding antibody fragment. In some respects, the antibody is an antibody fragment selected from the group consisting of a Fab, Fab', F(ab')2, FV, diabody, DART, and a single-chain antibody molecule (e.g., a BiTE).

[0038] Nucleic acids and sets of Petition 870260053005, dated 01 / 06 / 2026, p. 31 / 649 25 / 304 nucleic acids encoding ActRIl-binding proteins. Vectors and vector assemblies containing the nucleic acids and nucleic acid assemblies, and transformed host cells with the nucleic acids and vectors are also provided. In some aspects, the host cell is a hybridoma or mammalian host cell such as a murine myeloma NSO cell, a human PER.C6® cell or a Chinese hamster ovary (CHO) cell. Host cells including mammalian host cells and hybridomas that produce ActRIl-binding proteins are also provided.

[0039] Methods for producing an ActRIl-binding protein are also provided. In some aspects, the method comprises culturing a host cell capable of expressing the ActRIl-binding protein under conditions suitable for expressing the protein and optionally isolating the expressed ActRIl-binding protein.ActRIl-binding proteins prepared and / or isolated using methods disclosed herein or otherwise known in the art are also provided.

[0040] Pharmaceutical compositions comprising an ActRIl-binding protein and a pharmaceutically acceptable carrier are further provided. In some aspects, the description provides methods for treating and / or improving a condition in a subject associated with elevated ActRIl expression or ActRIl-mediated signaling. In some aspects, the methods decrease ActRIl-mediated signaling in the subject. The use of an ActRIl-binding protein provided herein (e.g., an anti-ActRHB and / or ActRHA binding antibody) in the manufacture or preparation of a medicament is also provided. In some embodiments, the medicament is for the treatment and / or improvement of a condition in a subject associated with elevated ActRIl expression or ActRIl-mediated signaling. In a further embodiment, the description provides the use of a Petition 870260053005, dated 01 / 06 / 2026, p. 32 / 649 26 / 304 ActRII binding protein, as supplied herein, in the manufacture of a medicament for the treatment of a disease or pathology described herein.

[0041] Conditions that can be treated and / or improved in an individual using the methods provided include, but are not limited to: muscle disorders such as degenerative muscle disease, muscular dystrophy, muscle atrophy or muscle wasting disorders; a fibrotic condition (e.g., a hepatic, pulmonary, vascular and / or ocular fibrotic condition, such as myocardial fibrosis and idiopathic pulmonary fibrosis (IPF)); metabolic disease (e.g., type II diabetes, insulin resistance, hyperglycemia and obesity); inflammatory disease or conditions, autoimmune disease, cardiovascular disease (e.g., congestive heart failure and hypertension); eye disease, such as age-related macular degeneration; lung disease, musculoskeletal disease, skeletal disease, such as osteoporosis; neurological disease; neuromuscular disease, degenerative disease, wound healing; weight loss;and cancer (e.g., carcinoma, myeloma, bone-loss-inducing cancer, pituitary cancer, and gastrointestinal cancer).

[0042] In some respects, the disclosed methods involve administering a pharmaceutical composition comprising an effective amount of an ActRII-binding protein to an individual in need thereof. In some respects, the ActRII-binding protein is administered alone. In other respects, the ActRII-binding protein is administered as a combination therapy. In other respects, the ActRII-binding protein is administered as a combination therapy to standard treatment / therapy.

[0043] Methods for blocking or reducing the activity of ActRII (e.g., ligand binding and / or signaling) are also provided. In some aspects, the method involves contacting a protein Petition 870260053005, dated 01 / 06 / 2026, page 33 / 649 27 / 304 ActRII binding protein and a cell expressing ActRII. In some cases, the method comprises contact between an ActRII-binding protein and a cell expressing ActRII in the presence of an ActRII ligand (e.g., activin A). In some aspects, the method is performed in vivo. In other aspects, the method is performed in vitro. In some aspects, the blocked or reduced ActRII activity is ActRI phosphorylation. In other aspects, the phosphorylated ActRI is ALK4 and / or ALK7. In further aspects, the blocked or reduced ActRII activity is Smad phosphorylation (e.g., Smad2 and / or Smad3). In some aspects, the description provides a method of blocking or reducing ActRII activity in a subject, comprising administering an effective amount of an ActRII-binding protein to a subject in need of it.In some respects, a method is provided for reducing ActRIIA activity in a subject, comprising administering an effective amount of an ActRIIA-binding protein to a subject in need of it. In some respects, a method is provided for reducing ActRIIB activity in a subject, comprising administering an effective amount of an ActRIIB-binding protein to a subject in need of it.

[0044] A method is also provided for blocking or reducing ActRII activity in a pathological state associated with increased ActRII expression and / or ActRII signaling, or in a pathological state that can be treated and / or improved by reducing or inhibiting the activity of an ActRII ligand. In some cases, the method comprises administering an ActRII-binding protein to an individual with increased ActRII expression or an ActRII ligand. In some respects, the pathological condition is a muscle disorder. In other respects, the muscle disorder is muscle loss or dystrophy. In some respects, the pathological condition is a condition Petition 870260053005, dated 01 / 06 / 2026, p. 34 / 649 28 / 304 metabolic, such as obesity or type II diabetes. In some aspects, the pathological condition is a fibrotic condition of the lung or liver. In additional aspects, the pathological condition is cancer. In other aspects, the cancer is myelofibrosis, myeloma (e.g., multiple myeloma), pituitary cancer, breast cancer, gastrointestinal cancer, or carcinoma. In additional aspects, the pathological condition is a bone-loss-inducing cancer (e.g., prostate and breast cancer). In some aspects, the description provides a method of blocking or reducing the activity of ActRIl in a pathological condition associated with cancer treatment-induced bone loss.

[0045] In some respects, the description provides a method of treating and / or improving a muscle disorder. In some cases, the method comprises administering an ActRIl-binding protein (e.g., an anti-ActRIl antibody) to a subject with a muscle disorder. Further provided is the use of an ActRIl-binding protein, as provided herein, in the manufacture of a medicament for the treatment or improvement of a muscle disorder. In other respects, the muscle disorder is muscle loss or dystrophy. In other respects, the subject is at risk of developing a muscle disorder. In further respects, the subject is at risk of developing muscle loss or dystrophy.

[0046] In some respects, the description provides a method for treating and / or improving a fibrotic condition. In some cases, the method comprises administering an ActRIl-binding protein (for example, in a pharmaceutical composition described herein) to a subject with a fibrotic condition. In other respects, the subject is at risk of developing a fibrotic condition. In some respects, the fibrotic condition is chronic. Further provided is the use of an ActRIl-binding protein, as provided herein, in the manufacture of a medicament for the treatment or improvement of a fibrotic condition. Petition 870260053005, dated 01 / 06 / 2026, page 35 / 649 29 / 304

[0047] In some respects, the description provides a method for reducing fibrosis in a subject. In some cases, the method comprises administering an ActRII-binding protein (for example, an anti-ActRII antibody, such as a complete ActRII antibody or a fragment of ActRII-binding antibody, and its variants and derivatives) to a subject with fibrosis. In some respects, the fibrosis is hepatic or pulmonary fibrosis. Further provided is the use of an ActRII-binding protein, as provided herein, in the manufacture of a medicament for the treatment or improvement of fibrosis.

[0048] In another aspect, the description provides a method for reducing the loss of liver or lung function caused by fibrosis in a subject. In some aspects, the method comprises administering an ActRII-binding protein (e.g., an anti-ActRII antibody, such as a complete ActRII antibody and its ActRII-binding fragment) to a subject in need thereof. In some aspects, the method reduces the loss of liver function in a subject. In some aspects, the method reduces the loss of lung function in a subject. BRIEF DESCRIPTION OF THE DRAWINGS / FIGURES

[0049] FIGS. 1A-1N represent the kinetic characterization of the binding of A01 cell line antibodies to hActRIIB and hActRIIA, as determined by BIACORE®-based analysis at 37°C. Monomeric or dimeric hActRIIB or hActRIIA were captured on a chip and then exposed to concentrations of A01 cell line antibodies. FIGS. 1A-1D represent the characterization of the binding of the A01 (parental) antibody to the ActRIIB monomer (Fig. 1A), ActRIIB dimer (Fig. 1B), ActRIIA monomer (Fig. 1C), and ActRIIA dimer (Fig. 1D). FIGS. 1E and 1F represent the characterization of the binding of the B01 antibody to the ActRIIB monomer (Figure 1E) and ActRIIB dimer (Figure 1F). 1G-1H describe the binding of antibody C01 to the ActRIIB monomer. Petition 870260053005, dated 01 / 06 / 2026, p. 36 / 649 30 / 304 (FIG. 1G) and ActRIIB dimer (FIG. 1H). FIGS. 1I-1J represent the binding of antibody D01 to the ActRIIB monomer (FIG. 1I) and to the ActRIIB dimer (FIG. 1J). FIGS. 1K-1L represent the binding of antibody E01 to the ActRIIB monomer (figure 1K) and ActRIIB dimer (figure 1L). FIGS. 1M-1N represent the binding of antibody F01 to the ActRIIB monomer (figure 1M) and ActRIIB dimer (figure 1N).

[0050] FIG. 2 represents the neutralizing activity of A01 cell line antibodies in a cell-based reporter gene assay. Assay responses with activin A alone (2 ng / ml) and activin A combined with 50 ng / ml of A01, B01, C01, D01, E01, and F01 cell line antibodies are included.

[0051] FIGS. 3A-3F represent the kinetic characterization of antibody binding from the G02 cell line to hActRIIB and hActRIIA, as determined by BIACORE®-based analysis at 37°C. Monomeric or dimeric hActRIIB or hActRIIA were captured on a chip and then exposed to the G01 cell line. FIGS. 3A-3D represent the characterization of antibody binding from G01 to ActRIIB monomer (FIG. 3A), ActRIIB dimer (FIG. 3B), ActRIIA monomer (FIG. 3C), and ActRIIA dimer (FIG. 3D). FIGS. 1E and 1F represent the characterization of antibody binding from H01 to ActRIIB monomer (Figure 3E) and ActRIIB dimer (Figure 3F).

[0052] FIG. 4 depicts the neutralizing activity of parental G01 and optimized H01 antibodies in a cell-based reporter gene assay. Assay responses are included in the absence of activin A, with activin A alone (2 ng / mL), and with activin A combined with 50 ng / mL of G01 or H01 antibodies from the G01 lineage.

[0053] FIGS. 5A-5P depict the kinetic characterization of the binding of A02 lineage antibodies to hActRIIB and hActRIIA, as determined by BIACORE®-based analysis at 37°C. Monomeric or dimeric hActRIIB or hActRIIA were captured on a chip and Petition 870260053005, dated 01 / 06 / 2026, p. 37 / 649 31 / 304 then exposed to A02 lineage antibodies. FIGS. 5A-5D represent the characterization of the binding of the A02 (parental) antibody to the ActRIIB monomer (Fig. 5A), ActRIIB dimer (Fig. 5B), ActRIIA monomer (Fig. 5C) and ActRIIA dimer (Fig. 5D). FIGS. 5E-5H represent the characterization of the binding of the B02 antibody to the ActRIIB monomer (Fig. 5E), ActRIIB dimer (Fig. 5F), ActRIIA monomer (Fig. 5G) and ActRIIA dimer (Fig. 5H). FIGS. 5I-5L represent the characterization of the binding of the C02 antibody to the ActRIIB monomer (Fig. 5I), ActRIIB dimer (Fig. 5J), monomer ActRIIA (Fig. 5K) and ActRIIA dimer (Fig. 5L). FIGS. 5M-5P represent the characterization of the binding of antibody D02 to the ActRIIB monomer (FIG. 5M), ActRIIB dimer (FIG. 5N), monomer ActRIIA (FIG. 5O) and ActRIIA dimer (FIG. 5P). FIGS. 5Q-5T represent the characterization of the binding of antibody D03 to the ActRIIB monomer (Fig. 5Q), ActRIIB dimer (Fig. 5R), monomer ActRIIA (Fig. 5S) and ActRIIA dimer (Fig. 5T).

[0054] FIGS. 6A-6B describe the neutralizing activity of A02 lineage antibodies in a cell-based reporter gene assay. Assay responses are included in the absence of activin A, with activin A alone (2 ng / mL), and with activin A combined with 50 ng / mL of A02 lineage antibodies. FIG. 6A illustrates the neutralizing activity of A02 (parental), B02, C02, and D02. FIG. 6B represents the neutralizing activity of D02 and D03.

[0055] FIGS. 7A-7F represent the kinetic characterization of the binding of the parental antibody E02 and the variant F02 to hActRIIB and hActRIIA, as determined by BIACORE®-based analysis at 37°C. Monomeric or dimeric hActRIIB or hActRIIA were captured on a chip and then exposed to E02 and F02. FIGS. 7A-7D represent the characterization of the binding of the parental antibody E02 to the ActRIIB monomer (FIG. 7A), ActRIIB dimer (FIG. 7B), ActRIIA monomer (FIG. Petition 870260053005, dated 01 / 06 / 2026, p. 38 / 649 32 / 304 7C) and ActRIIA dimer (FIG. 7D). FIGS. 7E and 7F represent the characterization of the binding of antibody F02 to the ActRIIB monomer (figure 7E) and the ActRIIB dimer (figure 7F).

[0056] FIGS. 8A-8D represent the kinetic characterization of the binding of antibody G02 to hActRIIB and hActRIIA as determined by BIACORE®-based analysis at 37°C. Monomeric or dimeric hActRIIB or hActRIIA were captured on a chip and then exposed to the evaluated anti-hActRII antibodies. FIGS. 8A-8D represent the characterization of the binding of antibody G02 to ActRIIB monomer (FIG. 8A), ActRIIB dimer (FIG. 8B), ActRIIA monomer (FIG. 8C) and ActRIIA dimer (FIG. 8D).

[0057] FIG. 9 represents the neutralizing activity of antibodies. Parental E02 and F02 variants that bind to ActRIIB and the ActRIIA-binding antibody G02 in a cell-based reporter gene assay. Assay responses are included in the absence of activin A, with activin A alone (2 ng / mL), and with activin A combined with 50 ng / mL of E02, F02, or G02 lineage antibodies. DETAILED DESCRIPTION

[0058] The description provides isolated recombinant ActRII-binding proteins. In some respects, the ActRII-binding proteins bind specifically to ActRIIB and / or ActRIIA. In other respects, the ActRII-binding proteins are anti-ActRII antibodies. Nucleic acids encoding the ActRII-binding proteins, vectors and host cells containing the nucleic acids, and methods for producing and utilizing the ActRII-binding proteins are also provided. The ActRII-binding proteins provided have uses in the diagnosis, treatment, and / or improvement of diseases and conditions associated with increased ActRII expression and / or signaling. Such uses include, but are not limited to, preventing and / or improving muscle disorders such as muscular dystrophy, muscle disease. Petition 870260053005, dated 01 / 06 / 2026, p. 39 / 649 33 / 304 degenerative, muscle atrophy or muscle wasting disorders; a fibrotic condition (e.g., a hepatic, pulmonary, vascular and / or ocular fibrotic condition, such as myocardial fibrosis and idiopathic pulmonary fibrosis (IPF); metabolic disease (e.g., type II diabetes and obesity); inflammatory disease or conditions, autoimmune disease, cardiovascular disease (e.g., congestive heart failure and hypertension); eye disease, such as age-related macular degeneration; lung disease, musculoskeletal disease, skeletal disease, neurological disease, such as osteoporosis; wound healing; weight loss; and cancer (e.g., carcinoma, myeloma, bone loss-inducing cancer, pituitary cancer and gastrointestinal cancer). Definitions

[0059] Unless otherwise defined, all technical and scientific terms used in this document have the same meaning as commonly understood by someone ordinarily skilled in the art to which this description relates. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; and the Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and the Oxford Dictionary of Biochemistry and Molecular Biology, Revised, 2000, Oxford University Press, provide someone skilled in the art with a general dictionary of many of the terms used in this description. The headings provided in this document are not limitations of the various aspects of the description, which can be obtained by reference to the descriptive report as a whole. Consequently, the terms defined immediately below are more fully defined by reference to the descriptive report in its entirety.

[0060] The terms a, an and the include plural referents, unless the context in which the term is used clearly indicates otherwise. The terms a (or an), as well as the Petition 870260053005, dated 01 / 06 / 2026, p. 40 / 649 34 / 304 The terms one or more and at least one may be used interchangeably in this document. Furthermore, and / or, where used in this document, should be taken as the specific description of each of the two specified characteristics or components with or without the other. Thus, the term and / or as used in a phrase such as A and / or B in this document is intended to include A and B, A or B, A (by itself) and B (by itself). Similarly, the term and / or as used in a phrase such as A, B and / or C is intended to cover each of the following aspects: A, B, and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (by itself); B (by itself); and C (by itself).

[0061] The term includes is generally used in the sense of including, that is, allowing the presence of one or more features or components. It is understood that wherever aspects are described in this document using the language including, analogous aspects otherwise described in terms of consisting of and / or consisting essentially of are also provided.

[0062] The terms about and approximately as used in connection with a numerical value throughout the specification and claims denote a range of precision, familiar and acceptable to a person skilled in the art. In general, this range of precision is ± 10%. Alternatively, and particularly in biological systems, the terms about and approximately may mean values ​​that are within an order of magnitude, preferably in the range < 5 times, and even more preferably in the range < 2 times of a given value.

[0063] Numerical intervals include the numbers that define the interval.

[0064] An ActRII-binding protein refers to a protein that binds specifically to ActRII (i.e., ActRIIB and / or ActRIIA), preferentially binding to the extracellular domain of ActRII. Petition 870260053005, dated 01 / 06 / 2026, p. 41 / 649 35 / 304

[0065] The terms ActRII type II activin receptor and ActRII are used interchangeably and refer to the type IIA activin receptor (ActRIIA) and / or type IIB activin receptor (ActRIIB), unless the context in which the term is used clearly indicates otherwise.

[0066] The terms type IIA activin receptor, receptor of ActRIIA and ActRIIA are used interchangeably herein, and refer to ActRIIA (also referred to as ACVR2A, ActRIIA, ActRII and EC 2.7.11.30 in the literature). The reference sequence for human ActRIIA is provided in RefSeq NO:NP_001607.1. The ActRIIA binding proteins provided bind to the extracellular domain of ActRIIA corresponding to the amino acid sequence of SEQ ID NO: 138.

[0067] The terms activin type IIB receptor, ActRIIB receptor, and ActRIIB are used interchangeably and refer to ActRIIB (also referred to as ACVR2B, ActRIIB, HTX4, ErbB3 receptor, and EC 2.7.11.30 in the literature). The reference sequence for human ActRIIB is provided in NCBI Reference Sequence NP_001097. The provided ActRIIB binding proteins bind to the extracellular domain of ActRIIB corresponding to the amino acid sequence of SEQ ID NO: 139.

[0068] The term compete or competes when used in the context of ActRII-binding proteins (e.g., neutralizing antibodies) means competition between antigen-binding proteins, as determined by an assay in which the antigen-binding protein (e.g., an anti-ActRII antibody or an ActRII-binding fragment thereof) under test prevents or inhibits the specific binding of a reference antigen-binding protein (e.g., a reference ligand or antibody) to a common antigen (e.g., an ActRIIA or ActRIIB extracellular domain or a fragment thereof). Numerous types of competitive binding assays can be used, for example: direct radioimmunoassay (RIA) or Petition 870260053005, dated 01 / 06 / 2026, p. 42 / 649 36 / 304 indirect solid-phase assay (see, for example, Moldenhauer et al., Scand. J. Immunol. 32: 77-82 (1990) and Morel et al., Molec. Immunol. 25:7-15 (1988)), direct or indirect solid-phase enzyme immunoassay (EIA), solid-phase biotin-avidin EIA (see, for example, Cheung, et al., Virology 176: 546-552 (1990) and Kirkland et al., J. Immunol. 137: 36143619 (1986)) and a sandwich-type competition assay (see, for example, Stahli et al., Methods in Enzymology 92: 242-253 (1983)). Typically, such an assay involves the use of purified antigen bound to a solid surface or cells with either of these, an unlabeled test antigen-binding protein, and a labeled reference antigen-binding protein.

[0069] Competitive inhibition is measured by determining the amount of marker bound to the solid surface or cells in the presence of the test antigen-binding protein. Generally, the test antigen-binding protein is present in excess. Antigen-binding proteins identified by the competition assay (competitor antigen-binding proteins) include ActRII-binding proteins that bind to the same epitope as the reference ActRII-binding protein, as well as ActRII-binding proteins that bind to an adjacent epitope sufficiently close to the epitope bound by the reference ActRII-binding protein for steric hindrance to occur. Typically, when a competing ActRII (e.g., ActRIIA or ActRIIB) is present in excess, it will inhibit the specific binding of an ActRII to the reference ActRII binding protein (e.g., ActRIIA or ActRIIB) by at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%.In some cases, a competitive antigen-binding protein inhibits the specific binding of a reference ActRII-binding protein by at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. Petition 870260053005, dated 01 / 06 / 2026, p. 43 / 649 37 / 304

[0070] The term epitope when used in the context of an ActRII protein refers to a determinant of the ActRII protein (e.g., human ActRIIA, human ActRIIB, murine ActRIIA, or murine ActRIIA) capable of binding to an ActRII-binding protein (e.g., an antibody) of the description. Epitopes generally consist of chemically active surface clusters of molecules, such as amino acids or sugar side chains, and generally have specific three-dimensional structural features as well as specific charge characteristics. Conformational and non-conformational epitopes are distinguished in that binding with the former and not the latter is lost in the presence of denaturing solvents. The ActRII epitope bound by an ActRII-binding protein can be easily determined using techniques known in the art.

[0071] Antigen-binding proteins, such as anti-ActRII binding antibodies and ActRII binding fragments, variants or derivatives thereof disclosed herein, may be described or specified in terms of the epitope(s) or portion(s) of an antigen, for example, a target polypeptide that they recognize or to which they specifically bind. For example, the portion of ActRII that specifically interacts with the antigen-binding domain of an ActRII-binding protein disclosed herein is an epitope. Epitopes may be formed from either contiguous amino acids or non-contiguous amino acids juxtaposed by secondary and / or tertiary folding of a protein. Epitopes formed from contiguous amino acids are typically retained upon exposure to denaturing solvents, while epitopes formed by tertiary folding are typically lost upon treatment with denaturing solvents.Epitope determinants can include chemically active surface clusters of molecules, such as amino acids, chains. Petition 870260053005, dated 01 / 06 / 2026, page 44 / 649 38 / 304 sugar side chains, phosphoryl or sulfonyl groups, and may have specific three-dimensional structural features, and / or specific charge characteristics. An epitope typically includes at least 3, 4, 5, 6, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35 amino acids in a single spatial conformation. Epitopes can be routinely determined using methods known in the art.

[0072] The terms inhibit, block, reduce, decrease, suppress, antagonize, and neutralize are used interchangeably and refer to any statistically significant reduction in activity (e.g., ActRII ligand binding and ActRII signaling), including complete blocking of activity. For example, inhibition or suppression may refer to a decrease of approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of activity compared to a control.

[0073] In some respects, the term decrease may refer to the ability of an ActRII-binding protein, such as an antibody or its ActRII-binding fragment, to significantly decrease (e.g., with a p-value less than or equal to 0.05) the phosphorylation of one or more Smads (e.g., Smad2 and / or Smad3) induced by contact of an ActRII-expressing cell and a type I receptor with an ActRII ligand such as activin A, relative to the extent of Smad phosphorylation in the cell when not in contact with the ActRII-binding protein. The ActRII-expressing cell (e.g., ActRIIB and / or ActRIIA) may be a natural cell or cell line or may be recombinantly produced by introducing a nucleic acid encoding ActRII (e.g., ActRIIB and / or ActRIIA) into a host cell.In one aspect, the ActRII-binding protein, for example, an ActRII antibody or its ActRII-binding fragment, decreases phosphorylation mediated by... Petition 870260053005, dated 01 / 06 / 2026, p. 45 / 649 39 / 304 ActRII ligand of one or more Smads (e.g., Smad2 and / or Smad3) at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or at about 100%, as determined, for example, by Western blotting followed by probing with an anti-phosphotyrosine antibody or by ELISA, using standard techniques and conditions described herein or otherwise known in the art.

[0074] In some respects, an ActRIIA-binding protein decreases ActRIIA ligand-mediated phosphorylation (e.g., activin A) of one or more Smads (e.g., Smad2 and / or Smad3) by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or by about 100%, as determined, for example, by Western blotting followed by probing with an anti-phosphotyrosine antibody or by ELISA (e.g., P-Smad ELISA) or an Smad-dependent reporter gene assay using techniques described herein or otherwise known in the art.

[0075] In further aspects, an ActRIIB-binding protein decreases ActRIIB ligand-mediated phosphorylation (e.g., activin A or GDF8) of one or more Smads (e.g., Smad2 and / or Smad3) by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or by about 100%, as determined, for example, by Western blotting followed by probing with an anti-phosphotyrosine antibody or by ELISA (e.g., a P-Smad ELISA assay) or an Smad-dependent reporter gene assay using standard techniques and conditions described herein or otherwise known in the art.

[0076] The terms antibody and immunoglobulin are used interchangeably here and include whole (complete) antibodies and antigen-binding fragments or single chains thereof. A typical antibody comprises at least two heavy (H) chains and two light (L) chains linked by disulfide bonds. Each chain Petition 870260053005, dated 01 / 06 / 2026, p. 46 / 649The 40 / 304 heavy chain comprises a variable heavy chain region (abbreviated in this document as VH) and a constant heavy chain region. The constant heavy chain region is composed of three domains, CHI, CH2, and CH3. Each light chain comprises a variable light chain region (abbreviated in this document as VL) and a constant light chain region. The constant light chain region is composed of one domain, CL. The VH and VL regions can be further subdivided into hypervariable regions, called complementarity-determining regions (CDRs), interspersed with more conserved regions, called framework regions (FWs). Each VH and VL is composed of three CDRs and four FWs, arranged from the amino terminus to the carboxyl terminus in the following order: FW1, CDR1, FW2, CDR2, FW3, CDR3, FW4. The variable regions of the heavy and light chains contain an antigen-binding domain.The constant regions of antibodies can mediate the binding of immunoglobulin to tissues or host factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. Exemplary antibodies include typical antibodies, scFvs, and combinations thereof where, for example, an scFv is covalently linked (e.g., via peptide bonds or via a chemical ligand) to the N- or C-terminus of the heavy chain and / or light chain of a typical antibody or intercalated within the heavy chain and / or light chain of a typical antibody.

[0077] As used herein, the terms antibody and immunoglobulin encompass intact polyclonal antibodies, intact monoclonal antibodies, antibody fragments (such as Fab, Fab', F(ab')2 and Fv fragments), single-chain Fv mutants and derivatives (scFv), multispecific antibodies such as bispecific antibodies, chimeric antibodies, humanized antibodies, human antibodies, Petition 870260053005, dated 01 / 06 / 2026, page 47 / 649 41 / 304 Fusion proteins comprising an antigen-determining portion of an antibody and any other modified immunoglobulin molecule comprising an antigen recognition site, provided the antibodies exhibit the desired biological activity. An antibody may be of any of the five major immunoglobulin classes: IgA, IgD, IgE, IgG, and IgM, or subclasses (isotypes) thereof (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), based on the identity of their constant heavy chain domains referred to as alpha, delta, epsilon, gamma, and mu, respectively. Different immunoglobulin classes have different and known subunit structures and three-dimensional configurations. Antibodies may be pure or conjugated to other molecules, such as toxins, radioisotopes, etc. The term IgG refers to a polypeptide belonging to the class of antibodies that are substantially encoded by a recognized immunoglobulin gamma gene.In humans, this class comprises IgG1, IgG2, IgG3, and IgG4. In mice, this class comprises IgG1, IgG2a, IgG2b, and IgG3.

[0078] The terms antibody ActRII, an antibody that binds to ActRII or anti-ActRII antibody refers to an antibody that is capable of binding to ActRII (e.g., ActRIIB and / or ActRIIA) with sufficient affinity for the antibody to be useful as a therapeutic agent or diagnostic reagent in targeting ActRIIB and / or ActRIIA, respectively.

[0079] Specifically, when used in the context of ActRII proteins, it generally means the ability of a binding protein, such as an antibody, to bind to ActRII (e.g., ActRIIB and / or ActRIIA, preferably human ActRIIA and / or human ActRIIB, preferably an extracellular domain of ActRIIB and / or ActRIIA) with greater affinity than the binding protein binds to an unrelated control protein. In some respects, the control protein is Petition 870260053005, dated 01 / 06 / 2026, p. 48 / 649 42 / 304 chicken egg white lysozyme. Preferably, the binding protein binds to ActRII with an affinity that is at least 100, 500, or 1000 times greater than the affinity for a control protein. Preferably, the binding protein has a binding affinity to human ActRII of < 1 X 10-7 M or < 1 X 10-8 as measured using a binding assay known in the art. In some respects, the binding affinity is measured using a radioimmunoassay (RIA) or BIACORE® (e.g., using ActRII (e.g., ActRIIB and / or ActRIIA) as analyte and ActRII-binding protein as ligand or vice versa).

[0080] In some respects, the extent of binding of an ActRII-binding protein (e.g., an anti-ActRII antibody) to a protein unrelated to ActRII is less than about 10% of the binding of the ActRII-binding protein to ActRII, as measured, for example, by radioimmunoassay (RIA), BIACORE® (using recombinant ActRII as analyte and ActRII-binding protein as ligand or vice versa), kinetic exclusion assay (KINEXA®), or other binding assays known in the art. In certain respects, the ActRII-binding protein is a complete antibody or an ActRII-binding antibody fragment having a dissociation constant (Kd) <1 μM, <100 nM, <10 nM, <1 nM, <0.1 nM, <10 pM, <1 pM, or <0.1 pM.

[0081] The terms antigen-binding antibody fragment (e.g., ActRII-binding antibody fragment, ActRIIA-binding antibody fragment, and ActRIIB-binding antibody fragment) refer to a fragment containing all or a portion of an antigen-binding variable region (e.g., CDR3) of an intact antibody. The antigen-binding function of an antibody has been shown to be performed by certain fragments of a complete antibody. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments. Petition 870260053005, dated 01 / 06 / 2026, p. 49 / 649 43 / 304 linear antibodies, single-chain antibodies, and multispecific antibodies formed by one or more antibody fragments. In some respects, the description provides ActRII-binding antibody fragments, where the antibody fragment is a Fab fragment, a Fab' fragment, an F(ab').2 fragment, an Fv fragment, a diabody, or a single-chain antibody molecule.

[0082] The Fc region includes polypeptides comprising the constant region of an antibody excluding the first immunoglobulin domain of the constant region. Thus, Fc refers to the last two immunoglobulin domains of the constant region of IgA, IgD, and IgG, the last three immunoglobulin domains of the constant region of IgE and IgM, and the N-terminal flexible hinge to these domains. For IgA and IgM, Fc may include the J chain. For IgG, Fc comprises the immunoglobulin domains Cy2 and Cy3 and the hinge between Cy1 and Cy2. Although the boundaries of the Fc region may vary, the Fc region of the human IgG heavy chain is typically defined to comprise residues C226 or P230 at its carboxyl terminus, where the numbering is in accordance with the EU index as established in Kabat (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, NIH, Bethesda, Md. (1991)).Fc may refer to this region in isolation or this region in the context of a complete antibody, an antibody fragment, or an Fc fusion protein. Polymorphisms have been observed at several different Fc positions, including, but not limited to, positions 270, 272, 312, 315, 356, and 358, numbered by the index UE, and therefore, small differences between the presented sequence and the sequences in the prior art may exist.

[0083] A monoclonal antibody refers to a homogeneous population of antibodies involved in the highly specific recognition and binding of a single antigenic determinant or epitope. This contrasts with polyclonal antibodies which typically Petition 870260053005, dated 01 / 06 / 2026, p. 50 / 649 44 / 304 include different antibodies directed against different antigenic determinants. The term monoclonal antibodies encompasses both intact and complete monoclonal antibodies, as well as antibody fragments (such as Fab, Fab', F(ab')2, Fv), single-chain mutants (scFv), fusion proteins comprising an antibody portion, and any other modified immunoglobulin molecule comprising an antigen recognition site. A monoclonal antibody can be produced in several ways, including, but not limited to, hybridoma, phage selection, recombinant expression, and transgenic animals.

[0084] The term chimeric antibodies refers to antibodies in which the amino acid sequence of the immunoglobulin molecule is derived from two or more species. Typically, the variable region of the light and heavy chains corresponds to the variable region of antibodies derived from one mammalian species (e.g., mouse, rat, rabbit, etc.) with the desired specificity, affinity, and antigen-binding capacity, while the constant regions are homologous to antibody sequences derived from another species (generally humans) to avoid triggering an immune response in that species.

[0085] The term humanized antibody refers to an antibody derived from a non-human immunoglobulin (e.g., murine) that has been modified to contain fewer, preferably minimal, non-human (e.g., murine) sequences. Typically, humanized antibodies are human immunoglobulins in which CDR residues are replaced by CDR residues from a non-human species (e.g., mouse, rat, rabbit, or hamster) that have specificity, affinity, and / or antigen-binding capacity (Jones, Nature 321:522-525 (1986); Riechmann, Nature 332:323-327 (1988); Verhoeyen, Science 239:1534-1536 (1988)). In some cases, Petition 870260053005, dated 01 / 06 / 2026, p. 51 / 649 45 / 304 The residues in the framework (FW) region of Fv from a human immunoglobulin are replaced by corresponding residues in a non-human species antibody that has the desired specificity, affinity, and antigen-binding capacity. The humanized antibody may be further modified by replacing additional residues in the Fv framework region and / or within the replaced non-human residues to refine and optimize the antibody's specificity, affinity, and / or capacity. Generally, the humanized antibody will comprise substantially all of at least one, and typically two or three, variable domains containing all or substantially all CDR regions that correspond to the non-human immunoglobulin, provided that all or substantially all FW regions are those of a consensus sequence of the human immunoglobulin.The humanized antibody may also comprise at least a portion of an immunoglobulin (Fc) constant region or domain, typically that of a human immunoglobulin. Examples of methods used to generate humanized antibodies are described in U.S. Patents 5,225,539 and 5,639,641.

[0086] The term human antibody means an antibody produced by a human or an antibody with an amino acid sequence corresponding to an antibody produced by a human produced using any technique known in the art. The term human antibody includes intact (complete) antibodies, fragments thereof and / or antibodies comprising at least one human heavy and / or light chain polypeptide such as an antibody comprising murine light chain and human heavy chain polypeptides.

[0087] An antagonist, blocking, or neutralizing binding protein is one that inhibits or reduces the activity of the antigen when... Petition 870260053005, dated 01 / 06 / 2026, p. 52 / 649 46 / 304 which binds, such as ActRIIB and / or ActRIIA. In some respects, the ActRII antagonist protein reduces or inhibits binding to ActRIIA by an ActRIIA ligand, such as activin A. In some respects, the ActRII antagonist protein reduces or inhibits binding to ActRIIB by an ActRIIB ligand, such as activin A. In certain respects, the ActRII antagonist binding protein substantially or completely inhibits ActRII activity. In some respects, ActRII activity is reduced by 10%, 20%, 30%, 50%, 70%, 80%, 90%, 95%, or 100%. In certain respects, the ActRII binding protein antagonist is an anti-ActRIIA antibody, such as a complete antibody or a fragment of an ActRIIA binding antibody. In other respects, the anti-ActRIIA antagonist antibody inhibits or reduces ActRIIA activity by at least 10%, 20%, 30%, 50%, 70%, 80%, 90%, 95%, or even 100%.In additional aspects, the antagonist ActRII-binding protein is an anti-ActRIIB antibody, such as a complete antibody or a fragment of ActRIIB-binding antibody. In other aspects, the antagonist anti-ActRIIB antibody inhibits or reduces the activity of ActRIIB by at least 10%, 20%, 30%, 50%, 70%, 80%, 90%, 95%, or even 100%.

[0088] The term binding affinity generally refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, binding affinity refers to intrinsic binding affinity which reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (KD). Affinity can be measured by common methods known in the art, including those described herein, and may be used for the purposes of this description. Petition 870260053005, dated 01 / 06 / 2026, p. 53 / 649 47 / 304

[0089] Potency is a measure of the pharmacological activity of a compound expressed in terms of the amount of the compound required to produce an effect of a given intensity. It refers to the amount of the compound needed to achieve a defined biological effect; the smaller the dose required, the more potent the drug. Potency is normally expressed as an IC50 value, in nM, unless otherwise indicated. IC50 is the median inhibitory concentration of a protein binding to ActRII, for example, an anti-ActRIIA or anti-ActRIIB antibody. In functional assays, IC50 is the concentration that reduces a biological response by 50% of its maximum. In ligand-receptor binding studies, IC50 is the concentration that reduces ligand-receptor binding by 50% of the maximum specific binding level. IC50 can be calculated by any number of means known in the art.The improvement in potency for the antibodies or other binding protein provided herein, compared with a reference anti-ActRII antibody or other ActRII binding protein, may be at least 2-fold, 4-fold, 6-fold, 8-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 110-fold, 120-fold, 130-fold, 140-fold, 150-fold, 160-fold, 170-fold, or at least 180-fold.

[0090] Antibody-dependent cell-mediated cytotoxicity or ADCC refers to a form of cytotoxicity in which secreted Ig binds to Fc receptors (FcRs) present on certain cytotoxic cells (e.g., Natural killer (NK) cells, neutrophils, and macrophages), allowing these cytotoxic effector cells to specifically bind to an antigen-bearing target cell and subsequently kill the target cell with cytotoxins. High-affinity specific IgG antibodies directed to the surface of target cells arm the cytotoxic cells and are absolutely necessary for this elimination. Target cell lysis is extracellular, requiring contact. Petition 870260053005, dated 01 / 06 / 2026, page 54 / 649 48 / 304 direct cell-to-cell interaction and does not involve complement. It is contemplated that, in addition to antibodies, other proteins comprising Fc regions, specifically Fc fusion proteins, with the ability to bind specifically to a target cell containing ActRII will be able to effect cell-mediated cytotoxicity. For simplicity, cell-mediated cytotoxicity resulting from the activity of an Fc fusion protein is also referred to here as ADCC activity.

[0091] An ActRII-binding protein (e.g., an ActRII antibody, including an ActRII-binding fragment, variant and its derivative), polynucleotide, vector, cell, or composition that is isolated is a protein (e.g., antibody), polynucleotide, vector, cell, or composition that is in a form not found in nature. Isolated proteins, polynucleotides, vectors, cells, or compositions include those that have been purified to a degree where they are no longer in a form in which they are found in nature. In some respects, an isolated protein, polynucleotide, vector, cell, or composition is substantially pure.Isolated proteins and isolated nucleic acids will be free or substantially free of material with which they are naturally associated, such as other polypeptides or nucleic acids with which they are found in their natural environment or the environment in which they are prepared (e.g., cell culture) when such preparation is carried out by recombinant DNA technology in vitro or in vivo. Proteins and nucleic acids may be formulated with diluents or adjuvants and, for practical purposes, isolated – for example, proteins will normally be mixed with gelatin or other carriers if used to coat microtiter plates for use in immunoassays, or mixed with pharmaceutically acceptable carriers or diluents when used in diagnostics. Petition 870260053005, dated 01 / 06 / 2026, page 55 / 649 49 / 304 or therapy.

[0092] The terms subject, individual, animal, patient, and mammal refer to any subject, particularly a mammalian subject, for whom diagnosis, prognosis, or therapy is desired. Mammalian subjects include, but are not limited to, humans, non-human primates, domestic animals, farm animals, rodents, and the like, who are to be the recipients of a particular treatment.

[0093] The term pharmaceutical formulation refers to a preparation in such a way as to allow the biological activity of the active ingredient to be effective, and which does not contain additional components at concentrations that would be unacceptably toxic to a subject to whom the formulation would be administered. Such a composition may be sterile.

[0094] An effective amount of a polypeptide, for example, an antigen-binding protein including an antibody, as disclosed herein, is an amount sufficient to accomplish a specifically stated purpose. An effective amount may be determined empirically and routinely in relation to the stated objectives.The term therapeutically effective amount refers to a quantity of a polypeptide, for example, an antigen-binding protein including an antibody or other drug effective in treating a disease or condition in an individual (e.g., a mammal such as a human) and providing some improvement or benefit to an individual who has the disease or condition. Thus, a therapeutically effective amount is an amount that provides some relief, mitigation, and / or reduction in at least one clinical symptom of the ActRII-mediated disease or condition. The clinical symptoms associated with the diseases or conditions that can be treated by the methods described are well known. Furthermore, the therapeutic effects need not be complete or curative, provided they are somewhat effective. Petition 870260053005, dated 01 / 06 / 2026, p. 56 / 649 50 / 304 benefit is provided to the subject. In some modalities, the term therapeutically effective refers to an amount of a therapeutic agent that is capable of reducing ActRII activity in a patient who needs it. The actual amount administered, as well as the rate and timing of administration, will depend on the nature and severity of what is being treated. The prescription of treatment, for example, decisions about dosage, etc., is the responsibility of general practitioners and other physicians. Appropriate doses of antibodies and their antigen-binding fragments are generally known; see, edermann et al., Int. J. Cancer 47: 659-664 (1991); Bagshawe et al., Ant. Immun. and Radiopharm. 4: 915-922 (1991).

[0095] A sufficient amount or an amount sufficient to achieve a particular result in a patient who has an ActRII-mediated disease or condition refers to an amount of a therapeutic agent (e.g., an antigen-binding protein including an antibody, as disclosed herein) that is effective in producing a desired effect, which is optionally a therapeutic effect (i.e., by administering a therapeutically effective amount). In some embodiments, such a particular result is a reduction in ActRII activity in a patient who needs it.

[0096] The term marker refers to a detectable compound or composition that is conjugated directly or indirectly with a moiety such as an anti-ActRII antibody in order to generate a labeled moiety. The marker may be detectable on its own (e.g., radioisotope markers or fluorescent markers) or, in the case of an enzymatic marker, it may catalyze the chemical alteration of a substrate compound or composition that is detectable.

[0097] Terms such as treating or treatment, treat or improve and improve refer to (a) therapeutic measures that Petition 870260053005, dated 01 / 06 / 2026, p. 57 / 649 51 / 304 cure, slow, reduce symptoms and / or halt the progression of a diagnosed pathological condition or disorder and (b) prophylactic or preventive measures that prevent and / or slow the development of a target disease or condition. Thus, subjects requiring treatment include those who already have the disease or condition; those at risk of developing the disease or condition; and those in whom the disease or condition should be prevented. In certain respects, a subject is successfully treated according to the methods provided herein if the subject shows, for example, total, partial or transient improvement or elimination of a symptom associated with the disease or condition. In some respects, the description provides a method for treating a muscular disorder, such as loss of muscle mass due to disease or disuse.In additional aspects, the description provides a method for treating a disease or condition selected from among muscular disorders, such as muscular dystrophy, degenerative muscle disease, muscle atrophy, or muscle wasting disorders; a fibrotic condition (e.g., a hepatic, pulmonary, vascular, and / or ocular fibrotic condition, such as myocardial fibrosis and idiopathic pulmonary fibrosis (IPF)); metabolic disease (e.g., type II diabetes and obesity); inflammatory disease or conditions; autoimmune disease; cardiovascular disease (e.g., congestive heart failure and hypertension); eye disease, such as age-related macular degeneration; lung disease; musculoskeletal disease; skeletal disease; neurological disease, such as osteoporosis; wound healing; weight loss; and cancer (e.g., carcinoma, myeloma, bone-loss-inducing cancer, pituitary cancer, and gastrointestinal cancer).In other respects, the description provides for the use of an ActRII-binding protein as provided herein in the manufacture of a medicament for the treatment or improvement of one or more of the diseases or conditions. Petition 870260053005, dated 01 / 06 / 2026, p. 58 / 649 52 / 304 mentioned above.

[0098] As used herein, “in combination with” or “combined therapies” refers to any form of administration such that additional therapies (e.g., second, third, fourth, etc.) are still effective in the body (e.g., multiple compounds are simultaneously effective in the individual, which may include synergistic effects of these compounds). Efficacy may not correlate with the measurable concentration of the agent in blood, serum, or plasma. For example, different therapeutic compounds may be administered in the same formulation or in a separate formulation, simultaneously or sequentially, and at different times. Thus, a subject receiving such treatment may benefit from a combined effect of different therapies. One or more ActRII-binding proteins of the description may be administered concurrently with, before, or subsequent to one or more other additional agents and / or supportive therapies.In general, each therapeutic agent will be administered at a dose and / or at a time determined for that specific agent. The particular combination to be used in a regimen will take into account the compatibility of the antagonist described herein with the therapy and / or the desired outcome.

[0099] The methods and techniques of the present application are generally carried out in accordance with conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present description, unless otherwise indicated. See, for example, Sambrook et al., Molecular Cloning: A Laboratory Manual, 3rd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (2001), Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates (1992), and Harlow and Lane Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (2001). Petition 870260053005, dated 01 / 06 / 2026, p. 59 / 649 53 / 304 Harbor, NY (1990), which are incorporated here by reference.

[0100] The terms cancer, tumor, cancerous, and malignant refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancers include, but are not limited to, carcinoma including adenocarcinomas, lymphomas, blastomas, melanomas, sarcomas, and leukemias. More particular examples of such cancers include squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, Hodgkin's and non-Hodgkin's lymphoma, pancreatic cancer, glioblastoma, glioma, cervical cancer, ovarian cancer, liver cancer such as hepatocellular carcinoma and hepatoma, bladder cancer, breast cancer (including cancer-mediated breast cancer; see, for example, Innes et al., Br. J.Cancer 94: 1057-1065 (2006)), colon cancer, colorectal cancer, endometrial carcinoma, myeloma (such as multiple myeloma), salivary gland carcinoma, basal cell carcinoma, melanoma, prostate cancer, vulvar cancer, thyroid cancer, testicular cancer, esophageal cancer, various types of head and neck cancer, and cancers of mucinous origin, such as mucinous ovarian cancer and cholangiocarcinoma (liver). In one particular aspect, the cancer is myelofibrosis, myeloma (e.g., multiple myeloma), or pituitary cancer. In another aspect, the cancer is breast cancer, gastrointestinal cancer, or a carcinoma (e.g., basal cell and squamous cell carcinomas). In a further aspect, the cancer is a bone-loss-inducing cancer.

[0101] The terms polynucleotide and nucleic acid are used interchangeably and are intended to encompass a single nucleic acid as well as multiple nucleic acids, and refer to an isolated nucleic acid molecule or construct, for example, messenger RNA (mRNA), complementary DNA (cDNA), or plasmid DNA (pDNA). In Petition 870260053005, dated 01 / 06 / 2026, p. 60 / 649 54 / 304 In certain embodiments, a polynucleotide may comprise a conventional phosphodiester bond or an unconventional bond (e.g., an amide bond, such as that found in peptide nucleic acids (PNA)). The term nucleic acid refers to any one or more nucleic acid segments, for example, cDNA or RNA fragments, present in a polynucleotide. When applied to a nucleic acid or polynucleotide, the term isolate refers to a nucleic acid molecule, DNA or RNA, that has been removed from its native environment, for example, a recombinant polynucleotide encoding an antigen-binding protein contained in a vector. It is considered an isolate for the purposes of this description. Other examples of an isolated polynucleotide include recombinant polynucleotides maintained in heterologous host cells or purified (partially or substantially) from other polynucleotides in a solution.Isolated RNA molecules include in vivo or in vitro RNA transcripts of polynucleotides of the present invention. Isolated polynucleotides or nucleic acids, according to the present invention, also include these synthetically produced molecules. In addition, polynucleotides or nucleic acids may be or may include regulatory elements such as promoters, enhancers, ribosome binding sites, or transcription termination signals.

[0102] The term vector refers to a construct that is capable of delivering and expressing one or more genes or sequences of interest in a host cell. Examples of vectors include, but are not limited to, viral vectors, pure DNA or RNA expression vectors, plasmid, cosmid or phage vectors, DNA or RNA expression vectors associated with cationic condensation agents, DNA or RNA expression vectors encapsulated in liposomes, and certain eukaryotic cells, such as producer cells. Petition 870260053005, dated 01 / 06 / 2026, page 61 / 649 55 / 304

[0103] The term host cell refers to a cell or a population of cells that harbor or are capable of harboring recombinant nucleic acid. Host cells can be prokaryotic (e.g., E. coli) or eukaryotic. Host cells can be fungal cells, including yeasts such as Saccharomyces cerevisiae, Pichia pastoris, or Schizosaccharomyces pombe. Host cells can also be from various animal cells, such as insect cells (e.g., Sf-9) or mammalian cells (e.g., HEK293F, CHO, COS-7, NIH-3T3, NS0, PER.C6®, and hybridoma). In additional aspects, the host cells are a CHO cell selected from the group consisting of CHO-K, CHO-0, CHOLec10, CHO-Lec13, CHO-Lec1, CHO Pro.-5, and CHO dhfr-. In particular aspects, the host cell is a hybridoma.

[0104] The terms polypeptide, peptide, and protein are used interchangeably in this document to refer to polymers of amino acids of any length. Polymers may be linear or branched, may comprise modified amino acids, and may be interrupted by non-amino acids. The terms also encompass an amino acid polymer that has been modified naturally or by intervention; for example, by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling component. Also included in the definition are, for example, polypeptides containing one or more analogs of an amino acid (including, for example, non-natural amino acids, etc.), as well as other modifications known in the art.It is understood that, because in some respects the ActRII-binding proteins provided are antibody-based, the ActRII-binding proteins may occur as single chains or associated chains.

[0105] A recombinant polypeptide, protein, or antibody Petition 870260053005, dated 01 / 06 / 2026, p. 62 / 649 56 / 304 refers to a polypeptide, protein, or antibody produced using recombinant DNA technology. Recombinantly produced polypeptides, proteins, and antibodies expressed in host cells are considered isolates for the purpose of this description, as are native or recombinant polypeptides that have been separated, fractionated, or partially or substantially purified by any suitable technique.

[0106] Also included in this description are fragments, variants or derivatives of polypeptides and any combination thereof. The term fragment when referring to polypeptides and proteins includes any polypeptides or proteins that retain at least some of the properties of the reference polypeptide or protein. Polypeptide fragments include proteolytic fragments as well as deletion fragments.

[0107] The term variant refers to an antibody or polypeptide sequence that differs from that of a parental antibody or polypeptide sequence by virtue of at least one amino acid modification. Antibody or polypeptide variants include fragments and also antibodies or polypeptides with altered amino acid sequences due to amino acid substitutions, deletions, or insertions. Variants may occur naturally or be unnaturally occurring. Unnaturally occurring variants may be produced using mutagenesis techniques known in the art. Variant polypeptides may comprise conservative or non-conservative amino acid substitutions, deletions, or additions.

[0108] The term derivatives applied to antibodies or polypeptides refers to antibodies or polypeptides that have been altered to exhibit additional characteristics not found in the native antibody or polypeptide. An example of a derivative antibody is a fusion or conjugate with a second polypeptide or other molecule. Petition 870260053005, dated 01 / 06 / 2026, page 63 / 649 57 / 304 (for example, a polymer such as PEG, a chromophore or a fluorophore) or atom (for example, a radioisotope).

[0109] The term amino acid substitution refers to the replacement of an amino acid residue present in a parent sequence by another amino acid residue. An amino acid can be substituted in a parent sequence, for example, through chemical peptide synthesis or through known recombinant methods. Consequently, references to an X-position substitution or X-position substitution refer to the replacement of an amino acid residue present at the X position by an alternative amino acid residue. In some embodiments, the substitution patterns can be described according to the AXY scheme, where A is the single-letter code corresponding to the amino acid residue naturally present at the X position and Y is the substituting amino acid residue.In other respects, substitution patterns can be described according to the XY scheme, where Y is the single-letter code corresponding to the amino acid residue replacing the amino acid residue naturally present at position X.

[0110] A conservative amino acid substitution is one in which the amino acid residue is replaced by an amino acid residue having a similar side chain. Families of amino acid residues with similar side chains have been previously defined, including basic side chains (e.g., Lys, Arg, His), acidic side chains (e.g., Asp, Glu), uncharged polar side chains (e.g., Gly, Asp, Gln, Ser, Thr, Tyr, Cys), nonpolar side chains (e.g., Ala, Val, Leu, Ile, Pro, Phe, Met, Trp), beta-branched side chains (e.g., Thr, Val, Ile), and aromatic side chains (e.g., Tyr, Phe, Trp, His). Thus, if one amino acid in a polypeptide is replaced by another Petition 870260053005, dated 01 / 06 / 2026, pp. 64 / 649 58 / 304 amino acids from the same family as the side chain, the substitution is considered conservative. Alternatively, a chain of amino acid residues can be conservatively substituted by a structurally similar chain that differs in order and / or composition from the members of the side chain family.

[0111] Non-conservative substitutions include those in which (a) a residue with an electropositive side chain (e.g., Arg, His, or Lys) is replaced with, or by, an electronegative residue (e.g., Glu or Asp), (b) a hydrophilic residue (e.g., Ser or Thr) is replaced with, or by, a hydrophobic residue (e.g., Ala, Leu, Ile, Phe, or Val), (c) a Cys or Pro is replaced with, or by, any other residue, or (d) a residue having a bulky hydrophobic or aromatic side chain (e.g., Val, His, Ile, or Trp) is replaced with, or by, one with a shorter side chain (e.g., Ala or Ser) or no side chain (e.g., Gly).

[0112] Other substitutions can be readily identified. For example, for the amino acid alanine, a substitution of any of the following can be made: D-Ala, Gly, beta-Ala, L-Cys, and D-Cys. For lysine, a substitute can be any of the following: D-Lys, Arg, DArg, homo-Arg, Met, D-Met, omitin, or D-ornithine. Generally, substitutions in functionally important regions that can induce changes in the properties of isolated polypeptides are those in which (a) a polar residue (e.g., Ser or Thr) is substituted with (or by) a hydrophobic residue (e.g., Leu, Ile, Phe, or Ala); (b) a Cys residue is substituted with (or by) any other residue; (c) a residue with an electropositive side chain (e.g., Lys, Arg, or His) is substituted with (or by) a residue with an electronegative side chain (e.g., Glu or Asp); or (d) a residue with a bulky side chain (e.g., Phe) is replaced with (or by) one not having that side chain (e.g., Gly). The probability Petition 870260053005, dated 01 / 06 / 2026, p. 65 / 649 59 / 304 The likelihood that one of the previous non-conservative substitutions might alter the functional properties of the protein is also correlated with the position of the substitution relative to functionally important regions of the protein: some non-conservative substitutions may, consequently, have little or no effect on biological properties.

[0113] The term amino acid insertion refers to the introduction of a new amino acid residue between two amino acid residues present in the parental sequence. An amino acid residue can be inserted into a parental sequence, for example, through chemical peptide synthesis or through recombinant methods known in the art. Therefore, the phrases insertion between X and Y positions or Kabat insertion between X and Y positions, where X and Y correspond to amino acid residue positions (e.g., a cysteine ​​amino acid residue insertion between positions 239 and 240), refers to the insertion of an amino acid residue between the X and Y positions, and also to the insertion into a nucleic acid sequence of a codon encoding an amino acid residue between the codons encoding the amino acid residues at the X and Y positions.

[0114] The term percentage of sequence identity between two polynucleotide or polypeptide sequences refers to the number of identical matching positions shared by the sequences over a comparison window, taking into account additions or deletions (i.e., gaps) that must be introduced for optimal alignment of the two sequences. A matching position is any position where an identical nucleotide or amino acid is displayed in both the target sequence and the reference sequence. Gaps displayed in the target sequence are not counted, as gaps are not nucleotides or amino acids. Similarly, gaps displayed in the reference sequence are not counted. Petition 870260053005, dated 01 / 06 / 2026, p. 66 / 649 60 / 304 since the nucleotides or amino acids of the target sequence are counted, not nucleotides or amino acids of the reference sequence. The percentage of sequence identity is calculated by determining the number of positions where the identical amino acid residue or nucleic acid base occurs in both sequences to yield the number of matching positions, dividing the number of matching positions by the total number of positions in the comparison window, and multiplying the result by 100 to yield the percentage of sequence identity. Sequence comparison and determination of the percentage of sequence identity between two sequences can be performed using readily available software programs. Suitable software programs are available from various sources for the alignment of both protein and nucleotide sequences.A suitable program for determining percentile sequence identity is bl2seq, part of the BLAST series of programs available on the US government's National Center for Biotechnology Information website (blast.ncbi.nlm.nih.gov). bl2seq performs a comparison between two sequences using the BLASTN or BLASTP algorithm. BLASTN is used to compare nucleic acid sequences, while BLASTP is used to compare amino acid sequences. Other suitable programs include, for example, Needle, Stretcher, Water, or Matcher, part of the EMBOSS series of bioinformatics programs and also available from the European Bioinformatics Institute (EBI) at www.ebi.ac.uk / Tools / psa.

[0115] The structure for carrying a CDR or a set of CDRs will generally be a heavy or light chain sequence of the antibody or a substantial portion thereof, wherein the CDR or set of CDRs is located at a site corresponding to the CDR or set of CDRs of the antibody's variable domains VH and VL of Petition 870260053005, dated 01 / 06 / 2026, p. 67 / 649 61 / 304 naturally occurring, encoded by rearranged immunoglobulin genes. The structures and locations of the variable domains of immunoglobulins and their CDRs can be readily determined by a person skilled in the art using known variable domain residue numbering programs and systems, such as Chothia, Chothia+, and Kabat, and can be routinely determined by reference to Kabat (Kabat et al., Sequences of Proteins of Immunological Interest. 4th Edition. USA DHHS. 1987) and tools available on the Internet (e.g., at bioinf.org.uk / abysis / sequence_input / key_annotation / key_annotation.html; and imuno.bme.nwu.edu), which is incorporated herein by reference in its entirety.

[0116] CDRs can also be transported by other carriers such as fibronectin, cytochrome B, albumin (e.g., ALBUdAb (Domantis / GSK) and ALB-Kunitz (Dyax)), unstructured repeat sequences of 3 or 6 amino acids (e.g., PASylation® technology and XTEN® technology) and sequences containing elastin-like repeat domains (see, for example, Pat. Appl. Application 61 / 442,106, which is incorporated herein by reference in its entirety).

[0117] A CDR amino acid sequence substantially as presented herein may be carried as a CDR in a human variable domain or in a substantial portion thereof. The HCDR3 sequences substantially as presented herein represent embodiments of the present description and each of them may be carried as an HCDR3 in a human heavy chain variable domain or in a substantial portion thereof.

[0118] The variable domains employed in this description may be derived from any human germline variable domain or rearranged, or may be a synthetic variable domain based on consensus sequences of human variable domains. Petition 870260053005, dated 01 / 06 / 2026, pp. 68 / 649 62 / 304 known. A CDR sequence (e.g., CDR3) can be introduced into a repertoire of variable domains without CDR (e.g., CDR3) using recombinant DNA technology.

[0119] For example, Marks et al., (Bio / Technology 10:779-783 (1992); which is incorporated herein by reference in its entirety) provides methods for producing antibody variable domain repertoires in which consensus primers directed to or adjacent to the 5' end of the variable domain area are used in conjunction with consensus primers for the third framework region of human VH genes to provide a CDR3-free VH variable domain repertoire. Marks et al. further describes how this repertoire can be combined with a CDR3 of a particular antibody. Using analogous techniques, the CDR3-derived sequences of the present description can be scrambled with CDR3-free VH or VL domain repertoires and the complete, scrambled VH or VL domains combined with a cognate VL or VH domain to provide antigen-binding proteins.The repertoire can then be displayed in a suitable host system, such as the phage display system from Intl. Appl. Publ. No. WO92 / 01047 or any other subsequent body of literature, including Kay et al. (1996) Phage Display of Peptides and Proteins: A Laboratory Manual, San Diego: Academic Press, so that appropriate antigen-binding proteins can be selected. A repertoire can consist of anything from 10⁴ individual members upwards, for example, from 10⁶ to 10⁸ or 10¹⁰ members. Other suitable host systems include yeast display, bacterial display, T7 display, and ribosome display. For a review of ribosome display, see Lowe et al., Curr. Pharm. Biotech. 517-527 (2004) and Intl. Appl. Publ. No. WO92 / 01047, each of which is incorporated herein by reference in its entirety. Analogous shuffling or. Petition 870260053005, dated 01 / 06 / 2026, pp. 69 / 649 63 / 304 Combinatorial techniques are also disclosed by Stemmer (Nature 370: 389-391 (1994), which is incorporated here by reference in its entirety), who describes the technique in relation to the β-lactamase gene, but notes that the approach can be used for antibody generation.

[0120] An ActRII-binding protein (e.g., an anti-ActRIIA antibody and an anti-ActRIIB antibody) competes with a reference molecule for binding to ActRII (e.g., ActRIIB and / or ActRIIA, respectively) if it binds to ActRII to the extent that it blocks, to some extent, the binding of the reference molecule to ActRII. The ability of proteins to compete for binding to ActRII and thus interfere with, block, or block each other's binding to ActRII can be determined by any competitive binding assay known in the art, including, for example, a competitive ELISA assay, surface plasmon resonance (SPR; BIACORE®, Biosensor, Piscataway, NJ), or according to methods described by Scatchard et al. (Ann. NY Acad. Sci. 51: 660672 (1949)).It can be said that an ActRII-binding protein competitively inhibits the binding of the reference molecule to ActRII, for example, by at least 90%, at least 80%, at least 70%, at least 60%, or at least 50%. In some respects, the ActRII-binding protein competitively inhibits the binding of the reference molecule to ActRIIA by at least 90%, at least 80%, at least 70%, at least 60%, or at least 50%. In other respects, the ActRII-binding protein competitively inhibits the binding of a reference molecule to ActRIIB by at least 90%, at least 80%, at least 70%, at least 60%, or at least 50%. ActRII binding proteins

[0121] Proteins that bind specifically to ActRII are Petition 870260053005, dated 01 / 06 / 2026, p. 70 / 649 64 / 304 supplied.

[0122] In some respects, the ActRII-binding protein binds to ActRII with an affinity that is at least 100, 500, or 1000 times greater than the affinity of the ActRII-binding protein for a control protein that is not a member of the TGF-beta receptor family. In certain respects, the ActRII-binding protein binds to ActRII and has a dissociation constant (Kd) of <1 μM, <100 nM, <10 nM, <1 nM, <0.1 nM, <10 pM, <1 pM, or <0.1 pM. In some respects, the ActRII-binding protein has a Kd for human ActRII within the range of <1 μM and >0.1 pM, <100 μM and >0.1 pM, or <100 μM and >1 pM.

[0123] In some aspects, BIACORE® analysis is used to determine the ability of an ActRII-binding protein (e.g., an anti-ActRII antibody) to compete with / block binding to the ActRII protein by a reference ActRII-binding protein (e.g., an anti-ActRII antibody). In another aspect where a BIACORE® instrument (e.g., the BIACORE® 3000) is operated according to the manufacturer's recommendations, the ActRII-Fc fusion protein is captured on a CM5 BIACORE® chip by previously bound antiniFc IgG to generate an ActRII-coated surface. Typically, 200-800 ActRII-Fc (dimeric) resonance units would be coupled to the chip (an amount that gives easily measurable levels of binding, but which is readily saturable by the test reagent concentrations to be used).

[0124] The two ActRII-binding proteins (designated A* and B*) Proteins to be evaluated for their ability to compete with / block each other are mixed in a one-to-one molar ratio at the binding sites in a suitable buffer to create a test mixture. When calculating concentrations on a binding site basis, the molecular weight of a binding protein is assumed. Petition 870260053005, dated 01 / 06 / 2026, p. 71 / 649 65 / 304 to ActRII is the total molecular weight of the ActRII-binding protein divided by the number of ActRII-binding sites on that ActRII-binding protein. The concentration of each ActRII-binding protein (i.e., A* and B*) in the test mixture must be high enough to readily saturate the binding sites for that ActRII-binding protein on the ActRII-Fc molecules captured on the BIACORE® chip. The ActRII-binding proteins A* and B* in the mixture are at the same molar concentration (on a binding basis), and this concentration would typically be between 1.00 and 1.5 micromolar (on a binding site basis). Separate solutions containing only ActRII-binding protein A* and only ActRII-binding protein B* are also prepared. The ActRII-binding protein A* and the ActRII-binding protein B* in these solutions must be in the same buffer and at the same concentration as in the test mixture.The test mixture is passed over the BIACORE® chip coated with ActRII-Fc and the total amount of binding is recorded. The chip is then treated to remove the bound ActRII-binding proteins without damaging the ActRII-Fc bound to the chip. Typically, this is done by treating the chip with 30 mM HCl for 60 seconds. The ActRII A* binding protein solution alone is then passed over the ActRII-Fc coated surface and the amount of binding is recorded. The chip is treated again to remove the bound antibody without damaging the ActRII-Fc bound to the chip. The ActRII B* binding protein solution alone is then passed over the ActRII-Fc coated surface and the amount of binding is recorded. The maximum theoretical binding of the mixture of ActRII A* binding protein and ActRII B* binding protein is then calculated and is the sum of the binding of each ActRII-binding protein when passed over the ActRII surface alone.If the actual recorded binding of the mixture is less than this theoretical maximum, then the two ActRII-binding proteins are competing with / blocking each other. Petition 870260053005, dated 01 / 06 / 2026, p. 72 / 649 66 / 304 one another. Thus, in general, an ActRII-binding blocking protein is one that binds to ActRII in the BIACORE® blocking assay above in such a way that during the assay and in the presence of a second ActRII-binding protein the recorded binding is between 80% and 0.1% (e.g., 80% to 4%) of the theoretical maximum binding, specifically between 75% and 0.1% (e.g., 75% to 4%) of the theoretical maximum binding, and more specifically between 70% and 0.1% (e.g., 70% to 4%) of the theoretical maximum binding (as defined above) of the two ActRII-binding proteins in combination.

[0125] The BIACORE® assay described above is an exemplary assay used to determine whether two ActRII-binding proteins, such as anti-ActRII antibodies, compete with / block each other for binding to ActRII. On rare occasions, certain ActRII-binding proteins may fail to bind to ActRII-Fc coupled via anti-Fc IgG to a BIACORE® CM5 chip (this may occur when the relevant binding site on ActRII is masked or destroyed by ActRII binding to Fc). In such cases, blocking can be determined using a labeled version of ActRII, for example, ActRII labeled with the His C-terminal. In this particular format, an anti-His antibody would be coupled to the BIACORE® chip and then the His-labeled ActRII would be passed over the chip surface and captured by the anti-His antibody.Cross-blocking analysis would be performed essentially as described above, except that after each chip regeneration cycle, the new His-labeled ActRII would be loaded back onto the coated surface with anti-His antibodies. In addition, several other known combinations of tags and binding proteins can be used for such blocking analysis (e.g., HA marker with anti-HA antibodies; FLAG marker with anti-FLAG antibodies; biotin marker with streptavidin). In general, an ELISA assay is described to determine whether a binding protein to ActRII is blocking or capable. Petition 870260053005, dated 01 / 06 / 2026, p. 73 / 649 67 / 304 to block the binding of a reference ActRII binding protein to ActRII.

[0126] In some respects, an ELISA is used to determine the ability of an ActRII-binding protein (e.g., an anti-ActRII antibody) to compete for binding to the ActRII protein with a reference ActRII-binding protein (e.g., an anti-ActRII antibody or an ActRII ligand). The general principle of such an assay is to have a reference ActRII-binding protein (e.g., an anti-ActRII antibody) coated in the wells of an ELISA plate. An excess amount of a second potentially blocking test ActRII-binding protein is added in solution (i.e., not bound to the ELISA plate). A limited amount of ActRII (or, alternatively, ActRII-Fc) is then added to the wells. The coated reference ActRII-binding protein and the test ActRII-binding protein in solution compete for binding to the limited number of ActRII (or ActRII-Fc) molecules.The plate is washed to remove ActRII that was not bound by the coated reference ActRII-binding protein and also to remove the solution-phase test ActRII-binding protein, as well as any complexes formed between the solution-phase test ActRII-binding protein and ActRII. The amount of bound ActRII is then measured using an appropriate ActRII detection reagent. A solution-phase test ActRII-binding protein that is able to block the binding of the coated reference ActRII-binding protein to ActRII will be able to cause a decrease in the number of ActRII molecules that the coated reference ActRII-binding protein can bind relative to the number of ActRII molecules that the coated reference ActRII-binding protein can bind in the absence of the second solution-phase test ActRII-binding protein. The background signal for the assay is defined as the signal obtained. Petition 870260053005, dated 01 / 06 / 2026, p. 74 / 649 68 / 304 wells with coated reference ActRII-binding protein, solution-phase test ActRII-binding protein, ActRII buffer only (i.e., without ActRII), and ActRII detection reagents. The positive control signal for the assay is defined as the signal obtained in wells with only coated reference ActRII-binding protein, solution-phase test ActRII-binding protein buffer only (i.e., ActRII-binding protein without solution-phase test), ActRII reagents, and ActRII detection reagents. The ELISA assay must be run such that the positive control signal is at least 3 times the background signal. As a control for methodological artifacts, the cross-blocking assay can be performed in the format described above and also reversed, with the test ActRII-binding protein as the coated antibody and the reference ActRII-binding protein as the solution-phase antibody.

[0127] In some respects, a reporter gene assay is used to determine the ability of an ActRII-binding protein (e.g., an anti-ActRII antibody) to neutralize ActRII (e.g., ActRIIB). In some respects, the reporter gene assay is performed using recombinant A204 cells to determine the ability of an ActRII-binding protein (e.g., an anti-ActRII antibody) to neutralize the activity of ActRII (e.g., ActRIIB). This assay is based on a human rhabdomyosarcoma cell line transfected with a pGL3 (CAGA) 12 plasmid containing a (CAGA) 12 motif (see, for example, Dennler et al. EMBO 17: 3091-3100 (1998) and U.S. Patent No. 8,765,385, each of which is incorporated herein by reference in its entirety) as well as a ReniUa reporter plasmid (pRLCMV) to control transfection efficiency.The CAGA12 motif is present in TGF-beta responsive genes (PAI-1 gene), therefore this vector is commonly used for signaling factors via Smad2 and Smad3. Regarding... Petition 870260053005, dated 01 / 06 / 2026, p. 75 / 649 69 / 304 measuring the ActRIIB binding activity of a candidate protein using this assay, since the A204 cell line primarily expresses ActRIIA instead of ActRIIB, it is not possible to directly test antibodies for potential ActRIIB neutralization capacity. Instead, this assay is intended to detect the ability of a candidate test ActRII protein ligand to neutralize the inhibitory effect of the soluble fusion protein ActRIIB-Fc on the activation of endogenous ActRIIA by ligands (such as activin A or GDF11) that can bind with high affinity to both ActRIIB and ActRIIA. Thus, in this assay, ligand-mediated activation of ActRIIA will occur despite the presence of ActRIIB-Fc if ActRIIB binding is neutralizing.

[0128] On the first day of the assay, A204 cells (ATCC HTB-82) are distributed into 48-well plates at 105 cells per well. On the second day, a solution containing 10 μg of pGL3 (CAGA) 12, 1 pg of pRLCMV, 30 pg of Fugene 6 (Roche Diagnostics), and 970 pg of OptiMEM (Invitrogen) is pre-incubated for 30 minutes, then added to McCoy's growth medium, which is applied to the laminated cells (500 pg / well) for overnight incubation at room temperature. On the third day, the medium is removed and the cells are incubated for 6 hours at 37°C with a mixture of ligands and inhibitors prepared as described below.

[0129] According to one aspect, the neutralizing potency of an ActRII-binding protein, such as an anti-ActRII antibody, is assessed by serial dilution of the test protein in a 48-well plate in a volume of 200 µl of assay buffer (McCoy medium + 0.1% BSA). For assays evaluating the ability of a candidate protein to neutralize ActRIIB activity, an equal volume of ActRIIB-Fc (200 pg / ml) is then added to assay buffer. The test solutions are incubated at 37°C for 30 minutes, then Petition 870260053005, dated 01 / 06 / 2026, p. 76 / 649 70 / 304 400 μL of activin A (10 ng / ml) are added to all wells, and 350 μL of this mixture are added to each well of the 48-well A204 cell plate. Each test protein concentration is tested in duplicate. For assays evaluating the ability of a candidate protein to neutralize ActRIIB activity, the final concentration of ActRIIB-Fc is 50 ng / ml (which is the IC50 for this activin A signaling inhibitor; the final concentration of activin A is 5 ng / ml). After incubation with test solutions for 6 hours, the cells are washed with phosphate-buffered saline containing 0.1% BSA, then lysed with passive lysis buffer (Promega E1941) and stored overnight at -70°C. On the fourth and final day, the plates are warmed to room temperature with gentle stirring.Cell lysates are transferred in duplicate to a chemiluminescence plate (96 wells) and analyzed in a luminometer with reagents from a dual-luciferase reporter assay system (Promega E1980) to determine normalized luciferase activity.

[0130] ActRIIB-dependent pharmacodynamic parameters can be measured as endpoints for in vivo testing of ActRIIB-binding proteins in order to identify binding proteins capable of neutralizing ActRIIB and providing a therapeutic benefit. An ActRIIB-neutralizing binding agent is defined as one capable of causing a statistically significant change, compared to vehicle-treated animals, in such a pharmacodynamic parameter. Such in vivo testing can be performed in any suitable mammal (e.g., mouse, rat, or monkey).

[0131] In some respects, the ActRII-binding protein binds to ActRIIA with an affinity that is at least 100, 500, or 1000 times greater than the affinity of the ActRII-binding protein for a Petition 870260053005, dated 01 / 06 / 2026, p. 77 / 649 71 / 304 control protein that is not a member of the TGF-beta receptor family. In some respects, the ActRII-binding protein binds to ActRIIA with an affinity that is at least 100, 500, or 1000 times greater than the affinity of the ActRII-binding protein for a control protein that is not a member of the TGF-beta receptor family. In certain respects, the ActRIIA-binding protein binds to ActRIIA and has a dissociation constant (Kd) of <1 μM, <100 nM, <10 nM, <1 nM, <0.1 nM, <10 pM, <1 pM, or <0.1 pM. In some respects, the ActRIIA-binding protein has a Kd for human ActRIIA within the range of <1 μM and > 0.1 pM, <100 μM and > 0.1 pM, or <100 μM and > 1 pM.

[0132] In some respects, the ActRII-binding protein binds to ActRIIB with an affinity that is at least 100, 500, or 1000 times greater than the affinity of the ActRII-binding protein for a control protein that is not a member of the TGF-beta receptor family. In some respects, the ActRII-binding protein binds to ActRIIB with an affinity that is at least 100, 500, or 1000 times greater than the affinity of the ActRII-binding protein for a control protein that is not a member of the TGF-beta receptor family. In certain respects, the ActRIIB-binding protein binds to ActRIIB and has a dissociation constant (Kd) of <1 μM, <100 nM, <10 nM, <1 nM, <0.1 nM, <10 pM, <1 pM, or <0.1 pM. In some respects, the ActRIIB-binding protein has a Kd for human ActRIIB within the range of <1 μM and >0.1 pM, <100 μM and >0.1 pM, or <100 μM and >1 pM.

[0133] In some respects, the ActRII-binding protein binds to ActRIIB and ActRIIA with an affinity that is at least 100, 500, or 1000 times greater than the affinity of the ActRII-binding protein for a control protein that is not a member of the TGF-beta receptor family. In some respects, the ActRII-binding protein Petition 870260053005, dated 01 / 06 / 2026, p. 78 / 649 72 / 304 ActRIl binds to ActRIIB and ActRHA with an affinity that is at least 100, 500, or 1000 times greater than the affinity of the ActRIl-binding protein for a control protein that is not a member of the TGF-beta receptor family. In certain respects, the ActRHA-binding protein binds to ActRIIB and has a dissociation constant (Kd) of <1 μM, <100 nM, <10 nM, <1 nM, <0.1 nM, <10 pM, <1 pM, or <0.1 pM. In some respects, the ActRHA and ActRIIB-binding protein has a Kd for human ActRIIB and ActRHA within the range of <1 μM and >0.1 pM, <100 μM and >0.1 pM, or <100 μM and >1 pM.

[0134] In some respects, the ActRIl-binding protein is an antibody that binds specifically to ActRIl. In further respects, the ActRIl-binding protein is a complete anti-ActRHA antibody or a complete anti-ActRHB antibody. In further respects, the antibody is a monoclonal antibody, a recombinant antibody, a human antibody, a humanized antibody, a chimeric antibody, a bispecific antibody, a multispecific antibody, or a fragment thereof of the ActRIl-binding antibody. In further respects, the antibody binds specifically to ActRIIB and / or ActRHA.

[0135] In some respects, the ActRIl-binding protein (e.g., an anti-ActRH antibody and an antibody fragment that binds to ActRIl) can bind to ActRIl molecules across species.

[0136] The mature extracellular ActRHA domain of human ActRHA (SEQ ID NO: 138) differs from the mouse ActRHA ortholog (Ref. P27038) by only two conserved amino acid substitutions (i.e., K19R and V72I). In additional respects, the ActRIl-binding protein can bind to both human ActRHA (hActRIIA) and murine ActRHA (murActRHA). In certain respects, the ActRIl-binding protein is an anti-ActRHA antibody (i.e., a Petition 870260053005, dated 01 / 06 / 2026, p. 79 / 649 73 / 304 full-length ActRIIA antibody and an ActRIIA-binding antibody fragment, and a variant and derivative thereof) can specifically bind to ActRIIA (e.g., hActRIIA or murActRIIA) with a dissociation constant or Kd of less than 10⁻⁸ M, less than 10⁻⁹ M, or less than 10⁻¹⁰ M, as determined by BIACORE® or KINEXA®. In other aspects, the anti-ActRIIA antibody binds to ActRIIA with a Kd <1 nM (e.g., as determined by BIACORE® analysis). In yet another aspect, the anti-ActRIIA antibody binds to ActRIIA with a Kd within one order of magnitude of 1 nM or within two orders of magnitude of 1 nM. In some respects, the ActRIIA-binding protein has a Kd for human ActRIIA within the range of <1 μM and > 0.1 pM, <100 μM and > 0.1 pM, or <100 μM and > 1 pM.

[0137] The mature extracellular domain of human ActRIIB (SEQ ID NO: 139) differs from the corresponding mouse ActRIIB ortholog sequence (Ref. NCBI Seq. NP 031423) by an amino acid substitution (i.e., A95P). In certain respects, the ActRII-binding protein is an anti-ActRIIB antibody (e.g., a full-length ActRIIB antibody and an ActRIIB-binding antibody fragment, and a variant and a derivative thereof) that specifically binds to ActRIIB (e.g., hActRIIB and murActRIIB) with a dissociation constant or Kd of less than 10⁻⁸ M, less than 10⁻⁹ M, or less than 10⁻¹⁰ M as determined by BIACORE® or KINEXA®. In other respects, the anti-ActRIIB antibody binds to ActRIIB with a Kd <1 nM, as determined by BIACORE® or KINEXA® analysis. In another aspect, the anti-ActRIIB antibody binds to ActRIIB with a Kd within an order of magnitude of 1nM or within two orders of magnitude of 1nM.In some respects, the ActRIIB binding protein has a Kd for human ActRIIB within the range of <1 μM and >0.1 pM, <100 μM and Petition 870260053005, dated 01 / 06 / 2026, p. 80 / 649 74 / 304 >0.1 pM or <1 nM and >1 pM.

[0138] In some respects, the anti-ActRII antibody is an ActRII-binding antibody fragment. In some respects, the ActRII-binding antibody fragment is: Fab, Fab', F(ab')2, Fv fragment, diabody, or single-chain antibody molecule. In additional respects, the ActRII antibody is Fd, single-chain Fv(scFv), disulfide-linked Fv, V-NAR domain, IgNar, intrabody, IgGACH2, minibody, F(ab')3, tetrabody, triabody, diabody, single-domain antibody, DVDIg, Fcab, mAb2, (scFv)2, scFv-Fc, or bis-scFv.

[0139] In additional aspects, the ActRII binding protein is an antibody that includes a VH and a VL. In some aspects, the anti-ActRII antibody further includes a constant region of the heavy chain or a fragment thereof. In some aspects, the antibody comprises a constant region of immunoglobulin heavy chain selected from the group consisting of: (a) a constant region of human IgA or a fragment thereof; (b) a constant region of human IgD or a fragment thereof; (c) a constant domain of human IgE or a fragment thereof; (d) a constant region of human IgG1 or a fragment thereof; (e) a constant region of human IgG2 or a fragment thereof; (f) a constant region of human IgG3 or a fragment thereof; (g) a constant region of human IgG4 or a fragment thereof; and (h) a constant region of human IgM or a fragment thereof.In certain respects, an ActRII-binding protein comprises a constant region of the heavy chain or a fragment thereof, for example, a constant region of human IgG or a fragment thereof. In other respects, the ActRII-binding protein comprises a constant domain of immunoglobulin heavy chain that has or has been mutated to have altered effector function and / or half-life.

[0140] In particular aspects, the ActRII binding protein is Petition 870260053005, dated 01 / 06 / 2026, page 81 / 649 75 / 304 an antibody comprising a constant region of the IgG1 heavy chain containing a mutation that diminishes effector function (see, for example, Idusogie et al., J. Immunol. 166:2571-2575 (2001); Sazinsky et al., PNAS USA 105:20167-20172 (2008); Davis et al., J. Rheumatol. 34:2204-2210 (2007); Bolt et al., Eur. J. Immunol. 23:403-411 (1993); Alegre et al., Transplantation 57:1537-1543 (1994); Xu et al., Cell Immunol. 200:16-26 (2000); Cole et al., Transplantation 68:563-571 (1999); Hutchins et al., PNAS USA 92:11980-11984 (1995); Reddy et al., J. Immunol. 164:1925-1933 (2000); WO97 / 11971, and WO07 / 106585; US Appl. Publ. 2007 / 0148167A1; McEarchern et al., Blood 109:1185-1192 (2007); Strohl, Curr. Op. Biotechnol. 20:685-691 (2009); and Kumagai et al., J. Clin. Pharmacol. 47:1489-1497 (2007), each of which is incorporated herein by reference in its entirety.

[0141] In some respects, the constant region of the heavy chain or its fragment includes one or more amino acid substitutions relative to a wild-type IgG constant domain where the modified IgG decreased ADCC compared to the half-life of an IgG with the wild-type IgG constant domain. Examples of Fc sequence manipulation modifications contained in the supplied antibodies that decrease ADCC include one or more modifications corresponding to: IgG1-K326W, E333S; IgG2-E333S; IgG1-N297A; IgG1-L234A, L235A; IgG2-V234A, G237A; IgG4-L235A, G237A, E318A; IgG4-S228P, L236E; IgG2-UE sequence 118-260; IgG4-UE 261-447 sequence; IgG2-H268Q, V309L, A330S, A331S; IgG1-C220S, C226S, C229S, P238S; IgG1-C226S, C229S, E233P, L234V, L235A; and IgG1-L234F, L235E, P331S, where the position numbering is in accordance with the EU index as in Kabat.

[0142] In certain respects, an ActRII-binding protein comprises a constant chain immunoglobulin domain Petition 870260053005, dated 01 / 06 / 2026, p. 82 / 649 76 / 304 heavy chain that has, or has undergone mutations to have, reduced CDC activity. In particular, the ActRII binding protein is an antibody comprising a constant region of IgG1 heavy chain containing a mutation that decreases CDC activity (see, for example, WO97 / 11971 and WO07 / 106585; US Appl. Publ. 2007 / 0148167A1; McEarchern et al., Blood 109: 1185-1192 (2007); Hayden-Ledbetter et al., Clin. Cancer 15: 2739-2746 (2009); Lazar et al., PNAS USA 103:4005-4010 (2006); Bruckheimer et al., Neoplasia 11:509-517 (2009); Strohl, Curr. Op. Biotechnol. 20:685-691 (2009); and Sazinsky et al., PNAS USA 105:20167-20172 (2008); each of which is incorporated herein by reference in its entirety). Examples of Fc sequence manipulation modifications contained in an anti-ActRII antibody that decrease CDC include one or more modifications corresponding to: IgG1-S239D, A330L, I332E; IgG2 EU sequence 118-260; IgG4 EU sequence 261-447; IgG2H268Q, V309L, A330S, A331S; IgG1-C226S, C229S, E233P, L234V, L235A; IgG1-L234F, L235E, P331S; and IgG1- C226S, P230S.

[0143] In additional aspects, the heavy chain constant region or its fragment includes one or more amino acid substitutions relative to a wild-type IgG constant domain wherein the modified IgG has a longer half-life compared to the half-life of an IgG with the wild-type IgG constant domain. For example, the IgG constant domain may contain one or more amino acid substitutions of amino acid residues at positions 251-257, 285-290, 308-314, 385-389 and 428-436, wherein the amino acid position numbering conforms to the EU index as established in Kabat. In certain aspects, the IgG constant domain may contain one or more amino acid substitutions at Kabat position 252 with Tyr, Phe, Trp or Thr; an amino acid substitution at Kabat position 254 with Petition 870260053005, dated 01 / 06 / 2026, page 83 / 649 77 / 304 Thr; an amino acid substitution at Kabat position 256 with Ser, Arg, Gln, Glu, Asp, or Thr; an amino acid substitution at Kabat position 257 with Leu; an amino acid substitution at Kabat position 309 with Pro; an amino acid substitution at Kabat position 311 with Ser; an amino acid substitution at Kabat position 428 with Thr, Leu, Phe, or Ser; an amino acid substitution at Kabat position 433 with Arg, Ser, Iso, Pro, or Gln; or an amino acid substitution at Kabat position 434 with Trp, Met, Ser, His, Phe, or Tyr. More specifically, the IgG constant domain may contain amino acid substitutions relative to a wild-type human IgG constant domain, including an amino acid substitution at Kabat position 252 with Tyr, an amino acid substitution at Kabat position 254 with Thr, and an amino acid substitution at Kabat position 256 with Glu.

[0144] In further aspects, the ActRII-binding protein is an antibody comprising a constant region of immunoglobulin light chain. In another aspect, the antibody comprises a constant region of human Ig kappa or a constant region of human Ig lambda.

[0145] In some aspects, the ActRII-binding protein comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, wherein the CDRs are present in a VH-VL pair disclosed in Table 1. In other embodiments, the ActRII-binding protein comprises a set of CDRs wherein the CDRs are present in a VH-VL pair selected from the group consisting of: (a) a VH sequence of SEQ ID NO: 2, 16, 22, 28, 34, or 40, and a VL sequence of SEQ ID NO: 9 wherein the protein binds to ActRIIB, (b) a VH sequence of SEQ ID NO: 63 or 77 and a VL sequence with the amino acid sequence of SEQ ID NO: 70 wherein the protein binds to ActRIIB; (c) a VH sequence of the SEQ ID Petition 870260053005, dated 01 / 06 / 2026, p. 84 / 649 78 / 304 (d) a VH sequence of SEQ ID NO: 84, 98, 105, 112 or 119, and a VL sequence of SEQ ID NO: 91, wherein the protein binds to ActRIIA; and (e) a VH sequence of SEQ ID NO: 125 and a VL sequence of SEQ ID NO: 132 wherein the protein binds to ActRIIA.

[0146] In other embodiments, the ActRII-binding protein comprises a set of CDRs wherein the CDRs are present in a VH and VL pair with: (a) a VH sequence of SEQ ID NO: 144 and a VL sequence of SEQ ID NO: 151, and wherein the protein binds to ActRIIB.

[0147] In other embodiments, the ActRII-binding protein comprises a set of CDRs wherein the CDRs are present in a VH and VL pair with: (a) a VH sequence of SEQ ID NO: 165 and a VL sequence of SEQ ID NO: 172, and wherein the protein binds to ActIIRA and ActRIIB.

[0148] In some respects, an ActRII-binding protein comprises a set of CDRs: (a) VH-CDR1, VH-CDR2, and VHCDR3 or (b) VL-CDR1, VL-CDR2, and VL-CDR3, wherein the set of CDRs is identical to, or has a total of one, two, three, four, five, six, seven, eight, nine, ten, or fewer than ten amino acid substitutions, deletions, and / or insertions from a reference set of CDRs disclosed in this document. In other respects, the ActRII-binding protein comprises a set of CDRs, wherein the set of CDRs is identical to, or has a total of one, two, three, four, five, six, seven, eight, nine, ten, or fewer than ten amino acid substitutions, deletions, and / or insertions from a reference set of CDRs in a VH or VL sequence disclosed in Table 1.

[0149] In some respects, an ActRII-binding protein comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, Petition 870260053005, dated 01 / 06 / 2026, p. 85 / 649 79 / 304 VL-CDR1, VL-CDR2, and VL-CDR3, wherein the set of CDRs is identical to, or has a total of one, two, three, four, five, six, seven, eight, nine, ten, or fewer than ten amino acid substitutions, deletions, and / or insertions from a reference set of CDRs disclosed in this document. In other respects, the ActRII-binding protein comprises a set of CDRs, wherein the set of CDRs is identical to, or has a total of one, two, three, four, five, six, seven, eight, nine, ten, or fewer than ten amino acid substitutions, deletions, and / or insertions from a reference set of CDRs in a pair of VH and VL sequences disclosed in Table 1.

[0150] In additional aspects, the ActRII-binding protein binds specifically to ActRII and comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, wherein the set of CDRs is identical to, or has a total of one, two, three, four, five, six, seven, eight, nine, ten, or fewer than ten, amino acid substitutions, deletions, and / or insertions from a reference set of CDRs wherein: (a)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:3, 17, 23, 29, 35, or 41; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:4, 18, 24, 30, or 36; (iii) VHCDR3 has the amino acid sequence SEQ ID NO:5; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO:10; (v) VL-CDR2 has the amino acid sequence SEQ ID NO:11; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO:12; and in which the protein binds to ActRIIB; (b)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:64 or 78;(ii) VH-CDR2 has the amino acid sequence SEQ ID NO:65 or 79; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:66 or 80; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO:71; (v) VL-CDR2 has the amino acid sequence SEQ ID NO:72; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO:73; and in which the protein binds to ActRIIB; (c)(i) VH-CDR1; Petition 870260053005, dated 01 / 06 / 2026, p. 86 / 649 (i) 80 / 304 has the amino acid sequence SEQ ID NO:3 or 58; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:4 or 59; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:46; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO:51; (v) VL-CDR2 has the amino acid sequence SEQ ID NO:52; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO:53; and wherein the protein binds to ActRIIB; (d)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:85, 99, 106 or 113; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:86, 100, 107, 114 or 120; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:87, 101, 108, 115 or 121; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO:92; (v) VL-CDR2 has the amino acid sequence SEQ ID NO:93; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO:94; and wherein the protein binds to ActRIIB and ActRIIA; or (e)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:126;(ii) VH-CDR2 has amino acid sequence SEQ ID NO:127; (iii) VH-CDR3 amino acid sequence SEQ ID NO:128; (iv) VL-CDR1 amino acid sequence SEQ ID NO:133; (v) VL-CDR2 amino acid sequence SEQ ID NO:134; and (vi) VL-CDR3 has amino acid sequence SEQ ID NO:135; and wherein the protein binds to ActRII. In further aspects, the ActRII-binding protein has at least one selected feature from the group consisting of: (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRII; (b) decreases the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRII in the presence of an ActRII ligand (e.g., activin A or GDF8); (c) decreases the phosphorylation of ALK4 and / or ALK7 in cells expressing ActRII and ALK4 and / or ALK7 in the presence of an ActRII ligand;and (d) binds to ActRII with a Kd ^ 1 nM and ^; Petition 870260053005, dated 01 / 06 / 2026, p. 87 / 649 81 / 304 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRII-binding protein has 2, 3, or 4 of the above characteristics. In some respects, the ActRII-binding protein has at least 2 or at least 3 of the above characteristics.

[0151] In additional aspects, the ActRII-binding protein binds specifically to ActRII and comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2 and VL-CDR3, wherein the set of CDRs is identical to or has a total of one, two, three, four, five, six, seven, eight, nine, ten or fewer than ten amino acid substitutions, deletions and / or insertions from a reference set of CDRs wherein (i) VH-CDR1 has the amino acid sequence of SEQ ID NO:145; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:146; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:147; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:152; (v) VL-CDR2 has the amino acid sequence SEQ ID NO:153; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO:154; and where the protein binds to ActRIIB.In additional aspects, the ActRIIB-binding protein has at least one selected feature from the group consisting of: (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRII; (b) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in ActRII-expressing cells in the presence of an ActRII ligand (e.g., activin A or GDF8); (c) decreasing the phosphorylation of ALK4 and / or ALK7 in ActRII-expressing cells and ALK4 and / or ALK7 in the presence of an ActRII ligand; and (d) binding to ActRII with a Kd ≥ 1 nM and ≥ 1 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRII-binding protein has 2, 3, or 4 of the above characteristics. In some respects, the binding protein a. Petition 870260053005, dated 01 / 06 / 2026, p. 88 / 649 82 / 304 ActRII has at least 2 or at least 3 of the above features.

[0152] In additional aspects, the ActRII-binding protein binds specifically to ActRII and comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2 and VL-CDR3, wherein the set of CDRs is identical to or has a total of one, two, three, four, five, six, seven, eight, nine, ten or fewer than ten amino acid substitutions, deletions and / or insertions from a reference set of CDRs wherein (i) VH-CDR1 has the amino acid sequence of SEQ ID NO:166; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:167; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:168; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO:173; (v) VL-CDR2 has the amino acid sequence SEQ ID NO:174; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO:175; and in which the protein binds to ActIIRA and ActRIIB.In additional aspects, the ActRII-binding protein has at least one selected feature from the group consisting of: (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRII; (b) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in ActRII-expressing cells in the presence of an ActRII ligand (e.g., activin A or GDF8); (c) decreasing the phosphorylation of ALK4 and / or ALK7 in ActRII-expressing cells and ALK4 and / or ALK7 in the presence of an ActRII ligand; and (d) binding to ActRII with a Kd ≥ 1 nM and ≥ 1 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRII-binding protein has 2, 3, or 4 of the above characteristics. In some respects, the ActRII-binding protein has at least 2 or at least 3 of the above characteristics.

[0153] In some respects, the ActRII-binding protein binds specifically to ActRII and comprises a set of CDRs that have Petition 870260053005, dated 01 / 06 / 2026, p. 89 / 649 83 / 304 a total of one, two, three, four, five, six, seven, eight, nine, ten, less than ten, or zero amino acid substitutions, deletions, and / or insertions from a reference set of CDRs wherein: (a)(i) VHCDR1 has the amino acid sequence of SEQ ID NO:3; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:4; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO:11; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:12; and wherein the protein binds to ActRIIB; (b)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO:17; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:18; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:5; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO:10; (v) VL-CDR2 has the amino acid sequence SEQ ID NO:11; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO:12;and wherein the protein binds to ActRIIB; (c)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:23; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:24; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:5; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO:10; (v) VL-CDR2 has the amino acid sequence SEQ ID NO:11; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO:12; and wherein the protein binds to ActRIIB; (d)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:29; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:30; (iii) VHCDR3 has the amino acid sequence SEQ ID NO:5; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO:10; (v) VL-CDR2 has the amino acid sequence SEQ ID NO:11; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO:12; and wherein the protein binds to ActRIIB; (e)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:35; (ii) VH-CDR2 has the amino acid sequence SEQ; Petition 870260053005, dated 01 / 06 / 2026, p. 90 / 649 84 / 304 ID NO:36; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO:11; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:12; and wherein the protein binds to ActRIIB; (f)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO:41; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:18; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO:11; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO:12; and in which the protein binds to ActRIIB; (g)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:64; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:65; (iii) VHCDR3 has the amino acid sequence SEQ ID NO:66; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO:71;(v) VL-CDR2 has the amino acid sequence SEQ ID NO:72; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO:73; and in which the protein binds to ActRIIB; and (h)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:78; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:79; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:80; (iv) VL-CDR1 has the amino acid sequence SEQ ID; NO:71; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO:72; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO:73; and in which the protein binds to ActRIIB; (i)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:3; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:4; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:46; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO:51; (v) VL-CDR2 has the amino acid sequence SEQ ID NO:52; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO:53; and in which the protein binds to ActRIIB. Petition 870260053005, dated 01 / 06 / 2026, p. 91 / 649 85 / 304 links to ActRIIB; (j)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO:58; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:59; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:46; (iv) VL-CDR1 has the amino acid sequence of SEQID NO:51; (v) VL-CDR2 has the amino acid sequence of SEQID NO:52; and (vi) VL-CDR3 has the amino acid sequence of SEQID NO:53; and wherein the protein binds to ActRIIB; (k)(i) VH-CDR1 has amino acid sequence SEQ ID NO:85; (ii) VH-CDR2 amino acid sequence SEQ ID NO:86; (iii) VH-CDR3 amino acid sequence SEQ ID NO:87; (iv) VL-CDR1 amino acid sequence SEQ ID NO:92; (v) VL-CDR2 amino acid sequence SEQ ID NO:93; and (vi) VL-CDR3 has amino acid sequence SEQ ID NO:94; and wherein the protein binds to ActRIIB and ActRIIA; (l)(i) VH-CDR1 has amino acid sequence SEQ ID NO:99; (ii) VH-CDR2 has amino acid sequence SEQ ID NO:100; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:101; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO:92; (v) VL-CDR2 has the amino acid sequence SEQ ID NO:93; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO:94; and in which the protein binds to ActRIIB and ActRIIA; (m)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:106;(ii) VH-CDR2 has the amino acid sequence SEQ ID NO:107, (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:108; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO:92; (v) VL-CDR2 has the amino acid sequence SEQ ID NO:93; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO:94; and in which the protein binds to ActRIIB and ActRIIA; (n)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:113; (ii) VH-CDR2 theme amino acid sequence SEQ ID NO:114; (iii) VH-CDR3 theme amino acid sequence SEQ ID NO:115; (iv) VL-CDR1 theme; Petition 870260053005, dated 01 / 06 / 2026, p. 92 / 649 86 / 304 amino acid sequence of SEQ ID NO:92; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO:93; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:94; and in which the protein binds to ActRIIB and ActRIIA; (o)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO:113; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:120; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:121; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:92; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO:93; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:94; and in which the protein binds to ActRIIB and ActRIIA; or (p)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:126; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:127; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:128; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO:133; (v) VL-CDR2 has the amino acid sequence SEQ ID NO:134;and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO:135; and in which the protein binds to ActRIIA. In additional aspects, the ActRIIB-binding protein has at least one feature selected from the group consisting of: (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRII; (b) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRII in the presence of an ActRII ligand (e.g., activin A or GDF8); (c) decreasing the phosphorylation of ALK4 and / or ALK7 in cells expressing ActRII and ALK4 and / or ALK7 in the presence of an ActRII ligand; and (d) binds to ActRII with a Kd ^ 1 nM and ^ 1 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRII-binding protein has 2, 3, or 4 of the above characteristics. In some respects, the ActRII-binding protein has at least 2; Petition 870260053005, dated 01 / 06 / 2026, page 93 / 649 87 / 304 or at least 3 of the above characteristics.

[0154] In some respects, the ActRII-binding protein binds specifically to ActRIIB and comprises a set of CDRs: VHCDR1, VH-CDR2, and VH-CDR3, wherein the set of CDRs is identical to or has a total of one, two, three, four, five, six, seven, eight, nine, ten or fewer than ten amino acid substitutions, deletions and / or insertions from a reference set of CDRs where: (a)(i) VHCDR1 has the amino acid sequence SEQ ID NO:3, 17, 23, 29, 35 or 41; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:4, 18, 24, 30 or 36; and (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:5; (b)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:3 or 58; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:4 or 59; and (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:46; or (c)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:64 or 78; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:65 or 79;and (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:66 or 80. In additional aspects, the ActRIIB-binding protein has at least one selected feature from the group consisting of: (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for ActRIIB binding; (b) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB in the presence of an ActRIIB ligand (e.g., activin A or GDF8); (c) decreasing the phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIB and ALK4 and / or ALK7 in the presence of an ActRIIB ligand; and (d) binds to ActRIIB with a Kd <1 nM and >1 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRIIB-binding protein has 2, 3, or 4 of the above characteristics. In some respects, the ActRIIB-binding protein has at least 2 or at least 3 of the; Petition 870260053005, dated 01 / 06 / 2026, page 94 / 649 88 / 304 features above.

[0155] In some respects, the ActRII-binding protein binds specifically to ActRIIB and comprises a set of CDRs: VHCDR1, VH-CDR2, and VH-CDR3, wherein the set of CDRs is identical to or has a total of one, two, three, four, five, six, seven, eight, nine, ten, or fewer than ten amino acid substitutions, deletions, and / or insertions from a reference set of CDRs wherein: (a)(i) VHCDR1 has the amino acid sequence of SEQ ID NO:3; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:4; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:5; and wherein the protein binds to ActRIIB; (b)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO:17; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:18; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:5; and where the protein binds to ActRIIB; (c)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:23; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:24;(iii) VH-CDR3 has the amino acid sequence SEQ ID NO:5; and in which the protein binds to ActRIIB; (d)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:29; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:30; (iii) VHCDR3 has the amino acid sequence SEQ ID NO:5; and in which the protein binds to ActRIIB; (e)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:35; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:36; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:5; and in which the protein binds to ActRIIB; (f)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:41; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:18; (iii) VHCDR3 has the amino acid sequence SEQ ID NO:5; and where the protein binds to ActRIIB; (g)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:64; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:65; (iii) VH-CDR3 has the sequence of; Petition 870260053005, dated 01 / 06 / 2026, p. 95 / 64989 / 304 amino acids of SEQ ID NO:66; and in which the protein binds to ActRIIB; (h)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO:78; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:79; (iii) VHCDR3 has the amino acid sequence of SEQ ID NO:80; and in which the protein binds to ActRIIB; (i)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO:3; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:4; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:46; and in which the protein binds to ActRIIB; or (j)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO:58; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:59; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:46; and the protein binds to ActRIIB.In additional aspects, the ActRIIB-binding protein has at least one selected feature from the group consisting of: (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB; (b) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in ActRIIB-expressing cells in the presence of an ActRIIB ligand (e.g., activin A or GDF8); (c) decreasing the phosphorylation of ALK4 and / or ALK7 in ActRIIB-expressing cells and ALK4 and / or ALK7 in the presence of an ActRIIB ligand; and (d) binding to ActRIIB with a Kd <1 nM and ^1 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRIIB-binding protein has 2, 3, or 4 of the above characteristics. In some respects, the ActRIIB-binding protein has at least 2 or at least 3 of the above characteristics.

[0156] In some respects, the ActRII-binding protein binds specifically to ActRIIB and comprises a set of CDRs: VLCDR1, VL-CDR2 and VL-CDR3, wherein the set of CDRs is identical to or has a total of one, two, three, four, five, six, seven, eight, nine, Petition 870260053005, dated 01 / 06 / 2026, p. 96 / 649 90 / 304 ten or fewer amino acid substitutions, deletions and / or insertions from a reference set of CDRs where: (a)(i) VLCDR1 has the amino acid sequence SEQ ID NO:10; (ii) VL-CDR2 has the amino acid sequence SEQ ID NO:11; and (iii) VL-CDR3 has the amino acid sequence SEQ ID NO:12; and wherein the protein binds to ActRIIB; (b)(i) VL-CDR1 has the amino acid sequence SEQ ID NO:71; (ii) VL-CDR2 has the amino acid sequence SEQ ID NO:72; and (iii) VL-CDR3 has the amino acid sequence SEQ ID NO:73; and wherein the protein binds to ActRIIB; or (c)(i) VL-CDR1 has the amino acid sequence SEQ ID NO:51; (ii) VL-CDR2 has the amino acid sequence SEQ ID NO:52; and (iii) VL-CDR3 has the amino acid sequence SEQ ID NO:53; and where the protein binds to ActRIIB.In additional aspects, the ActRIIB-binding protein has at least one selected feature from the group consisting of: (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB; (b) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in ActRIIB-expressing cells in the presence of an ActRIIB ligand (e.g., activin A or GDF8); (c) decreasing the phosphorylation of ALK4 and / or ALK7 in ActRIIB-expressing cells and ALK4 and / or ALK7 in the presence of an ActRIIB ligand; and (d) binding to ActRIIB with a Kd <1 nM and ^1 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRIIB-binding protein has 2, 3, or 4 of the above characteristics. In some respects, the ActRIIB-binding protein has at least 2 or at least 3 of the above characteristics.

[0157] In some respects, the ActRII-binding protein binds specifically to ActRIIB and ActRIIA and comprises a set of CDRs: VH-CDR1, VH-CDR2 and VH-CDR3, wherein the set of CDRs Petition 870260053005, dated 01 / 06 / 2026, p. 97 / 649 91 / 304 is identical to or has a total of one, two, three, four, five, six, seven, eight, nine, ten or fewer than ten amino acid substitutions, deletions and / or insertions from a reference set of CDRs in VHCDR1 has the amino acid sequence SEQ ID NO:85, 99, 106 or 113; VH-CDR2 has the amino acid sequence SEQ ID NO:86, 100, 107, 114 or 120; and VH-CDR3 has the amino acid sequence SEQ ID NO:87, 101, 108, 115 or 121.In additional aspects, the ActRIIB and ActRIIA binding protein has at least one selected feature of the group consisting of: (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB and / or ActRIIA; (b) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB and / or ActRIIA in the presence of an ActRIIB and / or ActRIIA ligand (e.g., activin A or GDF8); (c) decreasing the phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIB and / or ActRIIA and ALK4 and / or ALK7 in the presence of an ActRIIB and / or ActRIIA ligand; and (d) binds to ActRIIB and / or ActRIIA with a Kd ^1 nM and ^1 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRIIB and / or ActRIIA binding protein has 2, 3, or 4 of the above characteristics.In some respects, the ActRIIB and / or ActRIIA binding protein has at least 2 or at least 3 of the above characteristics.

[0158] In some respects, the ActRII-binding protein binds specifically to ActRIIB and ActRIIA and comprises a set of CDRs: VH-CDR1, VH-CDR2 and VH-CDR3, wherein the set of CDRs is identical to or has a total of one, two, three, four, five, six, seven, eight, nine, ten or fewer than ten amino acid substitutions, deletions and / or insertions from a reference set of CDRs where: (a)(i) VH-CDR1 has the amino acid sequence of SEQ ID Petition 870260053005, dated 01 / 06 / 2026, p. 98 / 649 92 / 304 (a)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:85; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:86; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:87; and in which the protein binds to ActRIIB and ActRIIA; (b)(i) VHCDR1 has the amino acid sequence SEQ ID NO:99; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:100; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:101; and in which the protein binds to ActRIIB and ActRIIA; (c)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:106; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:107; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:108; and in which the protein binds to ActRIIB and ActRIIA; (d)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:113; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:114; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:115; and in which the protein binds to ActRIIB and ActRIIA; or (e)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:113;(ii) VHCDR2 has the amino acid sequence SEQ ID NO:120; (iii) VHCDR3 has the amino acid sequence SEQ ID NO:121; and in which the protein binds to ActRIIB and ActRIIA. In additional aspects, the ActRII-binding protein has at least one selected feature from the group consisting of: (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB and / or ActRIIA; (b) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB and / or ActRIIA in the presence of an ActRIIB and / or ActRIIA ligand (e.g., activin A or GDF8); (c) decreases ALK4 and / or ALK7 phosphorylation in cells expressing ActRIIB and / or ActRIIA and ALK4 and / or ALK7 in the presence of an ActRIIB and / or ActRIIA ligand; and (d) binds to ActRIIB and / or ActRIIA with a Kd ≤1 nM and ≤1 pM (e.g., as determined by BIACORE® analysis). In some; Petition 870260053005, dated 01 / 06 / 2026, p. 99 / 649 93 / 304 aspects, the ActRIIB and / or ActRIIA binding protein has 2, 3, or 4 of the above characteristics. In some aspects, the ActRIIB and / or ActRIIA binding protein has at least 2 or at least 3 of the above characteristics.

[0159] In some respects, the ActRII-binding protein binds specifically to ActRIIB and ActRIIA and comprises a set of CDRs: VL-CDR1, VL-CDR2 and VL-CDR3, wherein the set of CDRs is identical to or has a total of one, two, three, four, five, six, seven, eight, nine, ten or fewer than ten amino acid substitutions, deletions and / or insertions from a reference set of CDRs wherein (i) VL-CDR1 has the amino acid sequence of SEQ ID NO:92; (ii) VLCDR2 has the amino acid sequence of SEQ ID NO:93; and (iii) VLCDR3 has the amino acid sequence of SEQ ID NO:94; and wherein the protein binds to ActRIIB and ActRIIA.In additional aspects, the ActRII-binding protein has at least one selected feature from the group consisting of: (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB and / or ActRIIA; (b) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB and / or ActRIIA in the presence of an ActRIIB and / or ActRIIA ligand (e.g., activin A or GDF8); (c) decreasing the phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIB and / or ActRIIA and ALK4 and / or ALK7 in the presence of an ActRIIB and / or ActRIIA ligand; and (d) binds to ActRIIB and / or ActRIIA with a Kd ^1 nM and ^1 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRIIB and / or ActRIIA binding protein has 2, 3, or 4 of the above characteristics.In some respects, the ActRIIB and / or ActRIIA binding protein has at least 2 or at least 3 of the above characteristics. Petition 870260053005, dated 01 / 06 / 2026, p. 100 / 649 94 / 304

[0160] In some respects, the ActRII-binding protein binds specifically to ActRIIA and comprises a set of CDRs: VHCDR1, VH-CDR2, and VH-CDR3, wherein the set of CDRs is identical to or has a total of one, two, three, four, five, six, seven, eight, nine, ten, or fewer than ten amino acid substitutions, deletions, and / or insertions from a reference set of CDRs in which VH-CDR1 has the amino acid sequence SEQ ID NO:126; VH-CDR2 has the amino acid sequence SEQ ID NO:127; and VH-CDR3 has the amino acid sequence SEQ ID NO:128.In additional aspects, the ActRIIA-binding protein has at least one feature selected from the group consisting of (a) competing with an ActRIIA ligand (e.g., activin A, activin B, GDF1, GDF3, or Nodal); (b) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in ActRIIA-expressing cells in the presence of an ActRIIA ligand (e.g., activin A); (c) decreasing the phosphorylation of ALK4 and / or ALK7 in ActRIIA-expressing cells and ALK4 and / or ALK7 in the presence of an ActRIIA ligand; and (d) binding to ActRIIA with a Kd <1 nM and >1 pM (e.g., as determined by BIACORE® analysis). In some aspects, the ActRIIA-binding protein has 2, 3, or 4 of the above features. In some respects, the ActRIIA-binding protein has at least 2 or at least 3 of the above characteristics.

[0161] In some respects, the ActRII-binding protein binds specifically to ActRIIA and comprises a set of CDRs: VLCDR1, VL-CDR2, and VL-CDR3, wherein the set of CDRs is identical to or has a total of one, two, three, four, five, six, seven, eight, nine, ten, or fewer than ten amino acid substitutions, deletions, and / or insertions from a reference set of CDRs in which VL-CDR1 has the amino acid sequence SEQ ID NO:133; VL-CDR2 has the amino acid sequence SEQ ID NO:134; and VL-CDR3 has the Petition 870260053005, dated 01 / 06 / 2026, p. 101 / 649 95 / 304 amino acid sequence of SEQ ID NO:135. In additional aspects, the ActRIIA-binding protein has at least one selected feature from the group consisting of (a) competing with an ActRIIA ligand (e.g., activin A, activin B, GDF1, GDF3, or Nodal); (b) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in ActRIIA-expressing cells in the presence of an ActRIIA ligand (e.g., activin A); (c) decreasing the phosphorylation of ALK4 and / or ALK7 in ActRIIA-expressing cells and ALK4 and / or ALK7 in the presence of an ActRIIA ligand; and (d) binding to ActRIIA with a Kd <1 nM and >1 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRIIA-binding protein has 2, 3, or 4 of the above characteristics. In some respects, the ActRIIA-binding protein has at least 2 or at least 3 of the above characteristics.

[0162] In additional aspects, the ActRII-binding protein binds specifically to ActRIIB and comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2 and VL-CDR3, wherein the set of CDRs is identical to or has a total of one, two, three, four, five, six, seven, eight, nine, ten or fewer than ten amino acid substitutions, deletions and / or insertions from a reference set of CDRs where: (a)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:3, 17, 23, 29, 35 or 41; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:4, 18, 24, 30 or 36; (iii) VHCDR3 has the amino acid sequence SEQ ID NO:5; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO:10; (v) VL-CDR2 has the amino acid sequence SEQ ID NO:11; or (vi) VL-CDR3 has the amino acid sequence SEQ ID NO:12; (b)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:3 or 58; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:4 or 59;(iii) VH-CDR3 has the amino acid sequence SEQ ID NO:46; (iv) VL-CDR1 has the; Petition 870260053005, dated 01 / 06 / 2026, p. 102 / 649 96 / 304 amino acid sequence of SEQ ID NO:51; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO:52; or (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:53; or (c)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO:64 or 78; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:65 or 79; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:66 or 80; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:71; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO:72; or (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:73. In other respects, the ActRIIB binding protein comprises a VH and a VL.In additional aspects, the ActRIIB-binding protein has at least one selected feature from the group consisting of (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB; (b) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in ActRIIB-expressing cells in the presence of an ActRIIB ligand (e.g., activin A or GDF8); (c) decreasing the phosphorylation of ALK4 and / or ALK7 in ActRIIB-expressing cells and ALK4 and / or ALK7 in the presence of an ActRIIB ligand; and (d) binding to ActRIIB with a Kd ≤1 nM and ≤1 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRIIB-binding protein has 2, 3, or 4 of the above characteristics. In some respects, the ActRIIB-binding protein has at least 2 or at least 3 of the above characteristics.

[0163] In additional aspects, the ActRII-binding protein binds specifically to ActRIIB and comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2 and VL-CDR3, wherein: (a)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO:3, 17, 23, 29, 35 or 41; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:4, 18, 24, 30 or 36; (iii) VH-CDR3 has the sequence of. Petition 870260053005, dated 01 / 06 / 2026, p. 103 / 649 (a)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO:5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO:11; or (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:12; (b)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO:3 or 58; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:4 or 59; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:46; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:51; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO:52; or (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:53; or (c)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:64 or 78; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:65 or 79; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:66 or 80; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO:71; (v) VL-CDR2 has the amino acid sequence SEQ ID NO:72; or (vi) VL-CDR3 has the amino acid sequence SEQ ID NO:73.In other respects, the ActRIIB-binding protein comprises a VH and a VL. In further respects, the ActRIIB-binding protein has at least one selected feature from the group consisting of (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB; (b) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB in the presence of an ActRIIB ligand (e.g., activin A or GDF8); (c) decreasing the phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIB and ALK4 and / or ALK7 in the presence of an ActRIIB ligand; and (d) binds to ActRIIB with a Kd ^1 nM and ^1 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRIIB-binding protein has 2, 3, or 4 of the above characteristics. In some respects, the ActRIIB-binding protein a. Petition 870260053005, dated 01 / 06 / 2026, p. 104 / 649 98 / 304 ActRIIB has at least 2 or at least 3 of the above features.

[0164] In additional aspects, the ActRII binding protein binds specifically to ActRIIB and ActRIIA and comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VLCDR2 and VL-CDR3, wherein the set of CDRs is identical to or has a total of one, two, three, four, five, six, seven, eight, nine, ten or less than ten amino acid substitutions, deletions and / or insertions from a reference set of CDRs where: (a) VHCDR1 has the amino acid sequence of SEQ ID NO: 85, 99, 106 or 113; (b) VH-CDR2 has the amino acid sequence of SEQ ID NO: 86, 100, 107, 114 or 120; (c) VH-CDR3 has the amino acid sequence SEQ ID NO: 87, 101, 108, 115 or 121; (d) VL-CDR1 has the amino acid sequence SEQ ID NO: 92; (e) VL-CDR2 has the amino acid sequence SEQ ID NO: 93;or (f) VL-CDR3 has the amino acid sequence SEQ ID NO: 94 In additional aspects, the ActRII-binding protein has at least one selected feature from the group consisting of: (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9 or BMP10) for binding to ActRIIB and / or ActRIIA; (b) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB and / or ActRIIA in the presence of an ActRIIB and / or ActRIIA ligand (e.g., activin A or GDF8); (c) decreases ALK4 and / or ALK7 phosphorylation in cells expressing ActRIIB and / or ActRIIA and ALK4 and / or ALK7 in the presence of an ActRIIB and / or ActRIIA ligand;(d) binds to ActRIIB and / or ActRIIA with a Kd ^1 nM and ^1 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRIIB and / or ActRIIA binding protein has 2, 3, or 4 of the above characteristics. In some respects, the ActRIIB and / or ActRIIA binding protein has at least 2 or at least 3 of the above characteristics. Petition 870260053005, dated 01 / 06 / 2026, p. 105 / 649 99 / 304

[0165] In additional aspects, the ActRII-binding protein binds specifically to ActRIIB and ActRIIA and comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VLCDR2 and VL-CDR3, wherein: (a) VH-CDR1 has the amino acid sequence of SEQ ID NO:85, 99, 106 or 113; (b) VH-CDR2 has the amino acid sequence of SEQ ID NO:86, 100, 107, 114 or 120; (c) VH-CDR3 has the amino acid sequence of SEQ ID NO:87, 101, 108, 115 or 121; (d) VL-CDR1 has the amino acid sequence of SEQ ID NO:92; (e) VL-CDR2 has the amino acid sequence SEQ ID NO:93; or (f) VL-CDR3 has the amino acid sequence SEQ ID NO:94.In additional aspects, the ActRII-binding protein has at least one selected feature from the group consisting of: (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB and / or ActRIIA; (b) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB and / or ActRIIA in the presence of an ActRIIB and / or ActRIIA ligand (e.g., activin A or GDF8); (c) decreasing the phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIB and / or ActRIIA and ALK4 and / or ALK7 in the presence of an ActRIIB and / or ActRIIA ligand; and (d) binds to ActRIIB and / or ActRIIA with a Kd ^1 nM and ^1 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRIIB and / or ActRIIA binding protein has 2, 3, or 4 of the above characteristics.In some respects, the ActRIIB and / or ActRIIA binding protein has at least 2 or at least 3 of the above characteristics.

[0166] In additional aspects, the ActRII-binding protein binds specifically to ActRIIA and comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2 and VL-CDR3, wherein the set of CDRs is identical to or has a total of one, two, three, Petition 870260053005, dated 01 / 06 / 2026, p. 106 / 649 100 / 304 four, five, six, seven, eight, nine, ten or fewer than ten amino acid substitutions, deletions and / or insertions from a reference set of CDRs where: (a) VH-CDR1 has the amino acid sequence of SEQ ID NO:126; (b) VH-CDR2 has the amino acid sequence of SEQ ID NO:127; (c) VH-CDR3 has the amino acid sequence of SEQ ID NO:128; (d) VL-CDR1 has the amino acid sequence of SEQ ID NO:133; (e) VL-CDR2 has the amino acid sequence of SEQ ID NO:134; or (f) VL-CDR3 has the amino acid sequence of SEQ ID NO:135.In additional aspects, the ActRIIA-binding protein has at least one feature selected from the group consisting of (a) competing with an ActRIIA ligand (e.g., activin A, activin B, GDF1, GDF3, or Nodal); (b) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in ActRIIA-expressing cells in the presence of an ActRIIA ligand (e.g., activin A); (c) decreasing the phosphorylation of ALK4 and / or ALK7 in ActRIIA-expressing cells and ALK4 and / or ALK7 in the presence of an ActRIIA ligand; and (d) binding to ActRIIA with a Kd ≤1 nM and ≤1 pM (e.g., as determined by BIACORE® analysis). In some aspects, the ActRIIA-binding protein has 2, 3, or 4 of the above features. In some respects, the ActRIIA-binding protein has at least 2 or at least 3 of the above characteristics.

[0167] In additional aspects, the ActRII-binding protein binds specifically to ActRIIA and comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2 and VL-CDR3, wherein: (a) VH-CDR1 has the amino acid sequence of SEQ ID NO:126; (b) VH-CDR2 has the amino acid sequence of SEQ ID NO:127; (c) VH-CDR3 has the amino acid sequence of SEQ ID NO:128; (d) VLCDR1 has the amino acid sequence of SEQ ID NO:133; (e) VLCDR2 has the amino acid sequence of SEQ ID NO:134; or (f) VLCDR3 has the amino acid sequence of SEQ ID NO:135. In aspects. Petition 870260053005, dated 01 / 06 / 2026, p. 107 / 649 101 / 304 additional, the ActRIIA-binding protein has at least one feature selected from the group consisting of (a) competing with an ActRIIA ligand (e.g., activin A, activin B, GDF1, GDF3, or Nodal); (b) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in ActRIIA-expressing cells in the presence of an ActRIIA ligand (e.g., activin A); (c) decreasing the phosphorylation of ALK4 and / or ALK7 in ActRIIA-expressing cells and ALK4 and / or ALK7 in the presence of an ActRIIA ligand; and (d) binding to ActRIIA with a Kd <1 nM and >1 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRIIA-binding protein has 2, 3, or 4 of the above features. In some respects, the ActRIIA-binding protein has at least 2 or at least 3 of the above characteristics.

[0168] In some respects, the ActRII-binding protein binds specifically to ActRII and comprises a set of CDRs wherein: (a)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:3, 17, 23, 29, 35 or 41; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:4, 18, 24, 30 or 36; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:5; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO:10; (v) VL-CDR2 has the amino acid sequence SEQ ID NO:11; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO:12; and wherein the protein binds to ActRIIB; (b)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:64 or 78; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:65 or 79; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:66 or 80; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO:71; (v) VL-CDR2 has the amino acid sequence SEQ ID NO:72; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO:73;and where the protein binds to ActRIIB; (c)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:3 or 58; (ii) VH-CDR2 has the sequence of; Petition 870260053005, dated 01 / 06 / 2026, p. 108 / 649 102 / 304 amino acids of SEQ ID NO:4 or 59; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:46; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:51; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO:52; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:53; and in which the protein binds to ActRIIB; (d)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO:85, 99, 106 or 113; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:86, 100, 107, 114 or 120; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:87, 101, 108, 115 or 121; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO:92; (v) VL-CDR2 has the amino acid sequence SEQ ID NO:93; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO:94; and wherein the protein binds to ActRIIB and ActRIIA; or (e)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:126; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:127; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:128;(iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:133; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO:134; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:135; and wherein the protein binds to ActRIIA.

[0169] In further aspects, the ActRII-binding protein comprises a set of CDRs wherein: (a)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO:3; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:4; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:5; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:10; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO:11; (vi) VL-CDR3 has the amino acid sequence SEQ ID NO:12; and in which the protein binds to ActRIIB; (b)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:17; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:18; (iii) VH-CDR3 has the amino acid sequence SEQ ID; Petition 870260053005, dated 01 / 06 / 2026, p. 109 / 649 103 / 304(i) VH-CDR1 has the amino acid sequence SEQ ID NO:5; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO:10; (v) VL-CDR2 has the amino acid sequence SEQ ID NO:11; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO:12; and wherein the protein binds to ActRIIB; (c)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:23; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:24; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:5; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO:10; (v) VL-CDR2 has the amino acid sequence SEQ ID NO:11; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO:12; and wherein the protein binds to ActRIIB; (d)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:29; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:30; (iii) VHCDR3 has the amino acid sequence SEQ ID NO:5; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO:10; (v) VL-CDR2 has the amino acid sequence SEQ ID NO:11;(vi) VL-CDR3 has amino acid sequence SEQ ID NO:12; and wherein the protein binds to ActRIIB; (e)(i) VH-CDR1 has amino acid sequence SEQ ID NO:35; (ii) VH-CDR2 has amino acid sequence SEQ ID NO:36; (iii) VH-CDR3 has amino acid sequence SEQ ID NO:5; (iv) VL-CDR1 has amino acid sequence SEQ ID NO:10; (v) VL-CDR2 has amino acid sequence SEQ ID NO:11; and (vi) VL-CDR3 has amino acid sequence SEQ ID NO:12; and wherein the protein binds to ActRIIB; (f)(i) VH-CDR1 has amino acid sequence SEQ ID NO:41; (ii) VH-CDR2 has amino acid sequence SEQ ID NO:18; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:5; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO:10; (v) VL-CDR2 has the amino acid sequence SEQ ID NO:11; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO:12; and in which the protein binds to ActRIIB; (g)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:64; (ii); Petition 870260053005, dated 01 / 06 / 2026, p. 110 / 649 104 / 304 (i) VH-CDR2 has the amino acid sequence SEQ ID NO:65; (iii) VHCDR3 has the amino acid sequence SEQ ID NO:66; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO:71; (v) VL-CDR2 has the amino acid sequence SEQ ID NO:72; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO:73; and wherein the protein binds to ActRIIB; and (h)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:78; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:79; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:80; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO:71; (v) VL-CDR2 has the amino acid sequence SEQ ID NO:72; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO:73; and in which the protein binds to ActRIIB; (i)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:3; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:4; (iii) Amino acid sequence of the VH-CDR3 theme of SEQ ID NO:46; (iv) Amino acid sequence of the VL-CDR1 theme of SEQ ID NO:51;(v) Amino acid sequence of the VL-CDR2 theme with SEQ ID NO:52; and (vi) VL-CDR3 has the amino acid sequence with SEQ ID NO:53; and in which the protein binds to ActRIIB; (j)(i) VH-CDR1 has the amino acid sequence with SEQ ID NO:58; (ii) VH-CDR2 has the amino acid sequence with SEQ ID NO:59; (iii) VH-CDR3 has the amino acid sequence with SEQ ID; NO:46; (iv) VL-CDR1 has the amino acid sequence of SEQID NO:51; (v) VL-CDR2 has the amino acid sequence of SEQID NO:52; and (vi) VL-CDR3 has the amino acid sequence of SEQID NO:53; and in which the protein binds to ActRIIB; (k)(i) VH-CDR1 has amino acid sequence SEQ ID NO:85; (ii) VH-CDR2 amino acid sequence SEQ ID NO:86; (iii) VH-CDR3 amino acid sequence SEQ ID NO:87; (iv) VL-CDR1 amino acid sequence SEQ ID NO:92; (v) VL-CDR2 amino acid sequence SEQ ID NO:93; and (vi) VL-CDR3 has the Petition 870260053005, dated 01 / 06 / 2026, p. 111 / 649 105 / 304 amino acid sequence of SEQ ID NO:94; and in which the protein binds to ActRIIB and ActRIIA; (l)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO:99; (ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:100; (iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:101; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:92; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO:93; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:94; and in which the protein binds to ActRIIB and ActRIIA; (m)(i) VH-CDR1 has the amino acid sequence of SEQ ID NO:106; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:107, (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:108; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO:92; (v) VL-CDR2 has the amino acid sequence SEQ ID NO:93; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO:94; and wherein the protein binds to ActRIIB and ActRIIA;(n)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:113; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:114; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:115; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO:92; (v) VL-CDR2 has the amino acid sequence SEQ ID NO:93; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO:94; and wherein the protein binds to ActRIIB and ActRIIA; or (o)(i) VH-CDR1 has the amino acid sequence SEQ ID NO:113; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO:120; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO:121; (iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:92; (v) VL-CDR2 has the amino acid sequence of SEQ ID NO:93; and (vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:94; and in which the protein binds to ActRIIB and ActRIIA.;

[0170] In some respects, a protein that binds to ActRII Petition 870260053005, dated 01 / 06 / 2026, p. 112 / 649 106 / 304 comprises a VH-CDR3 or VL-CDR3 sequence disclosed in this document. In other respects, the ActRII-binding protein comprises a VH-CDR3 or VL-CDR3 sequence disclosed in Table 1. In some respects, an ActRII-binding protein comprises a VH-CDR3 and a VL-CDR3 sequence disclosed in this document. In other respects, the ActRII-binding protein comprises a VH-CDR3 and a VL-CDR3 sequence disclosed in Table 1.

[0171] In other aspects, the description provides an ActRIIB-binding protein comprising a VH-CDR3 with the amino acid sequence of SEQ ID NO: 5, 46, 66, or 80. In some aspects, the ActRIIB-binding protein comprises a VH-CDR3 with the amino acid sequence of SEQ ID NO: 5. In other aspects, the ActRIIB-binding protein comprises a VH-CDR3 with the amino acid sequence of SEQ ID NO: 5 and a VH-CDR2 with the amino acid sequence of SEQ ID NO: 4, 18, 24, 30, or 36. In other aspects, the ActRIIB-binding protein comprises a VHCDR3 with the amino acid sequence of SEQ ID NO: 5, a VHCDR2 with the amino acid sequence of SEQ ID NO: 4, 18, 24, 30, or 36, and a VH-CDR1 with the amino acid sequence of SEQ ID NO: 3, 17, 23, 29, 35 or 41. In some respects, the ActRIIB binding protein comprises a VH-CDR3 with the amino acid sequence SEQ ID NO: 46.In other respects, the ActRIIB-binding protein comprises a VH-CDR3 with the amino acid sequence of SEQ ID NO: 46 and a VH-CDR2 with the amino acid sequence of SEQ ID NO: 4 or 59. In other respects, the ActRIIB-binding protein comprises a VH-CDR3 with the amino acid sequence of SEQ ID NO: 46, a VH-CDR2 with the amino acid sequence of SEQ ID NO: 4 or 59, and a VH-CDR1 with the amino acid sequence of SEQ ID NO: 3 or 58. In some respects, the protein... Petition 870260053005, dated 01 / 06 / 2026, p. 113 / 649 The ActRIIB binding protein 107 / 304 comprises a VH-CDR3 with the amino acid sequence SEQ ID NO: 66. In other aspects, the ActRIIB binding protein comprises a VH-CDR3 with the amino acid sequence SEQ ID NO: 66 and a VH-CDR2 with the amino acid sequence SEQ ID NO: 65. In other aspects, the ActRIIB binding protein comprises a VH-CDR3 with the amino acid sequence SEQ ID NO: 66, a VH-CDR2 with the amino acid sequence SEQ ID NO: 65, and a VH-CDR1 with the amino acid sequence SEQ ID NO: 64. In some aspects, the ActRIIB binding protein comprises a VH-CDR3 with the amino acid sequence SEQ ID NO: 80. In other aspects, the ActRIIB binding protein comprises a VH-CDR3 with the amino acid sequence SEQ ID NO: 80 and a VH-CDR2 with the amino acid sequence SEQ ID NO: 79.In other respects, the ActRIIB-binding protein comprises a VH-CDR3 with the amino acid sequence of SEQ ID NO: 80, a VH-CDR2 with the amino acid sequence of SEQ ID NO: 79, and a VH-CDR1 with the amino acid sequence of SEQ ID NO: 78. In further respects, the ActRIIB-binding protein has at least one feature selected from the group consisting of (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB; (b) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in ActRIIB-expressing cells in the presence of an ActRIIB ligand (e.g., activin A or GDF8); (c) decreases ALK4 and / or ALK7 phosphorylation in cells expressing ActRIIB and ALK4 and / or ALK7 in the presence of an ActRIIB ligand; and (d) binds to ActRIIB with a Kd <1 nM and >1 pM (e.g., as determined by BIACORE® analysis).In some respects, the ActRIIB-binding protein has 2, 3, or 4 of the above characteristics. In some respects, the protein... Petition 870260053005, dated 01 / 06 / 2026, p. 114 / 649 108 / 304 connection with ActRIIB has at least 2 or at least 3 of the above features.

[0172] In other aspects, the description provides an ActRIIB-binding protein comprising a VL-CDR3 with the amino acid sequence of SEQ ID NO: 12, 53, or 73. In some aspects, the ActRIIB-binding protein comprises a VL-CDR3 with the amino acid sequence of SEQ ID NO: 12. In other aspects, the ActRIIB-binding protein comprises a VL-CDR3 with the amino acid sequence of SEQ ID NO: 12 and a VL-CDR2 with the amino acid sequence of SEQ ID NO: 11. In other aspects, the ActRIIB-binding protein comprises a VL-CDR3 with the amino acid sequence of SEQ ID NO: 12, a VL-CDR2 with the amino acid sequence of SEQ ID NO: 11, and a VL-CDR1 with the amino acid sequence of SEQ ID NO: 10. In some aspects, the ActRIIB-binding protein comprises a VL-CDR3 with the Amino acid sequence of SEQ ID NO: 53.In other aspects, the ActRIIB-binding protein comprises a VL-CDR3 with the amino acid sequence of SEQ ID NO: 53 and a VL-CDR2 with the amino acid sequence of SEQ ID NO: 52. In other aspects, the ActRIIB-binding protein comprises a VL-CDR3 with the amino acid sequence of SEQ ID NO: 53, a VL-CDR2 with the amino acid sequence of SEQ ID NO: 52, and a VL-CDR1 with the amino acid sequence of SEQ ID NO: 51. In some aspects, the ActRIIB-binding protein comprises a VL-CDR3 with the amino acid sequence of SEQ ID NO: 73. In other aspects, the ActRIIB-binding protein comprises a VL-CDR3 with the amino acid sequence of SEQ ID NO: 73 and a VL-CDR2 with the amino acid sequence of SEQ ID NO: 72. In other aspects, the ActRIIB-binding protein comprises a VL-CDR3 with the amino acid sequence of SEQ ID NO: 73, a VL-CDR2 with the... Petition 870260053005, dated 01 / 06 / 2026, p. 115 / 649 109 / 304 amino acid sequence of SEQ ID NO: 72, and a VL-CDR1 with the amino acid sequence of SEQ ID NO: 71. In additional aspects, the ActRIIB binding protein has at least one selected feature from the group consisting of (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB; (b) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB in the presence of an ActRIIB ligand (e.g., activin A or GDF8); (c) decreasing the phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIB and ALK4 and / or ALK7 in the presence of an ActRIIB ligand; and (d) binds to ActRIIB with a Kd ≤1 nM and >1 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRIIB-binding protein has 2, 3, or 4 of the above characteristics.In some respects, the ActRIIB-binding protein has at least 2 or at least 3 of the above characteristics.

[0173] In other aspects, the description provides an ActRIIB and / or ActRIIA binding protein comprising a VH-CDR3 with the amino acid sequence of SEQ ID NO: 87, 101, 108, 115 or 121. In other aspects, the ActRII binding protein comprises a VH-CDR3 with the amino acid sequence of SEQ ID NO: 87, 101, 108, 115 or 121, and a VH-CDR2 with the amino acid sequence of SEQ ID NO: 86, 100, 107, 114 or 120. In other aspects, the ActRII binding protein comprises a VH-CDR3 with the amino acid sequence of SEQ ID NO: 87, 101, 108, 115 or 121, a VH-CDR2 with the amino acid sequence of SEQ ID NO: 86, 100, 107, 114, or 120, and a VH-CDR1 with the amino acid sequence of SEQ ID NO: 85, 99, 106, or 113. In some aspects, the ActRIIB and / or ActRIIA binding protein comprises a VH-CDR3 with the amino acid sequence of SEQ ID NO: 87. In other aspects, the protein of Petition 870260053005, dated 01 / 06 / 2026, p. 116 / 649 The ActRIIB and / or ActRIIA binding protein comprises a VH-CDR3 with the amino acid sequence of SEQ ID NO: 87 and a VH-CDR2 with the amino acid sequence of SEQ ID NO: 86. In other aspects, the ActRIIB and / or ActRIIA binding protein comprises a VH-CDR3 with the amino acid sequence of SEQ ID NO: 87, a VH-CDR2 with the amino acid sequence of SEQ ID NO: 86, and a VH-CDR1 with the amino acid sequence of SEQ ID NO: 85. In some aspects, the ActRIIB and / or ActRIIA binding protein comprises a VH-CDR3 with the amino acid sequence of SEQ ID NO: 101. In other aspects, the ActRIIB and / or ActRIIA binding protein comprises a VH-CDR3 with the amino acid sequence of SEQ ID NO: 101 and a VH-CDR2 with the amino acid sequence of SEQ ID NO: 101. SEQ ID NO: 100.In other aspects, the ActRIIB and / or ActRIIA binding protein comprises a VH-CDR3 with the amino acid sequence of SEQ ID NO: 101, a VH-CDR2 with the amino acid sequence of SEQ ID NO: 100, and a VH-CDR1 with the amino acid sequence of SEQ ID NO: 99. In some aspects, the ActRIIB and / or ActRIIA binding protein comprises a VH-CDR3 with the amino acid sequence of SEQ ID NO: 108. In other aspects, the ActRIIB and / or ActRIIA binding protein comprises a VH-CDR3 with the amino acid sequence of SEQ ID NO: 108 and a VH-CDR2 with the amino acid sequence of SEQ ID NO: 107. In other aspects, the ActRIIB and / or ActRIIA binding protein comprises a VH-CDR3 with the amino acid sequence of SEQ ID NO: 108, a VH-CDR2 with the amino acid sequence with SEQ ID NO: 107 and a VH-CDR1 with the amino acid sequence with SEQ ID NO: 106.In some respects, the ActRIIB and / or ActRIIA binding protein comprises a VH-CDR3 with the amino acid sequence of SEQ ID NO: 115. In other respects, the ActRIIB and / or ActRIIA binding protein comprises a VH-CDR3 with the amino acid sequence of SEQ. Petition 870260053005, dated 01 / 06 / 2026, p. 117 / 649 111 / 304 ID NO: 115 and a VH-CDR2 with the amino acid sequence of SEQ ID NO: 114. In other aspects, the ActRIIB and / or ActRIIA binding protein comprises a VH-CDR3 with the amino acid sequence of SEQ ID NO: 115, a VH-CDR2 with the amino acid sequence of SEQ ID NO: 114, and a VH-CDR1 with the amino acid sequence of SEQ ID NO: 113. In other aspects, the ActRIIB and / or ActRIIA binding protein comprises a VH-CDR3 with the amino acid sequence of SEQ ID NO: 121, a VH-CDR2 with the amino acid sequence of SEQ ID NO: 120, and a VH-CDR1 with the amino acid sequence of SEQ ID NO: 113.In additional aspects, the ActRII-binding protein has at least one selected feature from the group consisting of: (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB and / or ActRIIA; (b) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB and / or ActRIIA in the presence of an ActRIIB and / or ActRIIA ligand (e.g., activin A or GDF8); (c) decreasing the phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIB and / or ActRIIA and ALK4 and / or ALK7 in the presence of an ActRIIB and / or ActRIIA ligand; and (d) binds to ActRIIB and / or ActRIIA with a Kd ^1 nM and ^1 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRIIB and / or ActRIIA binding protein has 2, 3, or 4 of the above characteristics.In some respects, the ActRIIB and / or ActRIIA binding protein has at least 2 or at least 3 of the above characteristics.

[0174] In other respects, the description provides an ActRIIB and / or ActRIIA binding protein comprising a VL-CDR3 with the amino acid sequence of SEQ ID NO: 94. In some respects, the ActRIIB and / or ActRIIA binding protein comprises a VL-CDR3 with the amino acid sequence of SEQ ID NO: 94 and a VL-CDR2 Petition 870260053005, dated 01 / 06 / 2026, p. 118 / 649 112 / 304 with the amino acid sequence of SEQ ID NO: 93. In other respects, the ActRIIB binding protein comprises a VL-CDR3 with the amino acid sequence of SEQ ID NO: 94, a VL-CDR2 with the amino acid sequence of SEQ ID NO: 93, and a VL-CDR1 with the amino acid sequence of SEQ ID NO: 92.In additional aspects, the ActRII-binding protein has at least one selected feature from the group consisting of: (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB and / or ActRIIA; (b) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB and / or ActRIIA in the presence of an ActRIIB and / or ActRIIA ligand (e.g., activin A or GDF8); (c) decreasing the phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIB and / or ActRIIA and ALK4 and / or ALK7 in the presence of an ActRIIB and / or ActRIIA ligand; and (d) binds to ActRIIB and / or ActRIIA with a Kd ≤1 nM and ≤1 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRIIB and / or ActRIIA binding protein has 2, 3, or 4 of the above characteristics.In some respects, the ActRIIB and / or ActRIIA binding protein has at least 2 or at least 3 of the above characteristics.

[0175] In other aspects, the description provides an ActRIIB and / or ActRIIA binding protein comprising a VH antigen-binding domain 3 (ABD3) with the amino acid sequence of SEQ ID NO: 142. In other aspects, the ActRII binding protein comprises a VH-ABD3 with the amino acid sequence of SEQ ID NO: 142 and a VH antigen-binding domain 2 (VH-ABD2) with the amino acid sequence of SEQ ID NO: 141. In other aspects, the ActRII binding protein comprises a VH-ABD3 with the amino acid sequence of SEQ ID NO: 133, a VH-ABD2 with the Petition 870260053005, dated 01 / 06 / 2026, p. 119 / 649 113 / 304 amino acid sequence of SEQ ID NO: 141, and an antigen-binding domain 1 (VH-ABD1) VH with the amino acid sequence of SEQ ID NO: 140. In additional aspects, the ActRIIB and ActRIIA binding protein has at least one feature selected from the group consisting of: (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB or ActRIIA; (b) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB and / or ActRIIA in the presence of an ActRIIB and / or ActRIIA ligand (e.g., activin A); (c) decreases ALK4 and / or ALK7 phosphorylation in cells expressing ActRIIB / ActRIIA and ALK4 or ALK7 in the presence of an ActRIIB and / or ActRIIA ligand; and (d) binds to ActRIIB and / or ActRIIA with a Kd ^ 1 nM and ^ 1 pM (e.g., as determined by BIACORE® analysis).In some respects, the ActRIIB and ActRIIA binding protein has 2, 3, or 4 of the above characteristics. In some respects, the ActRIIB and ActRIIA binding protein has at least 2 or at least 3 of the above characteristics.

[0176] In other aspects, the description provides an ActRIIA-binding protein comprising a VH-CDR3 with the amino acid sequence of SEQ ID NO: 128. In other aspects, the ActRIIA-binding protein comprises a VH-CDR3 with the amino acid sequence of SEQ ID NO: 128 and a VH-CDR2 with the amino acid sequence of SEQ ID NO: 127. In other aspects, the ActRIIA-binding protein comprises a VH-CDR3 with the amino acid sequence of SEQ ID NO: 128, a VH-CDR2 with the amino acid sequence of SEQ ID NO: 127, and a VH-CDR1 with the amino acid sequence of SEQ ID NO: 126. In further aspects, the ActRIIA-binding protein has at least one feature selected from the group consisting of (a) competing with an ActRIIA ligand. Petition 870260053005, dated 01 / 06 / 2026, p. 120 / 649 114 / 304 (e.g., activin A, activin B, GDF1, GDF3, or Nodal); (b) decreases the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIA in the presence of an ActRIIA ligand (e.g., activin A); (c) decreases the phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIA and ALK4 and / or ALK7 in the presence of an ActRIIA ligand; and (d) binds to ActRIIA with a Kd ≤1 nM and ≤1 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRIIA-binding protein has 2, 3, or 4 of the above characteristics. In some respects, the ActRIIA-binding protein has at least 2 or at least 3 of the above characteristics.

[0177] In other respects, the description provides an ActRIIA-binding protein comprising a VL-CDR3 with the amino acid sequence of SEQ ID NO: 135.In other respects, the ActRII-binding protein comprises a VL-CDR3 with the amino acid sequence of SEQ ID NO: 135 and a VL-CDR2 with the amino acid sequence of SEQ ID NO: 134. In other respects, the ActRII-binding protein comprises a VL-CDR3 with the amino acid sequence of SEQ ID NO: 135, a VL-CDR2 with the amino acid sequence of SEQ ID NO: 134, and a VL-CDR1 with the amino acid sequence of SEQ ID NO: 133.In additional aspects, the ActRIIA-binding protein has at least one selected feature from the group consisting of (a) competing with an ActRIIA ligand (e.g., activin A, activin B, GDF1, GDF3, or Nodal); (b) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in ActRIIA-expressing cells in the presence of an ActRIIA ligand (e.g., activin A); (c) decreasing the phosphorylation of ALK4 and / or ALK7 in ActRIIA-expressing cells and ALK4 and / or ALK7 in the presence of an ActRIIA ligand; and (d) binding to ActRIIA with a Kd ≤1 nM and ≤1 pM (e.g., as determined by BIACORE® analysis). In some aspects, the ActRIIA-binding protein has 2, 3, or 4 of these characteristics. Petition 870260053005, dated 01 / 06 / 2026, p. 121 / 649 115 / 304 characteristics above. In some respects, the ActRIIA binding protein has at least 2 or at least 3 of the above characteristics.

[0178] In some respects, an ActRII binding protein comprises a VH or a VL that has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions compared to a reference VH or VL disclosed in this document. In further respects, the ActRII binding protein comprises a VH or a VL that has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions compared to a reference VH or VL disclosed in Table 1.In some respects, an ActRII-binding protein comprises a VH and VL pair that has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions compared to a reference VH and VL pair disclosed in this document. In some respects, an ActRII-binding protein comprises a VH and VL pair that has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions compared to a reference VH and VL pair disclosed in this document in Table 1.

[0179] In some respects, the ActRII binding protein comprises a VH and VL pair selected from the group consisting of: (a)(i) a VH sequence with a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen or zero amino acid substitutions, deletions and / or insertions from a reference VH sequence selected from the group consisting of SEQ ID NO: 2, 16, 22, 28, 34 or 40, and (ii) a VL sequence with a total of one, two, three, four, five, six, seven, eight, nine, ten, less Petition 870260053005, dated 01 / 06 / 2026, p. 122 / 649 (a) a VH sequence with a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen or zero amino acid substitutions, deletions and / or insertions from a reference VH sequence of SEQ ID NO:9, and where the protein binds to ActRIIB; (b)(i) a VH sequence with a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen or zero amino acid substitutions, deletions and / or insertions from a reference VH sequence of SEQ ID NO:45 or 57, and (ii) a VL sequence with a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen or zero amino acid substitutions, deletions and / or insertions from a reference VL sequence of SEQ ID NO:50, and where the protein binds to ActRIIB;(c)(i) a VH sequence with a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO:63 or 77, and (ii) a VL sequence with a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO:70, and in which the protein binds to ActRIIB;(d)(i) a VH sequence with a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VH sequence selected from the group consisting of SEQ ID NO:84, 98, 105, 112, or 119, and (ii) a VL sequence with a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO:91, and in which the protein binds to ActRIIB and ActRIIA; and (e)(i) a VH sequence with a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO:125, and; Petition 870260053005, dated 01 / 06 / 2026, p. 123 / 649 117 / 304 (ii) a VL sequence with a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen or zero amino acid substitutions, deletions and / or insertions from a reference VL sequence of SEQ ID NO:132, and in which the protein binds to ActRIIA.

[0180] In some respects, the ActRII-binding protein comprises a VH and VL pair with (i) a VH sequence with a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero, amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 144 (ii) and a VL sequence with a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO: 151, and the protein binds to ActRIIB.

[0181] In some respects, the ActRII-binding protein comprises a VH and VL pair with (i) a VH sequence with a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen or zero amino acid substitutions, deletions and / or insertions from a reference VH sequence of SEQ ID NO: 165 and (ii) a VL sequence with a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen or zero amino acid substitutions, deletions and / or insertions from a reference VL sequence of SEQ ID NO: 172 and the protein binds to ActIIRA and ActRIIB.

[0182] In a further aspect, the ActRII-binding protein comprises a VH and VL pair wherein the VH sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO:2; and the VL sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ Petition 870260053005, dated 01 / 06 / 2026, p. 124 / 649 118 / 304 (a) the VH sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO:16; and in which the protein binds to ActRIIB; (b) the VH sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VL sequence of SEQ ID NO:9; and in which the protein binds to ActRIIB; (c) the VH sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO:22; and the VL sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VL sequence with SEQ ID NO:9;(d) the VH sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VH sequence with SEQ ID NO:28; and the VL sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VL sequence with SEQ ID NO:9; and where the protein binds to ActRIIB; (e) the VH sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VH sequence with SEQ ID NO:34; and the VL sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VL sequence with SEQ ID NO:9;and where the protein binds to ActRIIB; (f) the VH sequence has; Petition 870260053005, dated 01 / 06 / 2026, p. 125 / 649 119 / 304 a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen or zero amino acid substitutions, deletions and / or insertions from a reference VH sequence of SEQ ID NO:40; and the VL sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen or zero amino acid substitutions, deletions and / or insertions from a reference VL sequence of SEQ ID NO:9; and wherein the protein binds to ActRIIB; (g) the sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen or zero amino acid substitutions, deletions and / or insertions from a reference VH sequence of SEQ ID NO:45; and the VL sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VL sequence with SEQ ID NO:50; wherein the protein binds to ActRIIB;(h) the VH sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VH sequence with SEQ ID NO:57; and the VL sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VL sequence with SEQ ID NO:50; wherein the protein binds to ActRIIB; (i) the VH sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VH sequence with SEQ ID NO:63; and the VL sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VL sequence with SEQ ID NO:70; and wherein the protein binds to ActRIIB;(j) the sequence VH has a total of one, two, three, four, five, six, seven, eight, nine,; Petition 870260053005, dated 01 / 06 / 2026, p. 126 / 649 120 / 304 ten, less than fifteen or zero amino acid substitutions, deletions and / or insertions from a reference VH sequence of SEQ ID NO:77; and the VL sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen or zero amino acid substitutions, deletions and / or insertions from a reference VL sequence of SEQ ID NO:70; and wherein the protein binds to ActRIIB; (k) the sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen or zero amino acid substitutions, deletions and / or insertions from a reference VH sequence of SEQ ID NO:84; and the VL sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VL sequence with SEQ ID NO:91; wherein the protein binds to ActRIIB and ActRIIA;(l) the VH sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VH sequence with SEQ ID NO:98; and the VL sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VL sequence with SEQ ID NO:91; wherein the protein binds to ActRIIB and ActRIIA; (m) the VH sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VH sequence with SEQ ID NO:105; and the VL sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VL sequence with SEQ ID NO:91;and in which the protein binds to ActRIIB and ActRIIA; (n) the VH sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than; Petition 870260053005, dated 01 / 06 / 2026, p. 127 / 649 121 / 304 fifteen or zero amino acid substitutions, deletions and / or insertions from a reference VH sequence of SEQ ID NO:112; and the VL sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen or zero amino acid substitutions, deletions and / or insertions from a reference VL sequence of SEQ ID NO:91; and wherein the protein binds to ActRIIB and ActRIIA; (o) the VH sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen or zero amino acid substitutions, deletions and / or insertions from a reference VH sequence of SEQ ID NO:119; and the VL sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VL sequence with SEQ ID NO:91; and wherein the protein binds to ActRIIB and ActRIIA;or (p) the VH sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VH sequence with SEQ ID NO:125; and the VL sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VL sequence with SEQ ID NO:132; and wherein the protein binds to ActRIIA.

[0183] In another aspect, the ActRII-binding protein comprises a VH and VL pair wherein the VH sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions and / or insertions from a reference VH sequence of SEQ ID NO: 144; and the VL sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions and / or insertions from a reference VL sequence of SEQ ID NO: 151, and wherein the protein binds to ActRIIB. Petition 870260053005, dated 01 / 06 / 2026, p. 128 / 649 122 / 304

[0184] In another aspect, the ActRII-binding protein comprises a VH and VL pair wherein the VH sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen or zero amino acid substitutions, deletions and / or insertions from a reference VH sequence of SEQ ID NO: 165; and the VL sequence has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen or zero amino acid substitutions, deletions and / or insertions from a reference VL sequence of SEQ ID NO: 172 and wherein the protein binds to ActIIRA and ActRIIB.

[0185] In some respects, an ActRII-binding protein comprises a VH or a VL that has at least 90%, 95%, 97%, 98%, or 99% sequence identity with a VH or a VL disclosed in this document. In other respects, the ActRII-binding protein comprises a VH or a VL that has at least 90%, 95%, 97%, 98%, or 99% sequence identity with a reference VH or VL disclosed in Table 1. In some respects, an ActRII-binding protein comprises a VH and a VL that have at least 90%, 95%, 97%, 98%, or 99% sequence identity with a VH and a VL disclosed in this document. In other respects, the ActRII-binding protein comprises a VH and a VL that have at least 90%, 95%, 97%, 98%, or 99% sequence identity with a reference VH and VL disclosed in Table 1.In additional aspects, the ActRIIB-binding protein has at least one selected feature from the group consisting of: (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRII; (b) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRII in the presence of an ActRII ligand (e.g., activin A or GDF8); (c) decreasing the phosphorylation of ALK4 and / or. Petition 870260053005, dated 01 / 06 / 2026, p. 129 / 649 123 / 304 ALK7 in cells expressing ActRII and ALK4 and / or ALK7 in the presence of an ActRII ligand; and (d) binds to ActRII with a Kd < 1 nM and > 1 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRII-binding protein has 2, 3, or 4 of the above characteristics. In some respects, the ActRII-binding protein has at least 2 or at least 3 of the above characteristics.

[0186] In some respects, the ActRII-binding protein binds specifically to ActRII and comprises a VH and VL pair selected from the group consisting of: (a)(i) a VH with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:2, 16, 22, 28, 34 or 40, and (ii) a VL with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:9, and in which the protein binds to ActRIIB; (b)(i) a VH with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:45 or 57, and (ii) a VL with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:50, and in which the protein binds to ActRIIB; (c)(i) a VH with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:63 or 77, and (ii) a VL with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:70, and in which the protein binds to ActRIIB;(d)(i) a VH with the amino acid sequence of SEQ ID NO:84, 98, 105, 112 or 119, and (ii) a VL with the amino acid sequence of SEQ ID NO:91, and in which the protein binds to ActRIIB and ActRIIA; and (e)(i) a VH with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:125, and (ii) a VL with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:132, and in which the protein binds to ActRIIA. In additional aspects, the ActRIIB-binding protein has at least one feature selected from the group consisting of: (a) competing with an ActRII ligand (by; Petition 870260053005, dated 01 / 06 / 2026, p. 130 / 649 124 / 304 example, activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9 or BMP10) for binding to ActRII; (b) decreases the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRII in the presence of an ActRII ligand (e.g., activin A or GDF8); (c) decreases the phosphorylation of ALK4 and / or ALK7 in cells expressing ActRII and ALK4 and / or ALK7 in the presence of an ActRII ligand; and (d) binds to ActRII with a Kd ≤ 1 nM and ≤ 1 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRII-binding protein has 2, 3 or 4 of the above characteristics. In some respects, the ActRII-binding protein has at least 2 or at least 3 of the above characteristics.

[0187] In some respects, the ActRII-binding protein binds to ActRIIB and comprises a VH and VL pair selected from (i) a VH with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO: 144, and (ii) a VL with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO: 151, and the protein binds to ActRIIB.In additional aspects, the ActRIIB-binding protein has at least one selected feature from the group consisting of: (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRII; (b) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in ActRII-expressing cells in the presence of an ActRII ligand (e.g., activin A or GDF8); (c) decreasing the phosphorylation of ALK4 and / or ALK7 in ActRII-expressing cells and ALK4 and / or ALK7 in the presence of an ActRII ligand; and (d) binding to ActRII with a Kd ≥ 1 nM and ≥ 1 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRII-binding protein has 2, 3, or 4 of the above characteristics. In some respects, the ActRII-binding protein has at least 2. Petition 870260053005, dated 01 / 06 / 2026, p. 131 / 649 125 / 304 or at least 3 of the above characteristics.

[0188] In some respects, the ActRII-binding protein binds to ActRIIB and comprises a VH with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO: 165 and (ii) a VL with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO: 172, and the protein binds to ActIIRA and ActRIIB.In additional aspects, the ActRII-binding protein has at least one selected feature from the group consisting of: (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRII; (b) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in ActRII-expressing cells in the presence of an ActRII ligand (e.g., activin A or GDF8); (c) decreasing the phosphorylation of ALK4 and / or ALK7 in ActRII-expressing cells and ALK4 and / or ALK7 in the presence of an ActRII ligand; and (d) binding to ActRII with a Kd ≥ 1 nM and ≥ 1 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRII-binding protein has 2, 3, or 4 of the above characteristics. In some respects, the ActRII-binding protein has at least 2 or at least 3 of the above characteristics.

[0189] In another aspect, the ActRII-binding protein binds specifically to ActRII and comprises a VH and VL pair selected from the group consisting of: (a) a VH sequence of SEQ ID NO:2, 16, 22, 28, 34 or 40, and a VL sequence of SEQ ID NO:9; wherein the protein binds to ActRIIB; (b) a VH sequence of SEQ ID NO:45 or 57, and a VL sequence of SEQ ID NO:50; wherein the protein binds to ActRIIB; (c) a VH sequence of SEQ ID NO:63 or 77, and a VL sequence of SEQ ID NO:70; wherein the protein binds to ActRIIB; (d) a VH sequence with SEQ ID NO:84, 98, 105, 112 or 119, and a VL sequence with SEQ ID NO:91; and wherein the protein is Petition 870260053005, dated 01 / 06 / 2026, p. 132 / 649 126 / 304 binds to ActRIIB; and (e) a VH sequence from SEQ ID NO:125, and a VL sequence from SEQ ID NO:132 wherein the protein binds to ActRIIA. In another aspect, the ActRII binding protein comprises a VH and VL pair selected from the group consisting of: (a) a VH sequence from SEQ ID NO:2 and a VL sequence from SEQ ID NO:9; (b) a VH sequence from SEQ ID NO:16 and a VL sequence from SEQ ID NO:9; (c) a VH sequence from SEQ ID NO:22 and a VL sequence from SEQ ID NO:9; (d) a VH sequence from SEQ ID NO:28 and a VL sequence from SEQ ID NO:9; (e) a VH sequence from SEQ ID NO:34 and a VL sequence from SEQ ID NO:9; (f) a VH sequence from SEQ ID NO:40 and a VL sequence from SEQ ID NO:9; (g) a VH sequence from SEQ ID NO:45 and a VL sequence from SEQ ID NO:50; (h) a VH sequence from SEQ ID NO:57 and a VL sequence from SEQ ID NO:50; (i) a VH sequence from SEQ ID NO:63 and a VL sequence from SEQ ID NO:70; (j) a VH sequence from SEQ ID NO:77 and a VL sequence from SEQ ID NO:70;(k) a VH sequence with SEQ ID NO:84 and a VL sequence with SEQ ID NO:91; (l) a VH sequence with SEQ ID NO:98 and a VL sequence with SEQ ID NO:91; (m) a VH sequence with SEQ ID NO:105 and a VL sequence with SEQ ID NO:91; (n) a VH sequence with SEQ ID NO:112 and a VL sequence with SEQ ID NO:91; (o) a VH sequence with SEQ ID NO:119 and a VL sequence with SEQ ID NO:91; and (p) a VH sequence with SEQ ID NO:125 and a VL sequence with SEQ ID NO:132.

[0190] In another aspect, the ActRII-binding protein binds specifically to ActRII and comprises a VH sequence of SEQ ID NO: 144 and a VL sequence of SEQ ID NO: 151; and the protein binds to ActRIIB.

[0191] In another aspect, the ActRII-binding protein binds specifically to ActRII and comprises a VH sequence of SEQ ID NO: 165 and a VL sequence of SEQ ID NO: 172, and the protein binds to ActIIRA and ActRIIB. Petition 870260053005, dated 01 / 06 / 2026, p. 133 / 649 127 / 304

[0192] In some respects, the ActRII binding protein comprises a VH and VL pair selected from the group consisting of: (a) a VH with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:2 and a VL with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:9 and wherein the protein binds to ActRIIB; (b) a VH with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:16 and a VL with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:9 and wherein the protein binds to ActRIIB; (c) a VH with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:22 and a VL with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:9, and in which the protein binds to ActRIIB;(d) a VH with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:28 and a VL with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:9, and in which the protein binds to ActRIIB; (e) a VH with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:34 and a VL with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:9, and in which the protein binds to ActRIIB; (f) a VH with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:40 and a VL with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:9, and in which the protein binds to ActRIIB; (g) a VH with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:45 and a VL with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:50, and in which the protein binds to ActRIIB;(h) a VH with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:57 and a VL with at least 90%, 95%,; Petition 870260053005, dated 01 / 06 / 2026, p. 134 / 649 128 / 304 97%, 98%, or 99% sequence identity with SEQ ID NO:50, wherein the protein binds to ActRIIB; (i) a VH with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO:63 and a VL with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO:70, and wherein the protein binds to ActRIIB; (j) a VH with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO:77 and a VL with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO:70; and wherein the protein binds to ActRIIB; (k) a VH with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:84 and a VL with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:91, and in which the protein binds to ActRIIB and ActRIIA;(l) a VH with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:98 and a VH with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:91, and in which the protein binds to ActRIIB and ActRIIA; (m) a VH with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:105 and a VL with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:91, and in which the protein binds to ActRIIB and ActRIIA; (n) a VH with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:112 and a VL with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:91, and in which the protein binds to ActRIIB and ActRIIA; (o) a VH with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:119 and a VL with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:91, and in which the protein binds to ActRIIB and ActRIIA;and (p) a VH with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:125 and a VL with; Petition 870260053005, dated 01 / 06 / 2026, p. 135 / 649 129 / 304 at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:132, and in which the protein binds to ActRIIA. In additional aspects, the ActRIIB-binding protein has at least one feature selected from the group consisting of: (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9 or BMP10) for binding to ActRII; (b) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRII in the presence of an ActRII ligand (e.g., activin A or GDF8); (c) decreases ALK4 and / or ALK7 phosphorylation in cells expressing ActRII and ALK4 and / or ALK7 in the presence of an ActRII ligand; and (d) binds to ActRII with a Kd ≤ 1 nM and ≤ 1 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRII-binding protein has 2, 3, or 4 of the above characteristics.In some respects, the ActRII-binding protein has at least 2 or at least 3 of the above characteristics.

[0193] In some respects, the ActRII-binding protein comprises a VH with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 144 and a VL with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 151, and the protein binds to ActRIIB. In further respects, the ActRIIB-binding protein has at least one feature selected from the group consisting of: (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRII; (b) decreases the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRII in the presence of an ActRII ligand (e.g., activin A or GDF8); (c) decreases the phosphorylation of ALK4 and / or ALK7 in cells expressing ActRII and ALK4 and / or ALK7 in the presence of an ActRII ligand; and (d) if Petition 870260053005, dated 01 / 06 / 2026, p. 136 / 649 130 / 304 binds to ActRII with a Kd ^ 1 nM and ^ 1 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRII-binding protein has 2, 3, or 4 of the above characteristics. In some respects, the ActRII-binding protein has at least 2 or at least 3 of the above characteristics.

[0194] In some respects, the ActRII-binding protein comprises a VH with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO: 165 and a VL with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO: 172, and the protein binds to ActIIRA and ActRIIB.In additional aspects, the ActRII-binding protein has at least one selected feature from the group consisting of: (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRII; (b) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in ActRII-expressing cells in the presence of an ActRII ligand (e.g., activin A or GDF8); (c) decreasing the phosphorylation of ALK4 and / or ALK7 in ActRII-expressing cells and ALK4 and / or ALK7 in the presence of an ActRII ligand; and (d) binding to ActRII with a Kd ≥ 1 nM and ≥ 1 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRII-binding protein has 2, 3, or 4 of the above characteristics. In some respects, the ActRII-binding protein has at least 2 or at least 3 of the above characteristics.

[0195] In some respects, the ActRII-binding protein comprises a VH and VL pair selected from the group consisting of: (a) a VH sequence from SEQ ID NO:2 and a VL sequence from SEQ ID NO:9; (b) a VH sequence from SEQ ID NO:16 and a VL sequence from SEQ ID NO:9; (c) a VH sequence from SEQ ID NO:22 and a VL sequence from SEQ ID NO:9; (d) a VH sequence from SEQ Petition 870260053005, dated 01 / 06 / 2026, page 137 / 649 131 / 304 (e) a VH sequence from SEQ ID NO:34 and a VL sequence from SEQ ID NO:9; (f) a VH sequence from SEQ ID NO:40 and a VL sequence from SEQ ID NO:9; (g) a VH sequence from SEQ ID NO:45 and a VL sequence from SEQ ID NO:50; (h) a VH sequence from SEQ ID NO:57 and a VL sequence from SEQ ID NO:50; (i) a VH sequence from SEQ ID NO:63 and a VL sequence from SEQ ID NO:70; (j) a VH sequence from SEQ ID NO:77 and a VL sequence from SEQ ID NO:70; (k) a VH sequence from SEQ ID NO:84 and a VL sequence from SEQ ID NO:91; (l) a VH sequence from SEQ ID NO:98 and a VL sequence from SEQ ID NO:91; (m) a VH sequence from SEQ ID NO:105 and a VL sequence from SEQ ID NO:91; (n) a VH sequence from SEQ ID NO:112 and a VL sequence from SEQ ID NO:91; (o) a VH sequence from SEQ ID NO:119 and a sequence from SEQ ID NO:91; and (p) a VH sequence from SEQ ID NO:125 and a sequence from SEQ ID NO:132.

[0196] In some respects, the ActRII binding protein comprises a VH sequence with SEQ ID NO: 144 and a VL sequence with SEQ ID NO: 151.

[0197] In some respects, the ActRII binding protein comprises a VH sequence with SEQ ID NO: 165 and a VL sequence with SEQ ID NO: 172.

[0198] In some respects, the ActRII-binding protein specifically binds to ActRIIB and comprises a VH with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 2, 16, 22, 28, 34, 40, 45, 57, 63, or 77. In some respects, the ActRII-binding protein comprises a VH with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 2. In some respects, the ActRII-binding protein comprises a VH with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 16. In some respects, the Petition 870260053005, dated 01 / 06 / 2026, p. 138 / 649 132 / 304 ActRII-binding protein comprises a VH with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 22. In some aspects, the ActRII-binding protein comprises a VH with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 28. In some aspects, the ActRII-binding protein comprises a VH with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 34. In some aspects, the ActRII-binding protein comprises a VH with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 40. In some aspects, the ActRII-binding protein comprises a VH with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 45. In some respects, the ActRII binding protein comprises a VH with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 57.In some respects, the ActRII-binding protein comprises a VH with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO:63. In some respects, the ActRII-binding protein comprises a VH with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO:77. In some respects, the ActRII-binding protein binds specifically to ActRIIB and comprises a VL with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 9, 50, and 70. In other respects, the ActRII-binding protein binds specifically to ActRIIB and comprises a VH with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 2, 16, 22, 28, 34, or 40, and a VL with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 9. In some additional respects, the ActRII-binding protein binds specifically to ActRIIB and comprises a VH with at least 90%, 95%, 97%, 98%. Petition 870260053005, dated 01 / 06 / 2026, p. 139 / 649 133 / 304 or 99% sequence identity with SEQ ID NO: 45 and 57. In some respects, the ActRII binding protein specifically binds to ActRIIB and comprises a VL with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 50. In some additional respects, the ActRII binding protein specifically binds to ActRIIB and comprises a VH with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 45 and 57, and a VL with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 50. In some respects, the ActRII-binding protein binds specifically to ActRIIB and comprises a VH and a VL, wherein the VH has at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 63 or 77; and the VL has at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 70.In some additional aspects, the ActRII-binding protein binds specifically to ActRIIB and comprises a VH with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 63 or 77, and a VL with less than 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 70.In additional aspects, the ActRIIB-binding protein has at least one selected feature from the group consisting of (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB; (b) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in ActRIIB-expressing cells in the presence of an ActRIIB ligand (e.g., activin A or GDF8); (c) decreasing the phosphorylation of ALK4 and / or ALK7 in ActRIIB-expressing cells and ALK4 and / or ALK7 in the presence of an ActRIIB ligand; and (d) binding to ActRIIB with a Kd <1 nM and >1 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRIIB-binding protein has... Petition 870260053005, dated 01 / 06 / 2026, p. 140 / 649 134 / 304 2, 3, or 4 of the above characteristics. In some respects, the ActRIIB-binding protein has at least 2 or at least 3 of the above characteristics.

[0199] In some respects, the ActRII-binding protein specifically binds to ActRIIB and comprises a VH with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO:144. In some respects, the ActRII-binding protein specifically binds to ActRIIB and comprises a VL with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO:151. In some respects, the ActRII-binding protein specifically binds to ActRIIB and comprises a VH and a VL, wherein the VH has at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO:144; and the VL has at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 151. In other respects, the ActRII-binding protein binds specifically to ActRIIB and comprises a VH with the amino acid sequence of SEQ ID NO: 144 and a VL with the amino acid sequence of SEQ ID NO: 151.In additional aspects, the ActRIIB-binding protein has at least one selected feature from the group consisting of (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB; (b) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in ActRIIB-expressing cells in the presence of an ActRIIB ligand (e.g., activin A or GDF8); (c) decreasing the phosphorylation of ALK4 and / or ALK7 in ActRIIB-expressing cells and ALK4 and / or ALK7 in the presence of an ActRIIB ligand; and (d) binding to ActRIIB with a Kd <1 nM and >1 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRIIB-binding protein has 2, 3, or 4 of the above characteristics. In some respects, the protein... Petition 870260053005, dated 01 / 06 / 2026, p. 141 / 649 135 / 304 connection with ActRIIB has at least 2 or at least 3 of the above features.

[0200] In some respects, the ActRII-binding protein specifically binds to ActIIRA and ActRIIB and comprises a VH with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO:165. In some respects, the ActRII-binding protein specifically binds to ActIIRA and ActRIIB and comprises a VL with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO:172. In some respects, the ActRII-binding protein specifically binds to ActIIRA and ActRIIB and comprises a VH and a VL, wherein the VH has at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO:165; and the VL has at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 172. In other respects, the ActRII-binding protein binds specifically to ActIIRA and ActRIIB and comprises a VH with the amino acid sequence of SEQ ID NO: 165 and a VL with the amino acid sequence of SEQ ID NO: 172.In other respects, the ActRII-binding protein has at least one feature selected from the group consisting of (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIA and / or ActRIIB; (b) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIA and / or ActRIIB in the presence of an ActRIIA and / or ActRIIB ligand (e.g., activin A or GDF8); (c) decreasing the phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIA and / or ActRIIB and ALK4 and / or ALK7 in the presence of an ActRIIA and / or ActRIIB ligand; and (d) binds to each of the ActRIIA and ActRIIB with a Kd ^1 nM and >1 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRII-binding protein has. Petition 870260053005, dated 01 / 06 / 2026, p. 142 / 649 136 / 304 2, 3, or 4 of the above characteristics. In some respects, the ActRII-binding protein has at least 2 or at least 3 of the above characteristics.

[0201] In some respects, the ActRII-binding protein specifically binds to ActRIIB and ActRIIA and comprises a VH with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 84, 98, 105, 112, or 119. In some respects, the ActRII-binding protein specifically binds to ActRIIB and ActRIIA and comprises a VH with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 84. In some respects, the ActRII-binding protein specifically binds to ActRIIB and ActRIIA and comprises a VH with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 98. In some respects, the ActRII binding protein specifically binds to ActRIIB and ActRIIA and comprises a VH with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: SEQ ID NO:105.In some respects, the ActRII-binding protein binds specifically to ActRIIB and ActRIIA and comprises a VH with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 112. In some respects, the ActRII-binding protein specifically binds to ActRIIB and ActRIIA and comprises a VH with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 119. In some respects, the ActRII-binding protein specifically binds to ActRIIB and ActRIIA and comprises a VL with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 91. In further respects, the ActRII-binding protein specifically binds to ActRIIB and ActRIIA and comprises a VH with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 91. Petition 870260053005, dated 01 / 06 / 2026, p. 143 / 649 137 / 304 NO:84, 98, 105, 112, or 119 and a VL with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO:91. In further aspects, the ActRII-binding protein specifically binds to ActRIIB and ActRIIA and comprises a VH with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO:84 and a VL with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO:91. In further aspects, the ActRII-binding protein specifically binds to ActRIIB and ActRIIA and comprises a VH with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 98 and a VL with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 91.In additional aspects, the ActRII-binding protein specifically binds to ActRIIB and ActRIIA and comprises a VH with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO:105 and a VL with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO:91. In additional aspects, the ActRII-binding protein specifically binds to ActRIIB and / or ActRIIA and comprises a VH with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO:112 and a VL with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO:91. In additional aspects, the ActRII-binding protein... It specifically links to ActRIIB and ActRIIA and comprises a VH with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO:119 and a VL with at least 90%, 95%, 97%, 98% or 99% sequence identity with SEQ ID NO: 91.In additional aspects, the ActRIIB and ActRIIA binding protein has at least one selected feature of the group consisting of: (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6,). Petition 870260053005, dated 01 / 06 / 2026, p. 144 / 649 138 / 304 (a) BMP7, BMP9, or BMP10) for binding to ActRIIB and ActRIIA; (b) decreases the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB and / or ActRIIA in the presence of an ActRIIB and / or ActRIIA ligand (e.g., activin A or GDF8); (c) decreases the phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIB / ActRIIA and ALK4 or ALK7 in the presence of an ActRIIB and / or ActRIIA ligand; and (d) binds to ActRIIB and / or ActRIIA with a Kd < 1 nM and > 1 pM (e.g., as determined by analysis of BIACORE®). In some respects, the ActRIIB and ActRIIA binding protein has 2, 3, or 4 of the above characteristics. In some respects, the ActRIIB and ActRIIA binding protein has at least 2 or at least 3 of the above characteristics.

[0202] In some respects, the ActRII-binding protein specifically binds to ActRIIA and comprises a VH with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 125. In some respects, the ActRII-binding protein specifically binds to ActRIIA and comprises a VL with at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 132. In some respects, the ActRII-binding protein specifically binds to ActRIIA and comprises a VH and a VL, wherein VH has at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 125; and VL has at least 90%, 95%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 132.In other respects, the ActRIIA-binding protein has at least one feature selected from the group consisting of (a) competing with an ActRIIA ligand (e.g., activin A, activin B, GDF1, GDF3, or Nodal); (b) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in ActRIIA-expressing cells in the presence of an ActRIIA ligand (e.g., activin A); (c) decreasing the phosphorylation of ALK4 and / or ALK7 in ActRIIA-expressing cells. Petition 870260053005, dated 01 / 06 / 2026, p. 145 / 649 139 / 304 ALK4 and / or ALK7 in the presence of an ActRIIA ligand; and (d) binds to ActRIIA with a Kd <1 nM and >1 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRIIA-binding protein has 2, 3, or 4 of the above characteristics. In some respects, the ActRIIA-binding protein has at least 2 or at least 3 of the above characteristics.

[0203] In further aspects, an ActRII-binding protein competes for binding to ActRII with an antibody comprising a pair of VH and VL sequences described in this document. In further aspects, an ActRII-binding protein competes for binding to ActRII with an antibody comprising a pair of VH and VL sequences disclosed in Table 1. In certain aspects, an ActRII-binding protein binds to the same epitope as an ActRII-binding protein disclosed in this document. In further aspects, an ActRII-binding protein binds to the same epitope as an ActRII-binding protein disclosed in Table 1. The ability of an ActRII-binding protein to compete for binding with and / or bind to the same ActRII epitope as a reference ActRII-binding protein can be readily determined using techniques disclosed in this document or otherwise known in the art.

[0204] In some aspects, the ActRII-binding protein binds specifically to ActRIIB and comprises a VH of SEQ ID NO: 2, 16, 22, 28, 34, 40, 45, 57, 63 or 77. In additional aspects, the ActRII-binding protein binds specifically to ActRIIB and comprises a VL of SEQ ID NO: 9, 50 or 70. In additional aspects, the ActRII-binding protein binds specifically to ActRIIB and comprises a VH of SEQ ID NO: 2, 16, 22, 28, 34, 40, 45, 57, 63 or 77; and a VL of SEQ ID NO: 9, 50, or 70. In some respects, the ActRII-binding protein binds specifically to ActRIIB and comprises a VH of SEQ ID NO: 144. In additional respects, the binding protein... Petition 870260053005, dated 01 / 06 / 2026, p. 146 / 649 140 / 304 to ActRII specifically binds to ActRIIB and comprises a VL of SEQ ID NO: 151. In additional aspects, the ActRII-binding protein specifically binds to ActRIIB and comprises a VH of SEQ ID NO: 144; and a VL of SEQ ID NO: 151. In other aspects, the ActRII-binding protein specifically binds to ActRIIB, but does not specifically bind to ActRIIA. In some aspects, the ActRII-binding protein specifically binds to ActRIIA and ActRIIB and comprises a VH of SEQ ID NO: 165. In additional aspects, the ActRII-binding protein specifically binds to ActRIIA and ActRIIB and comprises a VL of SEQ ID NO: 172. In additional aspects, the ActRII-binding protein specifically binds to ActRIIA and ActRIIB and comprises a VH of SEQ ID NO: 165; and a VL of SEQ ID NO: 172. In other respects, the ActRII-binding protein binds specifically to ActRIIA and ActRIIB.

[0205] In some respects, the ActRII-binding protein binds to NANWELERT amino acid residues (SEQ ID NO: 157) of ActRIIB. In some respects, the ActRII-binding protein binds to NANWELERT amino acid residues (SEQ ID NO: 157) of ActRIIB, but does not bind to ActRIIA. In some respects, the ActRII-binding protein binds to VKKGCWLDD amino acid residues (SEQ ID NO: 158) of ActRIIB, but does not bind to ActRIIA. In some respects, the ActRII-binding protein binds to both NANWELERT amino acid residues (SEQ ID NO: 157) and VKKGCWLDD amino acid residues (SEQ ID NO: 158) of ActRIIB. In other respects, the ActRII-binding protein binds to the amino acid residues NANWELERT (SEQ ID NO: 157) and VKKGCWLDD (SEQ ID NO: 158) of ActRIIB, but does not bind to ActRIIA.

[0206] In some respects, the ActRII-binding protein binds to a polypeptide selected from the group consisting of: (a) NANWELERT amino acid residues (SEQ ID NO: 157) of ActRIIB; (b) Petition 870260053005, dated 01 / 06 / 2026, p. 147 / 649 141 / 304 amino acid residues CCEGNFCNER (SEQ ID NO: 159) of ActRIIB; (c) amino acid residues CCEGNMCNEK (SEQ ID NO: 161) of ActRIIA; and (d) amino acid residues ECLFFNANWEKD (SEQ ID NO: 162) of ActRIIA.

[0207] In some respects, the ActRII-binding protein binds to a polypeptide or a set of polypeptides selected from the group consisting of: (a) NANWELERT amino acid residues (SEQ ID NO:157) and CCEGNFCNER amino acid residues (SEQ ID NO:159) of ActRIIB; (b) NANWELERT amino acid residues (SEQ ID NO:157) and VKKGCWLDD amino acid residues (SEQ ID NO:158) of ActRIIB; (c) NANWELERT amino acid residues (SEQ ID NO:157), CCEGNFCNER amino acid residues (SEQ ID NO:159), and GCWLDDFNCYDR amino acid residues (SEQ ID NO:160) of ActRIIB; (d) NANWELERT amino acid residues (SEQ ID NO:157) from ActRIIB and ECLFFNANWEKD amino acid residues (SEQ ID NO:162) from ActRIIA; (e) NANWELERT amino acid residues (SEQ ID NO:157), GCWLDDFNCYDR amino acid residues (SEQ ID NO:160), and VKKGCWLDD amino acid residues (SEQ ID NO:158) from ActRIIB;(f) CCEGNFCNER amino acid residues (SEQ ID NO:159) from ActRIIB and CCEGNMCNEK amino acid residues (SEQ ID NO:161) from ActRIIA; (g) CCEGNMCNEK amino acid residues (SEQ ID NO:161), ECLFFNANWEKD amino acid residues (SEQ ID NO:162), and CWLDDI NCYDRT amino acid residues (SEQ ID NO:163) from ActRIIA; (h) amino acid residues NANWELERT (SEQ ID NO:157), amino acid residues CCEGNFCNER (SEQ ID NO:159), and amino acid residues GCWLDDFNCYDR (SEQ ID NO:160) from ActRIIB, and amino acid residues CCEG NMCNEK (SEQ ID NO:161), amino acid residues ECLFFNANWEKD (SEQ ID NO:162), and amino acid residues CWLDDINCYDRT (SEQ ID NO:163) from ActRIIA.; Petition 870260053005, dated 01 / 06 / 2026, pp. 148 / 649 142 / 304

[0208] In some respects, the ActRII-binding protein competes for binding to ActRIIB with an antibody comprising a VH of SEQ ID NO: 2, 16, 22, 28, 34, 40, 45, 57, 63, 77 or 144, and a VL of SEQ ID NO: 9, 50, 70 or 151. In other respects, the ActRII-binding protein binds to the same ActRIIB and / or ActRIIA epitope as an antibody comprising a VH of SEQ ID NO: 2, 16, 22, 28, 34, 40, 45, 57, 63, 77 or 144, and a VL of SEQ ID NO: 9, 50, 70 or 151.

[0209] In some respects, the ActRIIB-binding protein (e.g., an anti-ActRIIB antibody) comprises a VH of SEQ ID NO: 2 and a VL of SEQ ID NO: 9. In some respects, an ActRIIB-binding protein competes for binding to ActRIIB with an antibody comprising a VH of SEQ ID NO: 2 and a VL of SEQ ID NO: 9. In other respects, the ActRIIB-binding protein binds to the same ActRIIB epitope as an antibody comprising a SEQ ID NO: 2 VH and a SEQ ID NO: 9 VL.

[0210] In some respects, the ActRIIB-binding protein comprises a VH of SEQ ID NO: 16 and a VL of SEQ ID NO: 9. In some respects, an ActRIIB-binding protein competes for binding to ActRIIB with an antibody comprising a VH of SEQ ID NO: 16 and a VL of SEQ ID NO: 9. In other respects, the ActRIIB-binding protein binds to the same ActRIIB epitope as an antibody comprising a VH of SEQ ID NO: 16 and a VL of SEQ ID NO: 9.

[0211] In some respects, the ActRIIB-binding protein comprises a VH of SEQ ID NO: 22 and a VL of SEQ ID NO: 9. In some respects, an ActRIIB-binding protein competes for binding to ActRIIB with an antibody comprising a VH of SEQ ID NO: 22 and a VL of SEQ ID NO: 9. In other respects, the ActRIIB-binding protein binds to the same ActRIIB epitope as a Petition 870260053005, dated 01 / 06 / 2026, p. 149 / 649 143 / 304 antibody comprising a VH of SEQ ID NO: 22 and a VL of SEQ ID NO: 9.

[0212] In some respects, the ActRIIB-binding protein comprises a VH of SEQ ID NO: 28 and a VL of SEQ ID NO: 9. In some respects, an ActRIIB-binding protein competes for binding to ActRIIB with an antibody comprising a VH of SEQ ID NO: 28 and a VL of SEQ ID NO: 9. In other respects, the ActRIIB-binding protein binds to the same ActRIIB epitope as an antibody comprising a VH of SEQ ID NO: 28 and a VL of SEQ ID NO: 9.

[0213] In some respects, the ActRIIB-binding protein comprises a VH of SEQ ID NO: 34 and a VL of SEQ ID NO: 9. In some respects, an ActRIIB-binding protein competes for binding to ActRIIB with an antibody comprising a VH of SEQ ID NO: 34 and a VL of SEQ ID NO: 9. In other respects, the ActRIIB-binding protein binds to the same ActRIIB epitope as an antibody comprising a VH of SEQ ID NO: 34 and a VL of SEQ ID NO: 9.

[0214] In some respects, the ActRIIB-binding protein comprises a VH of SEQ ID NO: 40 and a VL of SEQ ID NO: 9. In some respects, an ActRIIB-binding protein competes for binding to ActRIIB with an antibody comprising a VH of SEQ ID NO: 40 and a VL of SEQ ID NO: 9. In other respects, the ActRIIB-binding protein binds to the same ActRIIB epitope as an antibody comprising a VH of SEQ ID NO: 40 and a VL of SEQ ID NO: 9.

[0215] In some respects, the ActRIIB-binding protein comprises a VH of SEQ ID NO: 45 and a VL of SEQ ID NO: 50. In some respects, an ActRIIB-binding protein competes for binding to ActRIIB with an antibody comprising a VH of SEQ Petition 870260053005, dated 01 / 06 / 2026, p. 150 / 649 144 / 304 ID NO: 45 and a VL of SEQ ID NO: 50. In other respects, the ActRII-binding protein binds to the same ActRIIB epitope as an antibody comprising a VH of SEQ ID NO: 45 and a VL of SEQ ID NO: 50.

[0216] In some respects, the ActRIIB-binding protein comprises a VH of SEQ ID NO: 57 and a VL of SEQ ID NO: 50. In some respects, an ActRIIB-binding protein competes for binding to ActRIIB with an antibody comprising a VH of SEQ ID NO: 57 and a VL of SEQ ID NO: 50. In other respects, the ActRIIB-binding protein binds to the same ActRIIB epitope as an antibody comprising a VH of SEQ ID NO: 57 and a VL of SEQ ID NO: 50.

[0217] In some respects, the ActRIIB-binding protein comprises a VH of SEQ ID NO: 63 and a VL of SEQ ID NO: 70. In some respects, an ActRIIB-binding protein competes for binding to ActRIIB with an antibody comprising a VH of SEQ ID NO: 63 and a VL of SEQ ID NO: 70. In other respects, the ActRIIB-binding protein binds to the same ActRIIB epitope as an antibody comprising a VH of SEQ ID NO: 63 and a VL of SEQ ID NO: 70.

[0218] In some respects, the ActRIIB-binding protein comprises a VH of SEQ ID NO: 77 and a VL of SEQ ID NO: 70. In some respects, an ActRIIB-binding protein competes for binding to ActRIIB with an antibody comprising a VH of SEQ ID NO: 77 and a VL of SEQ ID NO: 70. In other respects, the ActRIIB-binding protein binds to the same ActRIIB epitope as an antibody comprising a VH of SEQ ID NO: 77 and a VL of SEQ ID NO: 70.

[0219] In some respects, the ActRIIB binding protein comprises a VH with SEQ ID NO: 144 and a VL with SEQ ID NO: 151. Petition 870260053005, dated 01 / 06 / 2026, p. 151 / 649 145 / 304 In some respects, an ActRIIB-binding protein competes for binding to ActRIIB with an antibody comprising a VH of SEQ ID NO: 144 and a VL of SEQ ID NO: 151. In other respects, the ActRIIB-binding protein binds to the same ActRIIB epitope as an antibody comprising a VH of SEQ ID NO: 144 and a VL of SEQ ID NO: 151.

[0220] In some respects, the ActRII-binding protein comprises a VH of SEQ ID NO: 165 and a VL of SEQ ID NO: 172. In some respects, an ActRIIB-binding protein competes for binding to ActRIIB with an antibody comprising a VH of SEQ ID NO: 165 and a VL of SEQ ID NO: 172. In other respects, the ActRII-binding protein binds to the same ActRIIB epitope as an antibody comprising a VH of SEQ ID NO: 165 and a VL of SEQ ID NO: 172.

[0221] In some respects, the ActRII-binding protein comprises a VH of SEQ ID NO: 165 and a VL of SEQ ID NO: 172. In some respects, an ActRIIA-binding protein competes for binding to ActRIIA with an antibody comprising a VH of SEQ ID NO: 165 and a VL of SEQ ID NO: 172. In other respects, the ActRII-binding protein binds to the same ActRIIA epitope as an antibody comprising a VH of SEQ ID NO: 165 and a VL of SEQ ID NO: 172.

[0222] In some respects, the ActRIIB-binding protein competes for binding to NANWELERT amino acid residues (SEQ ID NO: 157) of ActRIIB with an antibody comprising a VH of SEQ ID NO: 144 and a VL of SEQ ID NO: 151. In some respects, the ActRIIB-binding protein competes for binding to VKKGCWLDD amino acid residues (SEQ ID NO: 158) of ActRIIB with an antibody comprising a VH of SEQ ID NO: 144 and a VL of SEQ ID NO: 151. In some respects, the ActRIIB-binding protein Petition 870260053005, dated 01 / 06 / 2026, p. 152 / 649 146 / 304 competes for binding to NANWELERT amino acid residues (SEQ ID NO: 157) and VKKGCWLDD amino acid residues (SEQ ID NO: 158) of ActRIIB with an antibody comprising a VH from SEQ ID NO: 144 and a VL from SEQ ID NO: 151. In other respects, the ActRIIB-binding protein does not specifically bind to ActRIIA.

[0223] In some respects, the ActRII-binding protein competes for binding to ActRIIB and / or ActRIIA with an antibody comprising a VH of SEQ ID NO: 84, 98, 105, 112 or 119 and a VL of SEQ ID NO: 91. In other respects, the ActRII-binding protein binds to the same ActRIIB and / or ActRIIA epitope as an antibody comprising a VH of SEQ ID NO: 84, 98, 105, 112 or 119 and a VL of SEQ ID NO: 91.

[0224] In some respects, the ActRII-binding protein binds to CCEGNFCNER amino acid residues (SEQ ID NO: 159) of ActRIIB.

[0225] In some respects, the ActRII binding protein binds to GCWLDDFNCYDR amino acid residues (SEQ ID NO: 160) of ActRIIB.

[0226] In some aspects, the ActRII binding protein binds to NANWELERT amino acid residues (SEQ ID NO: 157) of ActRIIB. In some aspects, the ActRII binding protein binds to NANWELERT amino acid residues (SEQ ID NO: 157) and to GCWLDDFNCYDR amino acid residues (SEQ ID NO: 160) of ActRIIB. In some embodiments, the ActRII binding protein binds to NANWELERT amino acid residues (SEQ ID NO: 157) and to CCEGNFCNER amino acid residues (SEQ ID NO: 159) of ActRIIB. In other embodiments, the ActRII-binding protein binds to amino acid residues NANWELERT (SEQ ID NO: 157), amino acid residues CCEGNFCNER (SEQ ID NO: 159), and amino acid residues GCWLDDFNCYDR (SEQ ID NO: 160) of ActRIIB. Petition 870260053005, dated 01 / 06 / 2026, p. 153 / 649 147 / 304

[0227] In some respects, the ActRII-binding protein binds to CCEGNMCNEK amino acid residues (SEQ ID NO: 161) of ActRIIA.

[0228] In some respects, the ActRII-binding protein binds to the amino acid residues ECLFFNANWEKD (SEQ ID NO: 162) of ActRIIA. In other respects, the ActRII-binding protein binds to the amino acid residues CCEGNMCNEK (SEQ ID NO: 161) and ECLFFNANWEKD (SEQ ID NO: 162) of ActRIIA.

[0229] In some embodiments, the ActRII-binding protein binds to CWLDDINCYDRT amino acid residues (SEQ ID NO: 163) of ActRIIA. In other embodiments, the ActRII-binding protein binds to CCEGNMCNEK amino acid residues (SEQ ID NO: 161), ECLFFNANWEKD amino acid residues (SEQ ID NO: 162), and CWLDDINCYDRT amino acid residues (SEQ ID NO: 163) of ActRIIA.

[0230] In some respects, the ActRII-binding protein binds to CCEGNFCNER amino acid residues (SEQ ID NO: 159) of ActRIIB and to CCEGNMCNEK amino acid residues (SEQ ID NO: 161) of ActRIIA.

[0231] In some respects, the ActRII binding protein binds to amino acid residues NANWELERT (SEQ ID NO: 157) of ActRIIB and amino acid residues ECLFFNANWEKD (SEQ ID NO: 162) of ActRIIA. In other respects, the ActRII binding protein binds to amino acid residues CCEGNFCNER (SEQ ID NO: 159) and amino acid residues NANWELERT (SEQ ID NO: 157) of ActRIIB and amino acid residues CCEGNMCNEK (SEQ ID NO: 161) and amino acid residues ECLFFNANWEKD (SEQ ID NO: 162) of ActRIIA. In other respects, the ActRII binding protein binds to amino acid residues CCEGNFCNER (SEQ ID NO: 159), amino acid residues NANWELERT (SEQ ID NO: 157) and residues of Petition 870260053005, dated 01 / 06 / 2026, p. 154 / 649 148 / 304 amino acids GCWLDDFNCYDR (SEQ ID NO: 160) from ActRIIB and amino acid residues CCEGNMCNEK (SEQ ID NO: 161), amino acid residues ECLFFNANWEKD (SEQ ID NO: 162) and amino acid residues CWLDDINCYDRT (SEQ ID NO: 163) from ActRIIA.

[0232] In some respects, the ActRIIB binding protein and ActRIIA comprises a VH of SEQ ID NO: 84 and a VL of SEQ ID NO: 91. In some respects, an ActRIIB-binding protein competes for binding to ActRIIB and ActRIIA with an antibody comprising a VH of SEQ ID NO: 84 and a VL of SEQ ID NO: 91. In other respects, the ActRII-binding protein binds to the same epitope of ActRIIB and ActRIIA as an antibody comprising a VH of SEQ ID NO: 84 and a VL of SEQ ID NO: 91.

[0233] In some respects, the ActRIIB binding protein and ActRIIA comprises a VH of SEQ ID NO: 165 and a VL of SEQ ID NO: 172. In some respects, an ActRIIB-binding protein competes for binding to ActRIIB and ActRIIA with an antibody comprising a VH of SEQ ID NO: 165 and a VL of SEQ ID NO: 172. In other respects, the ActRII-binding protein binds to the same epitope of ActRIIB and ActRIIA as an antibody comprising a VH of SEQ ID NO: 165 and a VL of SEQ ID NO: 172.

[0234] In some respects, the ActRIIB and ActRIIA binding protein competes for binding to CCEGNFCNER amino acid residues (SEQ ID NO: 159) of ActRIIB with an antibody comprising a VH of SEQ ID NO: 84 and a VL of SEQ ID NO: 91. In some respects, the ActRIIB and ActRIIA binding protein competes for binding to NANWELERT amino acid residues (SEQ ID NO: 157) of ActRIIB with an antibody comprising a VH of SEQ ID NO: 84 and a VL of SEQ ID NO: 91. In further aspects, the ActRIIB and ActRIIA binding protein competes for binding to CCEGNFCNER amino acid residues (SEQ ID NO: 159) and amino acid residues. Petition 870260053005, dated 01 / 06 / 2026, p. 155 / 649 149 / 304 NANWELERT (SEQ ID NO:157) of ActRIIB with an antibody comprising a VH of SEQ ID NO: 84 and a VL of SEQ ID NO: 91.

[0235] In some respects, the ActRIIB binding protein and ActRIIA competes for binding to CCEGNFCNER amino acid residues (SEQ ID NO: 159) of ActRIIB with an antibody comprising a VH of SEQ ID NO: 165 and a VL of SEQ ID NO: 172. In some aspects, the ActRIIB and ActRIIA binding protein competes for binding to NANWELERT amino acid residues (SEQ ID NO: 157) of ActRIIB with an antibody comprising a VH of SEQ ID NO: 165 and a VL of SEQ ID NO: 172. In additional aspects, the ActRIIB and ActRIIA binding protein competes for binding to CCEGNFCNER amino acid residues (SEQ ID NO: 159) and NANWELERT amino acid residues (SEQ ID NO: 157) of ActRIIB with an antibody comprising a VH of SEQ ID NO: 165 and a VL of SEQ ID NO: 172.

[0236] In some respects, the ActRIIB binding protein and ActRIIA competes for binding to GCWLDDFNCYDR amino acid residues (SEQ ID NO: 160) of ActRIIB with an antibody comprising a SEQ ID NO: 84 VH and a SEQ ID NO: 91 VL.

[0237] In some respects, the ActRIIB binding protein and ActRIIA competes for binding to GCWLDDFNCYDR amino acid residues (SEQ ID NO: 160) of ActRIIB with an antibody comprising a VH of SEQ ID NO: 165 and a VL of SEQ ID NO: 172.

[0238] In some respects, the ActRIIB-binding protein and ActRIIA competes for binding to CCEGNFCNER amino acid residues (SEQ ID NO: 159), NANWELERT amino acid residues (SEQ ID NO: 157), and GCWLDDFNCYDR amino acid residues (SEQ ID NO: 160) of ActRIIB with an antibody comprising a VH of SEQ ID NO: 84 and a VL of SEQ ID NO: 91.

[0239] In some respects, the ActRIIB binding protein and Petition 870260053005, dated 01 / 06 / 2026, p. 156 / 649 150 / 304 ActRIIA competes for binding to CCEGNFCNER amino acid residues (SEQ ID NO: 159), NANWELERT amino acid residues (SEQ ID NO: 157), and GCWLDDFNCYDR amino acid residues (SEQ ID NO: 160) of ActRIIB with an antibody comprising a VH of SEQ ID NO: 165 and a VL of SEQ ID NO: 172.

[0240] In some aspects, the ActRII-binding protein binds specifically to ActRIIB and ActRIIA and comprises a VH of SEQ ID NO: 84, 98, 105, 112, or 119. In additional aspects, the ActRII-binding protein binds specifically to ActRIIB and ActRIIA and comprises a VL of SEQ ID NO: 91. In additional aspects, the ActRII-binding protein binds specifically to ActRIIB and ActRIIA and comprises a VH of SEQ ID NO: 84, 98, 105, 112 or 119; and a VL of SEQ ID NO:91.

[0241] In some aspects, the ActRII-binding protein binds specifically to ActRIIB and ActRIIA and comprises a VH of SEQ ID NO: 165. In additional aspects, the ActRII-binding protein binds specifically to ActRIIB and ActRIIA and comprises a VL of SEQ ID NO: 172. In additional aspects, the ActRII-binding protein binds specifically to ActRIIB and ActRIIA and comprises a VH of SEQ ID NO: 165; and a VL of SEQ ID NO: 172.

[0242] In some respects, the ActRIIB binding protein and ActRIIA comprises a VH of SEQ ID NO: 84 and a VL of SEQ ID NO: 91. In other respects, the ActRII binding protein binds to the same epitope of ActRIIB and ActRIIA as an antibody comprising a VH of SEQ ID NO: 84 and a VL of SEQ ID NO: 91.

[0243] In some respects, the ActRIIB binding protein and ActRIIA comprises a VH with SEQ ID NO: 98 and a VL with SEQ ID NO: 91. In some respects, an ActRIIB-binding protein competes for binding to ActRIIB and ActRIIA with an antibody that Petition 870260053005, dated 01 / 06 / 2026, p. 157 / 649 151 / 304 comprises a VH of SEQ ID NO: 98 and a VL of SEQ ID NO: 91. In other respects, the ActRII-binding protein binds to the same ActRIIB and ActRIIA epitope as an antibody comprising a VH of SEQ ID NO: 98 and a VL of SEQ ID NO: 91.

[0244] In some respects, the ActRIIB binding protein and ActRIIA comprises a VH of SEQ ID NO: 105 and a VL of SEQ ID NO: 91. In some respects, an ActRIIB-binding protein competes for binding to ActRIIB and ActRIIA with an antibody comprising a VH of SEQ ID NO: 105 and a VL of SEQ ID NO: 91. In other respects, the ActRII-binding protein binds to the same epitope of ActRIIB and ActRIIA as an antibody comprising a VH of SEQ ID NO: 105 and a VL of SEQ ID NO: 91.

[0245] In some respects, the ActRIIB binding protein and ActRIIA comprises a VH of SEQ ID NO: 112 and a VL of SEQ ID NO: 91. In some respects, an ActRIIB-binding protein competes for binding to ActRIIB and ActRIIA with an antibody comprising a VH of SEQ ID NO: 112 and a VL of SEQ ID NO: 91. In other respects, the ActRII-binding protein binds to the same epitope of ActRIIB and ActRIIA as an antibody comprising a VH of SEQ ID NO: 112 and a VL of SEQ ID NO: 91.

[0246] In some respects, the ActRIIB binding protein and ActRIIA comprises a VH of SEQ ID NO: 119 and a VL of SEQ ID NO: 91. In some respects, an ActRIIB-binding protein competes for binding to ActRIIB and ActRIIA with an antibody comprising a VH of SEQ ID NO: 119 and a VL of SEQ ID NO: 91. In other respects, the ActRII-binding protein binds to the same epitope of ActRIIB and ActRIIA as an antibody comprising a VH of SEQ ID NO: 119 and a VL of SEQ ID NO: 91.

[0247] In some respects, the ActRIIA binding protein comprises a VH with SEQ ID NO: 125 and a VL with SEQ ID NO: 132. Petition 870260053005, dated 01 / 06 / 2026, p. 158 / 649 152 / 304 In some respects, an ActRIIA-binding protein competes for binding to ActRIIA with an antibody comprising a VH of SEQ ID NO: 125 and a VL of SEQ ID NO: 132. In other respects, the ActRIIA-binding protein binds to the same ActRIIA epitope as an antibody comprising a VH of SEQ ID NO: 125 and a VL of SEQ ID NO: 132.

[0248] In some respects, the ActRII-binding protein binds specifically to ActRIIB and comprises a set of CDRs: VHCDR1, VH-CDR2 and VH-CDR3, wherein the set of CDRs is identical to or has a total of one, two, three, four, five, six, seven, eight, nine, ten or fewer than ten amino acid substitutions, deletions and / or insertions from a reference set of CDRs where: (a) VHCDR1 has the amino acid sequence SEQ ID NO:3 or 58; (b) VHCDR2 has the amino acid sequence SEQ ID NO:4 or 59; or (c) VH-CDR3 has the amino acid sequence SEQ ID NO:46.In additional aspects, the ActRIIB-binding protein has at least one selected feature from the group consisting of (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB; (b) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in ActRIIB-expressing cells in the presence of an ActRIIB ligand (e.g., activin A or GDF8); (c) decreasing the phosphorylation of ALK4 and / or ALK7 in ActRIIB-expressing cells and ALK4 and / or ALK7 in the presence of an ActRIIB ligand; and (d) binding to ActRIIB with a Kd ^1 nM and ^1 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRIIB-binding protein has 2, 3, or 4 of the above characteristics. In some respects, the ActRIIB-binding protein has at least 2 or at least 3 of the above characteristics.

[0249] In some respects, the ActRII binding protein binds Petition 870260053005, dated 01 / 06 / 2026, p. 159 / 649 153 / 304 specifically to ActRIIB and comprises a set of CDRs: VLCDR1, VL-CDR2 and VL-CDR3, wherein the set of CDRs is identical to or has a total of one, two, three, four, five, six, seven, eight, nine, ten or less than ten amino acid substitutions, deletions and / or insertions from a reference set of CDRs wherein: (a) VLCDR1 has the amino acid sequence of SEQ ID NO:51; (b) VL-CDR2 has the amino acid sequence of SEQ ID NO:52; or (c) VL-CDR3 has the amino acid sequence of SEQ ID NO:53.In additional aspects, the ActRIIB-binding protein has at least one selected feature from the group consisting of (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB; (b) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in ActRIIB-expressing cells in the presence of an ActRIIB ligand (e.g., activin A or GDF8); (c) decreasing the phosphorylation of ALK4 and / or ALK7 in ActRIIB-expressing cells and ALK4 and / or ALK7 in the presence of an ActRIIB ligand; and (d) binding to ActRIIB with a Kd ^1 nM and ^1 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRIIB-binding protein has 2, 3, or 4 of the above characteristics. In some respects, the ActRIIB-binding protein has at least 2 or at least 3 of the above characteristics.

[0250] In additional aspects, the ActRII-binding protein binds specifically to ActRIIB and comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2 and VL-CDR3, wherein the set of CDRs is identical to or has a total of one, two, three, four, five, six, seven, eight, nine, ten or fewer than ten amino acid substitutions, deletions and / or insertions from a reference set of CDRs where: (a) VH-CDR1 has the amino acid sequence SEQ ID NO: 3 or 58; (b) VH-CDR2 has the sequence. Petition 870260053005, dated 01 / 06 / 2026, p. 160 / 649 (a) VH-CDR3 has the amino acid sequence of SEQ ID NO: 4 or 59; (b) VL-CDR1 has the amino acid sequence of SEQ ID NO: 51; (c) VL-CDR2 has the amino acid sequence of SEQ ID NO: 52; or (d) VL-CDR3 has the amino acid sequence of SEQ ID NO: 53.In additional aspects, the ActRIIB-binding protein has at least one selected feature from the group consisting of (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9, or BMP10) for binding to ActRIIB; (b) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in ActRIIB-expressing cells in the presence of an ActRIIB ligand (e.g., activin A or GDF8); (c) decreasing the phosphorylation of ALK4 and / or ALK7 in ActRIIB-expressing cells and ALK4 and / or ALK7 in the presence of an ActRIIB ligand; and (d) binding to ActRIIB with a Kd ≥1 nM and >1 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRIIB-binding protein has 2, 3, or 4 of the above characteristics. In some respects, the ActRIIB-binding protein has at least 2 or at least 3 of the above characteristics.

[0251] In other respects, the ActRII-binding protein binds specifically to ActRIIB and ActRIIA and comprises a set of HV antigen-binding domains (ABDs): HV-ABD1, HV-ABD2, HV-ABD3, VL-ABD1, VL-ABD2 and VL-ABD3, wherein: (a) VH-ABD1 has the amino acid sequence SEQ ID NO: 140; (b) VH-ABD2 has the amino acid sequence SEQ ID NO: 141; (c) VH-ABD3 has the amino acid sequence SEQ ID NO: 142; (d) VL-ABD1 has the amino acid sequence SEQ ID NO: 92; (e) VL-ABD2 has the amino acid sequence SEQ ID NO: 93; or (f) VL-ABD3 has the amino acid sequence of SEQ ID NO: 94. In other respects, the ActRIIB binding protein comprises a VH and a VL. In Petition 870260053005, dated 01 / 06 / 2026, p. 161 / 649 155 / 304 additional aspects, the ActRIIB and ActRIIA binding protein has at least one feature selected from the group consisting of: (a) competing with an ActRII ligand (e.g., activin A, activin B, GDF1, GDF3, GDF8 (myostatin), GDF11, BMP6, BMP7, BMP9 or BMP10) for binding to ActRIIB or ActRIIA; (b) decreasing the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells expressing ActRIIB and / or ActRIIA in the presence of an ActRIIB and / or ActRIIA ligand (e.g., activin A); (c) decreasing the phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIB / ActRIIA and ALK4 or ALK7 in the presence of an ActRIIB and / or ActRIIA ligand; and (d) binds to ActRIIB and / or ActRIIA with a Kd < 1 nM and > 1 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRIIB and ActRIIA binding protein has 2, 3, or 4 of the above characteristics.In some respects, the ActRIIB and ActRIIA binding protein has at least 2 or at least 3 of the above characteristics.

[0252] In some respects, the ActRII binding protein specifically binds to ActRIIA and comprises a VH and a VL wherein the VH sequence is identical to or has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, deletions, and / or insertions from a reference VH sequence of SEQ ID NO: 125, and wherein the VL sequence is identical to or has a total of one, two, three, four, five, six, seven, eight, nine, ten, less than fifteen, or zero amino acid substitutions, additions, and / or deletions from a reference VL sequence of SEQ ID NO: 132. In other respects, the ActRIIA binding protein has at least one feature selected from the group consisting of (a) competing with an ActRIIA ligand (e.g., activin A, activin B, GDF1, GDF3, or Nodal); (b) decreases the phosphorylation of Smads (e.g., Smad2 and / or Smad3) in cells Petition 870260053005, dated 01 / 06 / 2026, p. 162 / 649 156 / 304 expressing ActRIIA in the presence of an ActRIIA ligand (e.g., activin A); (c) decreases ALK4 and / or ALK7 phosphorylation in cells expressing ActRIIA and ALK4 and / or ALK7 in the presence of an ActRIIA ligand; and (d) binds to ActRIIA with a Kd ≥1 nM and >1 pM (e.g., as determined by BIACORE® analysis). In some respects, the ActRIIA-binding protein has 2, 3, or 4 of the above characteristics. In some respects, the ActRIIA-binding protein has at least 2 or at least 3 of the above characteristics.

[0253] In some respects, the ActRIIA-binding protein is an antibody that binds specifically to ActRII. In some respects, anti-ActRII binds specifically to ActRIIB and / or ActRIIA. In some respects, the anti-ActRIl antibody is a murine antibody, a humanized antibody, a chimeric antibody, a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a multispecific antibody, or any combination thereof.In some respects, the anti-ActRIl antibody is an Fv fragment, a Fab fragment, an F(ab')2 fragment, a Fab' fragment, a dsFv fragment, an scFv fragment, or an sc(Fv)2 fragment.

[0254] In some respects, ActRII-binding protein binds specifically to ActRII (e.g., ActRIIA and / or ActRIIB) and blocks the activity of an ActRII ligand (e.g., GDF8 (myostatin) and / or activin). In some respects, ActRII-binding protein binds specifically to ActRII (e.g., and decreases the inhibition of muscle formation or the increase in fat formation associated with the activity of an ActRII ligand (e.g., GDF8 (myostatin and / or activin)). In some respects, ActRII-binding protein binds specifically to ActRII and treats or improves one or more conditions associated with a muscle disorder or a metabolic disorder. In some respects, muscle disorder is loss of muscle mass due to disease or disuse. Petition 870260053005, dated 01 / 06 / 2026, p. 163 / 649 157 / 304 indicates diabetes, obesity, hyperglycemia, or bone loss.

[0255] In certain aspects, the ActRIIB-binding protein (e.g., an anti-ActRHB antibody or an anti-ActRHB and ActRHA antibody) inhibits or decreases ActRIIB binding by GDF8-mediated or Smad ActRIIB signaling. In another aspect, the ActRIIB-binding protein decreases the inhibition of muscle formation or the increase in fat formation. In some aspects, the ActRIIB-binding protein binds to ActRIIB and inhibits or decreases one or more conditions associated with a muscle disorder or a metabolic disorder. In some aspects, the muscle disorder is loss of muscle mass due to disease or disuse. In some aspects, the metabolic disorder is diabetes, obesity, hyperglycemia, or bone loss that increases muscle mass or strength in a subject.

[0256] In certain aspects, blocking ActRII activity (e.g., ActRIIB and / or ActRHA) by an ActRII-binding protein (e.g., an anti-ActRHB antibody and an anti-ActRHA antibody) described herein inhibits or diminishes one or more conditions associated with a muscle disorder, such as muscle loss. In other aspects, blocking ActRII inhibits or diminishes one or more conditions associated with muscle loss due to disease or disuse. In certain aspects, the ActRII-binding protein (e.g., an anti-ActRHB antibody or an anti-ActRHB and ActRHA antibody) inhibits or diminishes binding to ActRIIB by GDF8. In another aspect, the ActRIIB-binding protein inhibits or diminishes the inhibition of muscle differentiation by an Smad-dependent pathway.

[0257] In some respects, the ActRII-binding protein binds specifically to ActRIIB and blocks ligand-mediated activity of ActRIIB. Some ActRIIB ligands, such as GDF8, are known to be a negative regulator of skeletal muscle tissue, and myostatin signaling is known to lead to muscle mass. A Petition 870260053005, dated 01 / 06 / 2026, p. 164 / 649 158 / 304 ligand-mediated signaling of ActRIIB can also modulate the production of muscle-specific enzymes (e.g., creatine kinase), stimulate myoblast proliferation, and modulate the differentiation of pre-adipocytes into adipocytes. Increased myostatin activity has been associated with muscle wasting disorders, muscle loss due to inactivity, and metabolic disorders, including diabetes, obesity, hyperglycemia, and bone loss. Increased ligand-mediated ActRIIB activity has also been associated with age-related increases in fat-to-muscle ratios and age-related muscle atrophy.In some respects, ActRII-binding protein binds specifically to ActRIIB and decreases the inhibition of muscle formation or the increase in fat formation associated with the activity of some ActRIIB ligands. In some respects, ActRII-binding protein binds specifically to ActRIIB and treats or improves one or more conditions associated with a muscle disorder or a metabolic disorder. In some respects, the muscle disorder is loss of muscle mass due to disease or disuse. In some respects, the metabolic disorder is diabetes, obesity, hyperglycemia, or bone loss. The ligand-mediated activity of ActRIIB can be determined using methods recognized in the art, such as those described herein.

[0258] In certain aspects, the blocking of ActRII (e.g., ActRIIB and / or ActRIIA) by an ActRII-binding protein (e.g., an anti-ActRHB antibody and an anti-ActRHA antibody) described herein, reduces one or more conditions associated with fibrosis. In particular aspects, the ActRIIB-binding protein inhibits or diminishes the development of ActRIIB-mediated fibrotic lesions, weight loss or other clinical symptoms, and / or altered expression of biological molecules (e.g., mRNA or protein expression) associated with the development of a fibrotic condition. In particular aspects, the ActRIIB-binding protein Petition 870260053005, dated 01 / 06 / 2026, p. 165 / 649 159 / 304 ActRIIA inhibits or reduces the development of ActRIIA-mediated fibrotic lesions, weight loss or other clinical symptoms, and / or altered expression of biological molecules (e.g., mRNA or protein expression) associated with the development of a fibrotic condition.

[0259] As noted above, an anti-ActRII antibody (e.g., a full-length ActRIIB antibody and an ActRII-binding antibody fragment, and a variant and derivative thereof) containing a VH and / or VL amino acid sequence that binds to ActRII may have at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with a sequence described herein. In some respects, the VH and / or VL amino acid sequences that bind to ActRII comprise 8, 7, 6, 5, 4, 3, 2, 1 amino acid additions, substitutions (e.g., conservative substitutions), or deletions relative to a sequence presented herein. In additional aspects, the VH and / or VL amino acid sequence that binds to ActRII comprises 1, 2, 3, 4, 5 or more amino acid additions, substitutions (e.g., conservative substitutions) or deletions relative to a sequence presented here.An anti-ActRII antibody containing VH and VL regions with a certain percentage of similarity to a VH or VL region or with one or more substitutions, deletions and / or insertions (e.g., conservative substitutions) can be obtained by mutagenesis (e.g., PCR-mediated or site-directed mutagenesis) of nucleic acid molecules encoding VH and / or VL regions described herein, followed by testing the encoded altered antibody for binding to ActRII and optionally for retained function testing using the functional assays described herein or a known assay in the art that can be routinely modified to test retained function.

[0260] The affinity or avidity of a protein for binding to ActRII, such as an anti-ActRIIB antibody (e.g., an ActRIIB antibody of Petition 870260053005, dated 01 / 06 / 2026, p. 166 / 649 The total length and a fragment of antibody binding to ActRII, and its variant and derivative), for hActRIIB, murActRIIB, can be determined experimentally using any suitable mode known in the art, for example, flow cytometry, enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay (RIA) or kinetics (e.g., BIACORE® or KINEXA® analysis). Competitive binding assay formats and direct binding assays can be readily employed. (See, for example, Berzofsky et al., Antibody-Antigen Interactions, In Fundamental Immunology, Paul, W.E., Ed., Raven Press: New York, NY (1984); Kuby, Immunology, W.H. Freeman and Company: New York, NY (1992); and methods described herein.) The measured affinity of a specific antibody-antigen interaction may vary if measured under different conditions (e.g., salt concentration, pH, temperature).Thus, affinity measurements and other ActRII binding parameters (e.g., KD or Kd, KonKoff) are made with standardized solutions of ActRII-binding proteins and ActRII, and the measurements are performed using standardized conditions and methods, as described herein or otherwise known in the art.

[0261] The description also provides a binding protein to ActRII, such as an ActRIIB antibody and / or an Anti-ActRIIA antibody as described in this document, wherein the ActRII-binding protein is conjugated with a heterologous agent. In certain respects, the heterologous agent is an antimicrobial agent, a therapeutic agent, a prodrug, a peptide, a protein, an enzyme, a lipid, a biological response modifier, a pharmaceutical agent, a lymphokine, a heterologous antibody or antibody fragment, a detectable marker, or a polyethylene glycol (PEG). Heteroconjugated ActRII-binding proteins are discussed in more detail elsewhere here. Petition 870260053005, dated 01 / 06 / 2026, p. 167 / 649 161 / 304

[0262] In certain respects, the ActRII-binding protein is not an anti-ActRII antibody. A variety of methods for identifying and producing non-antibody polypeptides that bind with high affinity to a protein target are known in the art. See, for example, Skerra, Curr. Opin. Biotech. 18:295-304 (2007); Hosse et al., Protein Science 15:14-27 (2006); Gill et al., Curr. Opin. Biotechnol. 17:653-658 (2006); Nygren, FEBS J. 275: 2668-2676 (2008); and Skerra, FEBS J. 275: 2677-2683 (2008), each of which is incorporated herein by reference in its entirety. In some respects, phage display technology can be used to identify / produce a protein that binds to ActRII.In some respects, the ActRII-binding protein comprises a protein scaffold based on a selected type of group consisting of VASP polypeptides, avian pancreatic polypeptide (aPP), tetranectin (based on CTLD3), afilin (based on γβ-crystalline / ubiquitin), a knottin, an SH3 domain, a PDZ domain, tendamistat, transferrin, ankyrin repeat consensus domain (e.g., DARPins), a lipocalin protein fold (e.g., anticalins and duocalins), a Protein Epitope Mimetic (PEM), a maximal / avimer domain, an antibody domain, a fibronectin domain (e.g., 10 Fn3, see, for example, US Publ. Application Nos. 2003 / 0170753 and 20090155275, each of which is incorporated herein by reference in its entirety), a domain of protein A (e.g., Affibodies) and thioredoxin.

[0263] In some respects, the description provides an ActRIIA-binding protein (e.g., an anti-ActRIIA antibody such as a full-length anti-ActRIIA antibody and an ActRIIA-binding antibody fragment) that competes for ActRIIA binding with an anti-ActRIIA antibody provided herein. In some respects, the description provides an ActRIIA-binding protein. Petition 870260053005, dated 01 / 06 / 2026, p. 168 / 649 162 / 304 which binds to the same ActRIIA epitope as an ActRIIA-binding protein provided here.

[0264] In some respects, the description provides an ActRIIB-binding protein (e.g., an anti-ActRIIB antibody such as, a full-length anti-ActRIIB antibody and an antibody fragment that binds to ActRIIB) that competes for ActRIIB binding with an anti-ActRIIB antibody provided herein. In some respects, the description provides an ActRIIB-binding protein that binds to the same ActRIIB epitope as an ActRIIB-binding protein provided herein. The ability of a test ActRIIB-binding protein to inhibit the binding of, for example, a reference binding protein such as an antibody comprising a VH sequence of SEQ ID NO: 40 and a VL sequence of SEQ ID NO: 9 or a VH sequence of SEQ ID NO: 119 and a VL sequence of SEQ ID NO: 91, to ActRIIB demonstrates that the test ActRIIB-binding protein can compete with the reference antibody for ActRIIB binding.According to non-limiting theory, such an ActRIIB-binding protein may bind to the same or a related (e.g., structurally similar or spatially proximal epitope) ActRIIB as the ActRIIB reference antibody with which it competes. In one aspect, the ActRIIB-binding protein binds to the same epitope on ActRIIB as an antibody comprising a VH sequence of SEQ ID NO: 40 and a VL sequence of SEQ ID NO: 9.

[0265] ActRII receptors, such as ActRIIB and, are known to exist. ActRIIA phosphorylate ActRI coreceptors (e.g., Alk4 and Alk7) and signal through phosphorylation of Smads (e.g., Smad2 and / or Smad3). In some respects, an ActRII-binding protein (e.g., an anti-ActRIIB antibody and an anti-ActRIIA antibody) can decrease ActRII-mediated phosphorylation of its ActRI receptor. Petition 870260053005, dated 01 / 06 / 2026, p. 169 / 64...

Claims

1. Activin receptor type II binding protein (ActRII), characterized in that it comprises a set of CDRs in which: (i) VH-CDR1 has the amino acid sequence SEQ ID NO: 166; (ii) VH-CDR2 has the amino acid sequence SEQ ID NO: 167; (iii) VH-CDR3 has the amino acid sequence SEQ ID NO: 168; (iv) VL-CDR1 has the amino acid sequence SEQ ID NO: 173; (v) VL-CDR2 has the amino acid sequence SEQ ID NO: 174; and (vi) VL-CDR3 has the amino acid sequence SEQ ID NO: 175; and in which the protein binds to ActRIIB.

2. ActRII-binding protein according to claim 1, characterized in that it comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2 and VLCDR3, wherein the CDRs are present in: (i) a variable region sequence of the heavy chain (VH) of SEQ ID NO:165, and (ii) a variable region sequence of the light chain (VL) of SEQ ID NO:172, and wherein the protein binds to the activin type IIB receptor (ActRIIB).

3. ActRII-binding protein according to claim 1 or 2, characterized in that the ActRII-binding protein antagonizes the activity of ActRII. Petition 870260053005, dated 01 / 06 / 2026, p. 312 / 649 2 / 6 4. ActRII-binding protein, according to any one of claims 1 to 3, characterized in that the binding protein has at least one feature selected from the group consisting of: (a) competing with activin A, activin B, BMP7, BMP9, BMP10, GDF8 (myostatin), GDF11, or Nodal, for binding to ActRIIB and / or ActRIIA; (b) decreasing the phosphorylation of one or more Smads in cells expressing ActRIIB and / or ActRIIA in the presence of an ActRIIB or ActRIIA ligand (e.g., activin A); (c) decreasing the phosphorylation of ALK4 and / or ALK7 in cells expressing ActRIIB and / or ActRIIA and ALK4 and / or ALK7 in the presence of an ActRIIB and / or ActRIIA ligand; and (d) connect ActRIIB and / or ActRIIA with a Kd of <1 nM and >1 pM (e.g., as determined by BIACORE® analysis).

5. ActRII-binding protein, according to any one of claims 1 to 4, characterized in that the ActRII-binding protein is an antibody that binds specifically to ActRII.

6. ActRII-binding protein, according to claim 5, characterized in that the antibody is a monoclonal antibody, a recombinant antibody, a human antibody, a humanized antibody, a chimeric antibody, a bispecific antibody, a multispecific antibody, or an ActRII-binding antibody fragment.

7. ActRII-binding protein according to claim 6, characterized in that the ActRII-binding antibody is selected from the group consisting of a Fab fragment, a Fab' fragment, an F(ab')2 fragment, an Fv fragment, a diabody, or a single-chain antibody molecule. Petition 870260053005, dated 01 / 06 / 2026, p. 313 / 649 3 / 6 8. ActRII-binding protein according to any one of claims 5 to 7, characterized in that the antibody further comprises a heavy chain immunoglobulin constant domain selected from the group consisting of: (a) a human IgA constant domain; (b) a human IgD constant domain; (c) a human IgE constant domain; (d) a human IgG1 constant domain; (e) a human IgG2 constant domain; (f) a human IgG3 constant domain; (g) a human IgG4 constant domain; and (h) a human IgM constant domain.

9. ActRII-binding protein according to any one of claims 5 to 8, characterized in that the antibody further comprises a constant light chain immunoglobulin domain selected from the group consisting of: (a) a human Ig kappa constant domain; and (b) a human Ig lambda constant domain.

10. ActRII-binding protein, according to any one of claims 5 to 9, characterized in that the antibody further comprises a constant domain of human IgG1 heavy chain and a constant domain of human lambda light chain.

11. Nucleic acid molecule or set of nucleic acid molecules, characterized in that it encodes an ActRII-binding protein, as defined in any one of claims 1 to 10, wherein said nucleic acid molecule is as set forth in SEQ ID NO: 164 and SEQ ID NO:

171.

12. Nucleic acid molecule or set of nucleic acid molecules according to claim 11, characterized in that it is a cDNA. Petition 870260053005, dated 01 / 06 / 2026, p. 314 / 649 4 / 6 13. Nucleic acid molecule or set of nucleic acid molecules, according to claim 11 or 12, characterized in that the nucleic acid molecule is operationally linked to a control sequence.

14. Vector, characterized in that it comprises the nucleic acid molecule, as defined in any one of claims 11 to 13.

15. Host cell, characterized in that it comprises the nucleic acid molecule, as defined in any one of claims 11 to 13, or the vector, as defined in claim 14, wherein the cell is a microorganism cell.

16. Method for producing the ActRII-binding protein, as defined in any one of claims 1 to 10, characterized in that it comprises culturing a host cell, as defined in claim 15, under conditions suitable for producing the ActRII-binding protein.

17. Method according to claim 16, characterized in that it further comprises isolating the ActRII-binding protein secreted from the host cell.

18. ActRII-binding protein, characterized in that it is produced using the method as defined in claim 16 or 17.

19. Pharmaceutical composition, characterized in that it comprises an ActRII-binding protein, as defined in any one of claims 1 to 10 or 18, and a pharmaceutically acceptable carrier.

20. Pharmaceutical composition, according to claim 19, characterized in that it is for use as a medicament.

21. Pharmaceutical composition, according to Petition 870260053005, dated 01 / 06 / 2026, page 315 / 649 5 / 6 claim 19, characterized by the fact that it further comprises a marker group or an effector group.

22. Pharmaceutical composition, according to claim 21, characterized in that the effector group is selected from the group consisting of a radioisotope, radionuclide, a toxin, a therapeutic agent and a chemotherapeutic agent.

23. Use of an ActRII-binding protein, as defined in any one of claims 1 to 10 or 18, or of a pharmaceutical composition, as defined in any one of claims 19 to 22, characterized in that it is for the manufacture of a medicament for the treatment and / or attenuation of a disease or condition associated with ActRII expression or elevated ActRII-mediated signaling in an individual.

24. Use according to claim 23, characterized in that the disease or condition is a selected member of the group consisting of: a degenerative muscle disease, muscular dystrophy, muscle atrophy, muscle wasting, a fibrotic condition (a hepatic, pulmonary, vascular or ocular fibrotic condition), myocardial fibrosis, idiopathic pulmonary fibrosis, metabolic disease, type II diabetes, obesity, inflammatory disease, autoimmune disease, eye disease, age-related macular degeneration, cardiovascular disease, congestive heart failure, hypertension, lung disease, musculoskeletal disease, skeletal disease, osteoporosis, neuromuscular disease, degenerative disease, wound healing and cancer.

25. Use according to claim 23 or 24, characterized in that the ActRII binding protein or pharmaceutical composition is to be administered alone or as a combination therapy.

26. Use of an ActRII-binding protein, as defined in Petition 870260053005, dated 01 / 06 / 2026, p. 316 / 649 6 / 6 in any of claims 1 to 10 or 18, or of the pharmaceutical composition, as defined in any of claims 19 to 22, characterized in that it is for the manufacture of a pharmaceutical composition to reduce the activity of ActRII in an individual.

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