Alk7 binding proteins and uses thereof

Abstract

The present disclosure provides ALK7 binding proteins, such as anti-ALK7 antibodies and compositions, and methods for making the same. In certain embodiments, the ALK7 binding proteins inhibit or antagonize ALK7 activity. Further, the present disclosure provides compositions and methods for diagnosing and treating the following diseases: overweight, obesity, diabetes, overweight, obesity, type 2 diabetes, and associated conditions thereof; metabolic disorders, and other diseases or conditions that can be treated, prevented, or ameliorated by targeting ALK7.

Description

[0001] This application is a divisional application of the invention patent application filed on April 21, 2017, with application number 201780029770.0 and entitled "ALK7 binding protein and its use".

[0002] Reference to the electronically submitted sequence list

[0003] The contents of the electronically submitted sequence list in the ASCII text file 3174.004PC01_SeqList.ST25txt (size: 72,898 bytes; and creation date: April 21, 2017), which was submitted with this application, are incorporated herein by reference in their entirety. Background Technology

[0004] Overweight and obesity have reached epidemic proportions in the United States and many other countries worldwide, and are increasing in all age groups, races, and ethnicities, and in both men and women. Overweight and obesity are also associated with other diseases or conditions that disrupt vital functions and lifestyles. Obesity is considered a serious risk factor for other diseases and conditions such as type 2 diabetes, inflammatory and cardiovascular diseases, lung diseases, fatty liver disease, neurological diseases, and liver and kidney diseases.

[0005] Type 2 diabetes is a chronic, progressive disease that has reached an epidemic proportion. There is no established cure for type 2 diabetes, but there are several recognized treatments that attempt to delay or mitigate the inevitable disease outcomes. Type 2 diabetes is initially treated by adjusting diet and exercise and by weight loss (most notably in obese subjects). The amount of weight loss that improves clinical performance is sometimes modest (e.g., 4.4 to 11 lbs); this may be due to aspects of adipose tissue activity, such as chemical signaling (especially in abdominal organs and surrounding visceral adipose tissue).

[0006] In light of the foregoing, there is a need for novel treatments for controlling and treating the prevalence of overweight, obesity, and type 2 diabetes. The purpose of this disclosure is to provide the use of the ALK7 binding protein and its applications in the diagnosis, treatment, prevention, and / or improvement of overweight, obesity, type 2 diabetes, and associated symptoms; metabolic disorders; and other diseases or symptoms that can be treated, prevented, or improved by targeting ALK7. Summary of the Invention

[0007] This disclosure provides an ALK7 binding protein and methods of using the ALK7 binding protein. In specific embodiments, the ALK7 binding protein is capable of inhibiting or blocking the binding of ALK7 to one or more homologous ALK7 ligands and / or one or more homologous ActRI receptors. In some embodiments, the ALK7 binding protein is capable of inhibiting or blocking the polymerization of ALK7 and ActRII receptors (ActRIIA or ActRIIB) as well as GDF1, GDF3, GDF8, activin B, activin A / B, or Nodal. This disclosure also provides methods of using the ALK7 binding protein for the diagnosis or treatment, prevention, and / or improvement of diseases or symptoms associated with ALK7 expression and / or elevated ALK7-mediated signaling. Such diseases or conditions include, but are not limited to, overweight, obesity (e.g., abdominal obesity); insulin resistance; metabolic syndrome and other metabolic diseases or conditions; lipid disorders such as low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia, or dyslipidemia; lipoprotein aberrations; decreased triglycerides; inflammation (e.g., liver inflammation and / or adipose tissue inflammation), fatty liver disease; non-alcoholic fatty liver disease; hyperglycemia; impaired glucose tolerance (IGT); hyperinsulinemia; high cholesterol (e.g., high LDL levels and hypercholesterolemia); cardiovascular diseases such as heart disease including coronary artery disease, congestive heart failure, stroke, peripheral vascular disease, disordered fibrinolysis, etc. Atherosclerosis; arteriosclerosis and hypertension; Syndrome X; restenosis; neuropathy; retinopathy; neurodegenerative disease; endothelial dysfunction, respiratory dysfunction, kidney disease (e.g., nephropathy); pancreatitis; polycystic ovary syndrome; elevated uric acid levels; hemochromatosis (iron overload); acanthosis nigricans (dark spots on the skin); and cancer (e.g., myeloma (e.g., multiple myeloma, plasmacytoma, focal myeloma, or extramedullary myeloma) or ovarian cancer, breast cancer, colon cancer, endometrial cancer, liver cancer, kidney cancer, pancreatic cancer, stomach cancer, uterine cancer, or colon cancer); and with one or more of the above diseases or conditions or with excessive weight (e.g., body mass index (BMI) ≥ 25 kg / m²). 2 This disclosure also provides, but is not limited to, methods for using antagonist ALK7 binding proteins such as antibodies to reduce weight (e.g., promote weight loss) and methods for using antagonist ALK7 binding proteins such as antibodies to reduce weight gain (e.g., prevent weight gain).

[0008] In some embodiments, the ALK7-binding protein specifically binds to ALK7. In other embodiments, the provided ALK7-binding protein specifically binds to ALK7 and has at least one feature selected from the group consisting of: (a) reducing the formation of complexes containing ALK7, type II receptor (e.g., ActRIIA or ActRIIB), and one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8) on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; (b) competing with ActRIIA or ActRIIB for binding to ALK7; and (c) competing with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8). (d) Competitive binding to ALK7 with F3 and / or GDF8; (e) Reducing phosphorylation of ALK7 in cells expressing ALK7 and type II receptors (e.g., ActRIIA or ActRIIB) in the presence of one or more TGF-β superfamily ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); (f) Reducing phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); (c) Phosphorylation of Smad (e.g., Smad2 and / or Smad3) at ≤1 nM and ≥1 pM (e.g., as by...). K (determined by analysis) DThe ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7 binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7 binding protein has at least two, at least three, or at least four of the above characteristics. In another embodiment, the ALK7 binding protein cross-blocks the binding of antibodies having the ALK7-binding VH and VL pairs disclosed herein to ALK7 or competitively binds to ALK7 with said antibodies. In another embodiment, the ALK7 binding protein is an anti-ALK7 antibody or an ALK7-binding antibody fragment.

[0009] In some embodiments, the ALK7 binding protein comprises a set of complementarity-determining regions (CDRs): heavy chain variable region (VH)-CDR1, VH-CDR2, VH-CDR3, and light chain variable region (VL)-CDR1, VL-CDR2, and VL-CDR3, wherein the CDRs are present in the heavy chain variable region (VH) and light chain variable region (VHL) pairs disclosed in Table 1A. In some embodiments, the ALK7 binding protein comprises a set of CDRs present in the VH and VL pairs selected from the group consisting of: (a) the VH sequence of SEQ ID NO:4 and the VL sequence of SEQ ID NO:13; (b) the VH sequence of SEQ ID NO:22 and the VL sequence of SEQ ID NO:31; (c) the VH sequence of SEQ ID NO:40 and the VL sequence of SEQ ID NO:49; and (d) the VH sequence of SEQ ID NO:58 and the VL sequence of SEQ ID NO:67.

[0010] In some embodiments, the ALK7 binding protein comprises a set of complementarity-determining regions (CDRs): heavy chain variable region (VH)-CDR1, VH-CDR2, VH-CDR3, and light chain variable region (VL)-CDR1, VL-CDR2, and VL-CDR3, wherein the CDRs are present in the heavy chain variable region (VH) and light chain variable region (VHL) pairs disclosed in Table 1B or Table 3. In some embodiments, the ALK7 binding protein comprises a set of CDRs present in the VH and VL pairs selected from the group consisting of: (a) the VH sequence of SEQ ID NO:152 and the VL sequence of SEQ ID NO:98; (b) the VH sequence of SEQ ID NO:159 and the VL sequence of SEQ ID NO:110; and (c) the VH sequence of SEQ ID NO:165 and the VL sequence of SEQ ID NO:171. In some embodiments, the ALK7 binding protein comprises a set of CDRs present in a VH and VL pair selected from the group consisting of: (a) the VH sequence of SEQ ID NO:91 and the VL sequence of SEQ ID NO:98; (b) the VH sequence of SEQ ID NO:105 and the VL sequence of SEQ ID NO:110; (c) the VH sequence of SEQ ID NO:117 and the VL sequence of SEQ ID NO:124; (d) the VH sequence of SEQ ID NO:128 and the VL sequence of SEQ ID NO:135; and (e) the VH sequence of SEQ ID NO:140 and the VL sequence of SEQ ID NO:148.

[0011] In another embodiment, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, wherein the CDR set 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 compared to the reference CDR set, wherein: (a)(i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:1; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:2; (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:3; (iv) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:10; (v) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:11; and (vi) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:10. (b)(i) VH-CDR1 contains the amino acid sequence of SEQ ID NO:19; (ii) VH-CDR2 contains the amino acid sequence of SEQ ID NO:20; (iii) VH-CDR3 contains the amino acid sequence of SEQ ID NO:21; (iv) VL-CDR1 contains the amino acid sequence of SEQ ID NO:28; (v) VL-CDR2 contains the amino acid sequence of SEQ ID NO:29; and (vi) VL-CDR3 contains the amino acid sequence of SEQ ID NO:30; (c)(i) VH-CDR1 contains the amino acid sequence of SEQ ID NO:37; (ii) VH-CDR2 contains the amino acid sequence of SEQ ID NO:38; (iii) VH-CDR3 contains the amino acid sequence of SEQ ID NO:39; (iv) VL-CDR1 contains the amino acid sequence of SEQ ID NO:46; (v) VL-CDR2 contains the amino acid sequence of SEQ ID NO:47; and (vi) VL-CDR3 contains the amino acid sequence of SEQ ID NO:12. The amino acid sequence of NO:48; or (d)(i)VH-CDR1 contains the amino acid sequence of SEQ ID NO:55; (ii)VH-CDR2 contains the amino acid sequence of SEQ ID NO:56; (iii)VH-CDR3 contains the amino acid sequence of SEQ ID NO:57; (iv)VL-CDR1 contains the amino acid sequence of SEQ ID NO:64; (v)VL-CDR2 contains the amino acid sequence of SEQ ID NO:65; and (vi)VL-CDR3 contains the amino acid sequence of SEQ ID NO:66; and wherein the protein binds ALK7.

[0012] In another embodiment, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, wherein the CDR set 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 compared to the reference CDR set, wherein: (a)(i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:88; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:89; (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:90; (iv) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:95; (v) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:96; and (vi) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:95. (b)(i) VH-CDR1 contains the amino acid sequence of SEQ ID NO: 102; (ii) VH-CDR2 contains the amino acid sequence of SEQ ID NO: 103; (iii) VH-CDR3 contains the amino acid sequence of SEQ ID NO: 104; (iv) VL-CDR1 contains the amino acid sequence of SEQ ID NO: 107; (v) VL-CDR2 contains the amino acid sequence of SEQ ID NO: 108; and (vi) VL-CDR3 contains the amino acid sequence of SEQ ID NO: 109; (c)(i) VH-CDR1 contains the amino acid sequence of SEQ ID NO: 114; (ii) VH-CDR2 contains the amino acid sequence of SEQ ID NO: 115; (iii) VH-CDR3 contains the amino acid sequence of SEQ ID NO: 116; (iv) VL-CDR1 contains the amino acid sequence of SEQ ID NO: 121; (v) VL-CDR2 contains the amino acid sequence of SEQ ID NO: 97; (b)(i) VH-CDR1 contains the amino acid sequence of SEQ ID NO: 102; (ii) VH-CDR2 contains the amino acid sequence of SEQ ID NO: 103; (iii) VH-CDR3 contains the amino acid sequence of SEQ ID NO: 116; (iv) VL-CDR1 contains the amino acid sequence of SEQ ID NO: 121; (v) VL-CDR2 contains the amino acid sequence of SEQ ID NO: 97; (iv) VL-CDR1 contains the amino acid sequence of SEQ ID NO: 121; (v) VL-CDR2 contains the amino acid sequence of SEQ ID NO: 97; (iv) VH ... (vi) VL-CDR3 contains the amino acid sequence of SEQ ID NO:122; (d)(i) VH-CDR1 contains the amino acid sequence of SEQ ID NO:125; (ii) VH-CDR2 contains the amino acid sequence of SEQ ID NO:126; (iii) VH-CDR3 contains the amino acid sequence of SEQ ID NO:127; (iv) VL-CDR1 contains the amino acid sequence of SEQ ID NO:132; (v) VL-CDR2 contains the amino acid sequence of SEQ ID NO:133; and (vi) VL-CDR3 contains the amino acid sequence of SEQ ID NO:134.Or (e)(i) VH-CDR1 contains the amino acid sequence of SEQ ID NO:137; (ii) VH-CDR2 contains the amino acid sequence of SEQ ID NO:138; (iii) VH-CDR3 contains the amino acid sequence of SEQ ID NO:139; (iv) VL-CDR1 contains the amino acid sequence of SEQ ID NO:145; (v) VL-CDR2 contains the amino acid sequence of SEQ ID NO:146; and (vi) VL-CDR3 contains the amino acid sequence of SEQ ID NO:147; and wherein said protein binds ALK7.

[0013] In some embodiments, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs, wherein (a)(i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:1; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:2; (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:3; (iv) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:10; (v) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:11; and (vi) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:12; (b)(i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:19; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:20; (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:21; (iv) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:28; and (v) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:12. (vi) VL-CDR3 contains the amino acid sequence of SEQ ID NO:29; (c)(i) VH-CDR1 contains the amino acid sequence of SEQ ID NO:37; (ii) VH-CDR2 contains the amino acid sequence of SEQ ID NO:38; (iii) VH-CDR3 contains the amino acid sequence of SEQ ID NO:39; (iv) VL-CDR1 contains the amino acid sequence of SEQ ID NO:46; (v) VL-CDR2 contains the amino acid sequence of SEQ ID NO:47; and (vi) VL-CDR3 contains the amino acid sequence of SEQ ID NO:48; or (d)(i) VH-CDR1 contains the amino acid sequence of SEQ ID NO:55; (ii) VH-CDR2 contains the amino acid sequence of SEQ ID NO:56; (iii) VH-CDR3 contains the amino acid sequence of SEQ ID NO:57; (iv) VL-CDR1 contains the amino acid sequence of SEQ ID NO:64; and (v) VL-CDR2 contains the amino acid sequence of SEQ ID NO:30. The amino acid sequence of SEQ ID NO:65; and (vi)VL-CDR3 contains the amino acid sequence of SEQ ID NO:66; and said protein binds ALK7.

[0014] In some embodiments, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs, wherein (a)(i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO: 88; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO: 89; (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO: 90; (iv) VL-CDR1 comprises the amino acid sequence of SEQ ID NO: 95; (v) VL-CDR2 comprises the amino acid sequence of SEQ ID NO: 96; and (vi) VL-CDR3 comprises the amino acid sequence of SEQ ID NO: 97; (b)(i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO: 102; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO: 103; (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO: 104; (iv) VL-CDR1 comprises the amino acid sequence of SEQ ID NO: 107; and (v) VL-CDR2 comprises the amino acid sequence of SEQ ID NO: 88. (vi) VL-CDR3 contains the amino acid sequence of SEQ ID NO: 108; (c)(i) VH-CDR1 contains the amino acid sequence of SEQ ID NO: 114; (ii) VH-CDR2 contains the amino acid sequence of SEQ ID NO: 115; (iii) VH-CDR3 contains the amino acid sequence of SEQ ID NO: 116; (iv) VL-CDR1 contains the amino acid sequence of SEQ ID NO: 121; (v) VL-CDR2 contains the amino acid sequence of SEQ ID NO: 122; and (vi) VL-CDR3 contains the amino acid sequence of SEQ ID NO: 123; (d)(i) VH-CDR1 contains the amino acid sequence of SEQ ID NO: 125; (ii) VH-CDR2 contains the amino acid sequence of SEQ ID NO: 126; (iii) VH-CDR3 contains the amino acid sequence of SEQ ID NO: 127; (iv) VL-CDR1 contains the amino acid sequence of SEQ ID NO: 109; (c)(i) VH-CDR1 contains the amino acid sequence of SEQ ID NO: 114; (ii) VH-CDR2 contains the amino acid sequence of SEQ ID NO: 115; (iii) VH-CDR3 contains the amino acid sequence of SEQ ID NO: 127; (iv) VL-CDR1 contains the amino acid sequence of SEQ ID NO: 129; (iv) VL-CDR1 contains the amino acid sequence of SEQ ID NO: 129; (v) VH-CDR2 contains the amino acid sequence of SEQ ID NO: 129; (vi) VL-CDR3 contains the amino acid sequence of SEQ ID NO: 129; (v) VH-CDR2 contains the amino acid sequence of SEQ ID NO: 129; (vi) VH-CDR3 contains the amino acid sequence of SEQ ID NO: 129; (v) V (v) VL-CDR2 contains the amino acid sequence of SEQ ID NO:133; and (vi) VL-CDR3 contains the amino acid sequence of SEQ ID NO:134; or (e)(i) VH-CDR1 contains the amino acid sequence of SEQ ID NO:137; (ii) VH-CDR2 contains the amino acid sequence of SEQ ID NO:138; (iii) VH-CDR3 contains the amino acid sequence of SEQ ID NO:139; (iv) VL-CDR1 contains the amino acid sequence of SEQ ID NO:145;(v) VL-CDR2 contains the amino acid sequence of SEQ ID NO:146; and (vi) VL-CDR3 contains the amino acid sequence of SEQ ID NO:147; and wherein said protein binds ALK7.

[0015] In some embodiments, the ALK7 binding protein specifically binds to ALK7 and comprises a VH and VL pair selected from the group consisting of: (a)(i) a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with SEQ ID NO:4 and (ii) a VL having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with SEQ ID NO:13; (b)(i) a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with SEQ ID NO:22 or SEQ ID NO:132 and (ii) a VL having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with SEQ ID NO:31; (c)(i) a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with SEQ ID NO:4; NO:40 VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with SEQ ID NO:49; and (d)(i) VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with SEQ ID NO:58; and (ii) VL having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with SEQ ID NO:67; wherein said protein binds ALK7.

[0016] In some embodiments, the ALK7 binding protein specifically binds to ALK7 and comprises a VH and VL pair selected from the group consisting of: (a)(i) a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with SEQ ID NO:91 and (ii) a VL having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with SEQ ID NO:98; (b)(i) a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with SEQ ID NO:105 or SEQ ID NO:132 and (ii) a VL having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with SEQ ID NO:110; (c)(i) a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with SEQ ID NO:110; and (c)(i) a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with SEQ ID NO:110. (ii) VH with at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:117 and (ii) VL with at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:124; (d)(i) VH with at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:128 and (ii) VL with at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:135; and (e)(i) VH with at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:140 and (ii) VL with at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:124. NO:148 has a VL with at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and said protein binds ALK7.

[0017] In one embodiment, the ALK7 binding protein comprises a VH and a VL containing a VH sequence of SEQ ID NO:40 or SEQ ID NO:58 and a VL sequence of SEQ ID NO:49 or SEQ ID NO:67; and the protein binds ALK7. In another embodiment, the ALK7 binding protein comprises a VH sequence of SEQ ID NO:40 and a VL sequence of SEQ ID NO:49, and the protein binds ALK7. In yet another embodiment, the ALK7 binding protein comprises a VH sequence of SEQ ID NO:58 and a VL sequence of SEQ ID NO:67, and the protein binds ALK7.

[0018] In one embodiment, the ALK7 binding protein comprises a VH and VL pair containing the VH sequence of SEQ ID NO:4 and the VL sequence of SEQ ID NO:13, and the protein binds to ALK7.

[0019] In one embodiment, the ALK7 binding protein comprises a VH and VL pair containing the VH sequence of SEQ ID NO:22 and the VL sequence of SEQ ID NO:31, and the protein binds to ALK7.

[0020] In one embodiment, the ALK7 binding protein comprises a VH and VL pair containing the VH sequence of SEQ ID NO:40 and the VL sequence of SEQ ID NO:49, and the protein binds to ALK7.

[0021] In one embodiment, the ALK7 binding protein comprises a VH and VL pair containing the VH sequence of SEQ ID NO:58 and the VL sequence of SEQ ID NO:67, and the protein binds to ALK7.

[0022] In one embodiment, the ALK7 binding protein comprises a VH and VL pair containing the VH sequence of SEQ ID NO:91 and the VL sequence of SEQ ID NO:98, and the protein binds to ALK7.

[0023] In one embodiment, the ALK7 binding protein comprises a VH and VL pair containing the VH sequence of SEQ ID NO:105 and the VL sequence of SEQ ID NO:110, and the protein binds to ALK7.

[0024] In one embodiment, the ALK7 binding protein comprises a VH and VL pair containing the VH sequence of SEQ ID NO:117 and the VL sequence of SEQ ID NO:124, and the protein binds to ALK7.

[0025] In one embodiment, the ALK7 binding protein comprises a VH and VL pair containing the VH sequence of SEQ ID NO:128 and the VL sequence of SEQ ID NO:135, and the protein binds to ALK7.

[0026] In one embodiment, the ALK7 binding protein comprises a VH and VL pair containing the VH sequence of SEQ ID NO:140 and the VL sequence of SEQ ID NO:148, and the protein binds to ALK7.

[0027] In some embodiments, the ALK7 binding protein comprises VH and VL pairs selected from the group consisting of: (a)(i) a VH sequence having 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 sequence selected from the group consisting of SEQ ID NO:4; and (ii) a VL sequence having 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 VL sequence of SEQ ID NO:13; (b)(i) a VH sequence having 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 sequence of SEQ ID NO:22; and (ii ...iii) a VH sequence having 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 sequence of SEQ ID NO:22; and (iv) a VH sequence having a total Compared to the reference VL sequence of NO:31, it 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; (c)(i) compared to the reference VH sequence of SEQ ID NO:40, it 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; and (ii) compared to the reference VL sequence of SEQ ID NO:49, it 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; and (d)(i) compared to the reference VH sequence of SEQ ID NO:58, it 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; and (ii) compared to SEQ ID NO:40, it 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; and (ii) compared to the reference VH sequence of SEQ ID NO:49 ...iii) compared to the reference VH sequence of SEQ ID NO:49, it 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; and Compared to the reference VL sequence of NO:67, there are VL sequences 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; and the protein therein binds ALK7.

[0028] In some embodiments, the ALK7 binding protein comprises VH and VL pairs selected from the group consisting of: (a)(i) a VH sequence having 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 sequence selected from the group consisting of SEQ ID NO:91; and (ii) a VL sequence having 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 VL sequence of SEQ ID NO:98; (b)(i) a VH sequence having 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 sequence of SEQ ID NO:105; and (ii) a VH sequence having 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 sequence of SEQ ID NO:91; and (ii) a VH sequence having 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 sequence of SEQ ID NO:98; and (iii) a VL sequence having 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 sequence of SEQ ID NO:98; and (iv ... (c)(i) VL sequences having 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 the reference VL sequence of SEQ ID NO:110; and (ii) VL sequences having 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 the reference VL sequence of SEQ ID NO:110; and (d)(i) VL sequences having 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 the reference VL sequence of SEQ ID NO:124; and (ii) VL sequences having 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 the reference VL sequence of SEQ ID NO:128; and (ii) VL sequences having 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 the reference VL sequence of SEQ ID NO:110; The VL sequence of NO:135 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 the reference VL sequence of SEQ ID NO:140; and (e)(i) 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 the reference VL sequence of SEQ ID NO:148; and wherein the protein binds ALK7.

[0029] In some embodiments, the ALK7-binding protein is an antibody that specifically binds to ALK7. In other embodiments, the antibody is a monoclonal antibody, recombinant antibody, human antibody, humanized antibody, chimeric antibody, bispecific antibody, or multispecific antibody. In some embodiments, the ALK7-binding protein is an ALK7-binding antibody fragment. In some embodiments, the antibody is an antibody fragment selected from the group consisting of: Fab, Fab', F(ab')2, Fv, dimer, DART, and single-chain antibody molecules (e.g., BiTE).

[0030] In some embodiments, the ALK7-binding protein specifically binds to ALK7 between amino acids 20-113 of SEQ ID NO:85. In some embodiments, the ALK7-binding protein specifically binds to ALK7 between amino acids 20-113 of SEQ ID NO:85 and inhibits the binding of one or more ALK ligands (e.g., GDF1, GDF3, GDF8, activin B, activin A / B, and / or Nodal) to ALK7. In some embodiments, the ALK7 binding protein specifically binds to ALK7 between amino acids 20-113 of SEQ ID NO:85 and contacts one or more amino acids selected from the group consisting of: (a) Glu at position 21 of SEQ ID NO:85; (b) Leu at position 22 of SEQ ID NO:85; (c) Ser at position 23 of SEQ ID NO:85; (d) Pro at position 24 of SEQ ID NO:85; (e) Gly at position 25 of SEQ ID NO:85; (f) Leu at position 26 of SEQ ID NO:85; (g) Lys at position 27 of SEQ ID NO:85; (h) Cys at position 28 of SEQ ID NO:85; (i) Val at position 29 of SEQ ID NO:85; (j) Cys at position 30 of SEQ ID NO:85; (k) Leu at position 31 of SEQ ID NO:85; (l) Glu at position 21 ... Leu at position 32 of SEQ ID NO: 85; (m) Cys at position 33 of SEQ ID NO: 85; (n) Asp at position 34 of SEQ ID NO: 85; (o) Ser at position 35 of SEQ ID NO: 85; (p) Ser at position 36 of SEQ ID NO: 85; (q) Asn at position 37 of SEQ ID NO: 85; (r) Phe at position 38 of SEQ ID NO: 85; (s) Thr at position 39 of SEQ ID NO: 85; (t) Cys at position 40 of SEQ ID NO: 85; (u) Gln at position 41 of SEQ ID NO: 85; (v) Thr at position 42 of SEQ ID NO: 85; (w) Glu at position 43 of SEQ ID NO: 85; (x) Gly at position 44 of SEQ ID NO: 85; (y) Ala at position 45 of SEQ ID NO: 85; (z) at position 32 of SEQ ID NO: 85; Cys at position 46 of SEQ ID NO:85; (aa) Trp at position 47 of SEQ ID NO:85; (ab) Ala at position 48 of SEQ ID NO:85;(ac) Ser at position 49 of SEQ ID NO: 85; (ad) Val at position 50 of SEQ ID NO: 85; (ae) Met at position 51 of SEQ ID NO: 85; (af) Leu at position 52 of SEQ ID NO: 85; (ag) Thr at position 53 of SEQ ID NO: 85; (ah) Asn at position 54 of SEQ ID NO: 85; (ai) Gly at position 55 of SEQ ID NO: 85; (aj) Lys at position 56 of SEQ ID NO: 85; (ak) Glu at position 57 of SEQ ID NO: 85; (al) Gln at position 58 of SEQ ID NO: 85; (am) Val at position 59 of SEQ ID NO: 85; (an) Ile at position 60 of SEQ ID NO: 85; (ao) Lys at position 61 of SEQ ID NO: 85; (ap) Ser at position 62 of SEQ ID NO: 85; (aq) at position 49 of SEQ ID NO: 85; Cys at position 63 of SEQ ID NO: 85; (ar) Val at position 64 of SEQ ID NO: 85; (as) Ser at position 65 of SEQ ID NO: 85; (at) Leu at position 66 of SEQ ID NO: 85; (au) Pro at position 67 of SEQ ID NO: 85; (av) Glu at position 68 of SEQ ID NO: 85; (aw) Leu at position 69 of SEQ ID NO: 85; (ax) Asn at position 70 of SEQ ID NO: 85; (ay) Ala at position 71 of SEQ ID NO: 85; (az) Gln at position 72 of SEQ ID NO: 85; (ba) Val at position 73 of SEQ ID NO: 85; (bb) Phe at position 74 of SEQ ID NO: 85; (bc) Cys at position 75 of SEQ ID NO: 85; (bd) His at position 76 of SEQ ID NO: 85; (be) at position 63 of SEQ ID NO: 85; Ser at position 77 of SEQ ID NO: 85; (bf) Ser at position 78 of SEQ ID NO: 85; (bg) Asn at position 79 of SEQ ID NO: 85; (bh) Asn at position 80 of SEQ ID NO: 85; (bi) Val at position 81 of SEQ ID NO: 85; (bj) Thr at position 82 of SEQ ID NO: 85; (bk) Lys at position 83 of SEQ ID NO: 85;(bl) Thr at position 84 of SEQ ID NO: 85; (bm) Glu at position 85 of SEQ ID NO: 85; (bn) Cys at position 86 of SEQ ID NO: 85; (bo) Cys at position 87 of SEQ ID NO: 85; (bp) Phe at position 88 of SEQ ID NO: 85; (bq) Thr at position 89 of SEQ ID NO: 85; (br) Asp at position 90 of SEQ ID NO: 85; (bs) Phe at position 91 of SEQ ID NO: 85; (bt) Cys at position 92 of SEQ ID NO: 85; (bu) Asn at position 93 of SEQ ID NO: 85; (bv) Asn at position 94 of SEQ ID NO: 85; (bw) Ile at position 95 of SEQ ID NO: 85; (bx) Thr at position 96 of SEQ ID NO: 85; (by) at position 84 of SEQ ID NO: 85; Leu at position 97 of SEQ ID NO: 85; (bz) His at position 98 of SEQ ID NO: 85; (ca) Leu at position 99 of SEQ ID NO: 85; (cb) Pro at position 100 of SEQ ID NO: 85; (cc) Thr at position 101 of SEQ ID NO: 85; (cd) Ala at position 102 of SEQ ID NO: 85; (ce) Ser at position 103 of SEQ ID NO: 85; (cf) Pro at position 104 of SEQ ID NO: 85; (cg) Asn at position 105 of SEQ ID NO: 85; (ch) Ala at position 106 of SEQ ID NO: 85; (ci) Pro at position 107 of SEQ ID NO: 85; (cj) Lys at position 108 of SEQ ID NO: 85; (ck) Leu at position 109 of SEQ ID NO: 85; (cl) at position 97 of SEQ ID NO: 85; Gly at position 110 of SEQ ID NO:85; (cm) Pro at position 111 of SEQ ID NO:85; (cn) Met at position 112 of SEQ ID NO:85; and (co) Glu at position 113 of SEQ ID NO:85. In some embodiments, the ALK7 binding protein specifically binds to ALK7 between amino acids 20-113 of SEQ ID NO:85 and contacts one or more amino acids selected from the group consisting of: (a) Glu at position 21 of SEQ ID NO:85; (b) Leu at position 22 of SEQ ID NO:85;(c) Ser at position 23 of SEQ ID NO: 85; (d) Pro at position 24 of SEQ ID NO: 85; (e) Gly at position 25 of SEQ ID NO: 85; (f) Leu at position 26 of SEQ ID NO: 85; (g) Lys at position 27 of SEQ ID NO: 85; (h) Cys at position 28 of SEQ ID NO: 85; (i) Val at position 29 of SEQ ID NO: 85; (j) Cys at position 30 of SEQ ID NO: 85; (k) Leu at position 31 of SEQ ID NO: 85; (l) Leu at position 32 of SEQ ID NO: 85; (m) Cys at position 33 of SEQ ID NO: 85; (n) Asp at position 34 of SEQ ID NO: 85; (o) Ser at position 35 of SEQ ID NO: 85; (p) Ser at position 36 of SEQ ID NO: 85; (q) at position 23 of SEQ ID NO: 85; (r) Asn at position 37 of SEQ ID NO: 85; (s) Thr at position 38 of SEQ ID NO: 85; (t) Cys at position 40 of SEQ ID NO: 85; (u) Gln at position 41 of SEQ ID NO: 85; (v) Thr at position 42 of SEQ ID NO: 85; (w) Glu at position 43 of SEQ ID NO: 85; (x) Gly at position 44 of SEQ ID NO: 85; (y) Ala at position 45 of SEQ ID NO: 85; (z) Cys at position 46 of SEQ ID NO: 85; (aa) Trp at position 47 of SEQ ID NO: 85; (ab) Ala at position 48 of SEQ ID NO: 85; (ac) Ser at position 49 of SEQ ID NO: 85; (ad) Val at position 50 of SEQ ID NO: 85; (ae) at position 37 of SEQ ID NO: 85; (s) Thr at position 39 of SEQ ID NO: 85; (t) Cys at position 40 of SEQ ID NO: 85; (u) Gln at position 41 of SEQ ID NO: 85; (v) Thr at position 42 of SEQ ID NO: 85; (w) Glu at position 43 of SEQ ID NO: 85; (x) Gly at position 44 of SEQ ID NO: 85; (y) Ala at position 45 of SEQ ID NO: 85; (z) Cys at position 46 of SEQ ID NO: 85; (aa) Trp at position 47 of SEQ ID NO: 85; (ab) Ala at position 48 of SEQ ID NO: 85; (ac) Ser at position 49 of SEQ ID NO: 85; (ad) Val at position 50 of SEQ ID NO Met at position 51 of SEQ ID NO:85; (af) Leu at position 52 of SEQ ID NO:85; (ag) Thr at position 53 of SEQ ID NO:85; (ah) Asn at position 54 of SEQ ID NO:85; (ai) Gly at position 55 of SEQ ID NO:85; (aj) Lys at position 56 of SEQ ID NO:85; (ak) Glu at position 57 of SEQ ID NO:85; (al) Gln at position 58 of SEQ ID NO:85;(am) Val at position 59 of SEQ ID NO: 85; (an) Ile at position 60 of SEQ ID NO: 85; (ao) Lys at position 61 of SEQ ID NO: 85; (ap) Ser at position 62 of SEQ ID NO: 85; (aq) Cys at position 63 of SEQ ID NO: 85; (ar) Val at position 64 of SEQ ID NO: 85; (as) Ser at position 65 of SEQ ID NO: 85; (at) Leu at position 66 of SEQ ID NO: 85; (au) Pro at position 67 of SEQ ID NO: 85; (av) Glu at position 68 of SEQ ID NO: 85; (aw) Leu at position 69 of SEQ ID NO: 85; (ax) Asn at position 70 of SEQ ID NO: 85; (ay) Ala at position 71 of SEQ ID NO: 85; (az) Gln at position 72 of SEQ ID NO: 85; (ba) Val at position 59 of SEQ ID NO: 85; (aq) Cys at position 63 of SEQ ID NO: 85; (ar) Val at position 64 of SEQ ID NO: 85; (as) Ser at position 65 of SEQ ID NO: 85; (ap) Ser at position 62 of SEQ ID NO: 85; (aq) Cys at position 63 of SEQ ID NO: 85; (ar) Val at position 64 of SEQ ID NO: 85; (aq) Ser at position 65 ... Val at position 73 of SEQ ID NO: 85; (bb) Phe at position 74 of SEQ ID NO: 85; (bc) Cys at position 75 of SEQ ID NO: 85; (bd) His at position 76 of SEQ ID NO: 85; (be) Ser at position 77 of SEQ ID NO: 85; (bf) Ser at position 78 of SEQ ID NO: 85; (bg) Asn at position 79 of SEQ ID NO: 85; (bh) Asn at position 80 of SEQ ID NO: 85; (bi) Val at position 81 of SEQ ID NO: 85; (bj) Thr at position 82 of SEQ ID NO: 85; (bk) Lys at position 83 of SEQ ID NO: 85; (bl) Thr at position 84 of SEQ ID NO: 85; (bm) Glu at position 85 of SEQ ID NO: 85; (bn) ... Cys at position 86 of SEQ ID NO: 85; (bo) Cys at position 87 of SEQ ID NO: 85; (bp) Phe at position 88 of SEQ ID NO: 85; (bq) Thr at position 89 of SEQ ID NO: 85; (br) Asp at position 90 of SEQ ID NO: 85; (bs) Phe at position 91 of SEQ ID NO: 85; (bt) Cys at position 92 of SEQ ID NO: 85; (bu) Asn at position 93 of SEQ ID NO: 85;(bv) Asn at position 94 of SEQ ID NO: 85; (bw) Ile at position 95 of SEQ ID NO: 85; (bx) Thr at position 96 of SEQ ID NO: 85; (by) Leu at position 97 of SEQ ID NO: 85; (bz) His at position 98 of SEQ ID NO: 85; (ca) Leu at position 99 of SEQ ID NO: 85; (cb) Pro at position 100 of SEQ ID NO: 85; (cc) Thr at position 101 of SEQ ID NO: 85; (cd) Ala at position 102 of SEQ ID NO: 85; (ce) Ser at position 103 of SEQ ID NO: 85; (cf) Pro at position 104 of SEQ ID NO: 85; (cg) Asn at position 105 of SEQ ID NO: 85; (ch) Ala at position 106 of SEQ ID NO: 85; (ci) at position 94 of SEQ ID NO: 85; Pro at position 107 of SEQ ID NO:85; (cj) Lys at position 108 of SEQ ID NO:85; (ck) Leu at position 109 of SEQ ID NO:85; (cl) Gly at position 110 of SEQ ID NO:85; (cm) Pro at position 111 of SEQ ID NO:85; (cn) Met at position 112 of SEQ ID NO:85; and (co) Glu at position 113 of SEQ ID NO:85; and inhibits the binding of one or more ALK7 ligands (e.g., GDF1, GDF3, GDF8, activin B, activin A / B, and / or Nodal) to ALK7. In some embodiments, the ALK7 binding protein specifically binds to ALK7 between amino acids 20-113 of SEQ ID NO:85 and increases lipolysis (e.g., lipolysis of white adipocytes and / or brown adipocytes). In some embodiments, the ALK7 binding protein specifically binds to ALK7 between amino acids 20-113 of SEQ ID NO:85 and contacts one or more amino acids selected from the group consisting of: (a) Glu at position 21 of SEQ ID NO:85; (b) Leu at position 22 of SEQ ID NO:85; (c) Ser at position 23 of SEQ ID NO:85; (d) Pro at position 24 of SEQ ID NO:85; (e) Gly at position 25 of SEQ ID NO:85; (f) Leu at position 26 of SEQ ID NO:85; (g) Lys at position 27 of SEQ ID NO:85;(h) Cys at position 28 of SEQ ID NO: 85; (i) Val at position 29 of SEQ ID NO: 85; (j) Cys at position 30 of SEQ ID NO: 85; (k) Leu at position 31 of SEQ ID NO: 85; (l) Leu at position 32 of SEQ ID NO: 85; (m) Cys at position 33 of SEQ ID NO: 85; (n) Asp at position 34 of SEQ ID NO: 85; (o) Ser at position 35 of SEQ ID NO: 85; (p) Ser at position 36 of SEQ ID NO: 85; (q) Asn at position 37 of SEQ ID NO: 85; (r) Phe at position 38 of SEQ ID NO: 85; (s) Thr at position 39 of SEQ ID NO: 85; (t) Cys at position 40 of SEQ ID NO: 85; (u) at position 40 of SEQ ID NO: 85; (v) Gln at position 41 of SEQ ID NO: 85; (w) Glu at position 43 of SEQ ID NO: 85; (x) Gly at position 44 of SEQ ID NO: 85; (y) Ala at position 45 of SEQ ID NO: 85; (z) Cys at position 46 of SEQ ID NO: 85; (aa) Trp at position 47 of SEQ ID NO: 85; (ab) Ala at position 48 of SEQ ID NO: 85; (ac) Ser at position 49 of SEQ ID NO: 85; (ad) Val at position 50 of SEQ ID NO: 85; (ae) Met at position 51 of SEQ ID NO: 85; (af) Leu at position 52 of SEQ ID NO: 85; (ag) Thr at position 53 of SEQ ID NO: 85; (ah) Asn at position 54 of SEQ ID NO: 85; (ai) at position 45 of SEQ ID NO: 85; Gly at position 55 of SEQ ID NO: 85; (aj) Lys at position 56 of SEQ ID NO: 85; (ak) Glu at position 57 of SEQ ID NO: 85; (al) Gln at position 58 of SEQ ID NO: 85; (am) Val at position 59 of SEQ ID NO: 85; (an) Ile at position 60 of SEQ ID NO: 85; (ao) Lys at position 61 of SEQ ID NO: 85; (ap) Ser at position 62 of SEQ ID NO: 85; (aq) Cys at position 63 of SEQ ID NO: 85;(ar) Val at position 64 of SEQ ID NO: 85; (as) Ser at position 65 of SEQ ID NO: 85; (at) Leu at position 66 of SEQ ID NO: 85; (au) Pro at position 67 of SEQ ID NO: 85; (av) Glu at position 68 of SEQ ID NO: 85; (aw) Leu at position 69 of SEQ ID NO: 85; (ax) Asn at position 70 of SEQ ID NO: 85; (ay) Ala at position 71 of SEQ ID NO: 85; (az) Gln at position 72 of SEQ ID NO: 85; (ba) Val at position 73 of SEQ ID NO: 85; (bb) Phe at position 74 of SEQ ID NO: 85; (bc) Cys at position 75 of SEQ ID NO: 85; (bd) His at position 76 of SEQ ID NO: 85; (be) Ser at position 77 of SEQ ID NO: 85; (bf) in SEQ ID NO: 85 Ser at position 78 of SEQ ID NO: 85; (bg) Asn at position 79 of SEQ ID NO: 85; (bh) Asn at position 80 of SEQ ID NO: 85; (bi) Val at position 81 of SEQ ID NO: 85; (bj) Thr at position 82 of SEQ ID NO: 85; (bk) Lys at position 83 of SEQ ID NO: 85; (bl) Thr at position 84 of SEQ ID NO: 85; (bm) Glu at position 85 of SEQ ID NO: 85; (bn) Cys at position 86 of SEQ ID NO: 85; (bo) Cys at position 87 of SEQ ID NO: 85; (bp) Phe at position 88 of SEQ ID NO: 85; (bq) Thr at position 89 of SEQ ID NO: 85; (br) Asp at position 90 of SEQ ID NO: 85; (bs) at position 88 of SEQ ID NO: 85; Phe at position 91 of SEQ ID NO: 85; (bt) Cys at position 92 of SEQ ID NO: 85; (bu) Asn at position 93 of SEQ ID NO: 85; (bv) Asn at position 94 of SEQ ID NO: 85; (bw) Ile at position 95 of SEQ ID NO: 85; (bx) Thr at position 96 of SEQ ID NO: 85; (by) Leu at position 97 of SEQ ID NO: 85; (bz) His at position 98 of SEQ ID NO: 85;(ca) Leu at position 99 of SEQ ID NO: 85; (cb) Pro at position 100 of SEQ ID NO: 85; (cc) Thr at position 101 of SEQ ID NO: 85; (cd) Ala at position 102 of SEQ ID NO: 85; (ce) Ser at position 103 of SEQ ID NO: 85; (cf) Pro at position 104 of SEQ ID NO: 85; (cg) Asn at position 105 of SEQ ID NO: 85; (ch) Ala at position 106 of SEQ ID NO: 85; (ci) Pro at position 107 of SEQ ID NO: 85; (cj) Lys at position 108 of SEQ ID NO: 85; (ck) Leu at position 109 of SEQ ID NO: 85; (cl) Gly at position 110 of SEQ ID NO: 85; (cm) Pro at position 111 of SEQ ID NO: 85; (cn) at position 99 of SEQ ID NO: 85; Met at position 112 of SEQ ID NO:85; and Glu at position 113 of SEQ ID NO:85; and increase lipolysis (e.g., lipolysis of white adipocytes and / or brown adipocytes).

[0031] In some embodiments, the ALK7-binding protein specifically binds to ALK7 between amino acids 28-92 of SEQ ID NO:85. In some embodiments, the ALK7-binding protein specifically binds to ALK7 between amino acids 28-92 of SEQ ID NO:85 and inhibits the binding of one or more ALK7 ligands (e.g., GDF1, GDF3, GDF8, activin B, activin A / B, and / or Nodal) to ALK7. In some embodiments, the ALK7 binding protein specifically binds to ALK7 between amino acids 28-92 of SEQ ID NO:85 and contacts one or more amino acids selected from the group consisting of: (a) Cys at position 28 of SEQ ID NO:85; (b) Val at position 29 of SEQ ID NO:85; (c) Cys at position 30 of SEQ ID NO:85; (d) Leu at position 31 of SEQ ID NO:85; (e) Leu at position 32 of SEQ ID NO:85; (f) Cys at position 33 of SEQ ID NO:85; (g) Asp at position 34 of SEQ ID NO:85; (h) Ser at position 35 of SEQ ID NO:85; (i) Ser at position 36 of SEQ ID NO:85; (j) Asn at position 37 of SEQ ID NO:85; (k) Phe at position 38 of SEQ ID NO:85; (l) ... Thr at position 39 of SEQ ID NO:85; (m) Cys at position 40 of SEQ ID NO:85; (n) Gln at position 41 of SEQ ID NO:85; (o) Thr at position 42 of SEQ ID NO:85; (p) Glu at position 43 of SEQ ID NO:85; (q) Gly at position 44 of SEQ ID NO:85; (r) Ala at position 45 of SEQ ID NO:85; (s) Cys at position 46 of SEQ ID NO:85; (t) Trp at position 47 of SEQ ID NO:85; (u) Ala at position 48 of SEQ ID NO:85; (v) Ser at position 49 of SEQ ID NO:85; (w) Val at position 50 of SEQ ID NO:85; (x) Met at position 51 of SEQ ID NO:85; (y) Leu at position 52 of SEQ ID NO:85; (z) at position 39 of SEQ ID NO:85; Thr at position 53 of SEQ ID NO:85; (aa) Asn at position 54 of SEQ ID NO:85; (ab) Gly at position 55 of SEQ ID NO:85;(ac) Lys at position 56 of SEQ ID NO: 85; (ad) Glu at position 57 of SEQ ID NO: 85; (ae) Gln at position 58 of SEQ ID NO: 85; (af) Val at position 59 of SEQ ID NO: 85; (ag) Ile at position 60 of SEQ ID NO: 85; (ah) Lys at position 61 of SEQ ID NO: 85; (ai) Ser at position 62 of SEQ ID NO: 85; (aj) Cys at position 63 of SEQ ID NO: 85; (ak) Val at position 64 of SEQ ID NO: 85; (al) Ser at position 65 of SEQ ID NO: 85; (am) Leu at position 66 of SEQ ID NO: 85; (an) Pro at position 67 of SEQ ID NO: 85; (ao) Glu at position 68 of SEQ ID NO: 85; (ap) Leu at position 69 of SEQ ID NO: 85; (aq) Lys at position 56 ... Asn at position 70 of SEQ ID NO: 85; (ar) Ala at position 71 of SEQ ID NO: 85; (as) Gln at position 72 of SEQ ID NO: 85; (at) Val at position 73 of SEQ ID NO: 85; (au) Phe at position 74 of SEQ ID NO: 85; (av) Cys at position 75 of SEQ ID NO: 85; (aw) His at position 76 of SEQ ID NO: 85; (ax) Ser at position 77 of SEQ ID NO: 85; (ay) Ser at position 78 of SEQ ID NO: 85; (az) Asn at position 79 of SEQ ID NO: 85; (ba) Asn at position 80 of SEQ ID NO: 85; (bb) Val at position 81 of SEQ ID NO: 85; (bc) Thr at position 82 of SEQ ID NO: 85; (bd) Lys at position 83 of SEQ ID NO: 85; (be) at position 74 of SEQ ID NO: 85; (ar) Ala at position 71 of SEQ ID NO: 85; (as) Gln at position 72 of SEQ ID NO: 85; (at) Val at position 73 of SEQ ID NO: 85; (be) Phe at position 74 of SEQ ID NO: 85; (av) Cys at position 75 of SEQ ID NO: 85; (aw) His at position 76 of SEQ ID NO: 85; (ax) Ser at position 77 of SEQ ID NO: 85; (ay) Ser at position 78 of SEQ ID NO: 85; (az) Asn at position 79 of SEQ ID NO: 85; (ba) Asn at position 80 of SEQ ID NO: 85; (bb) Val at position 81 of SEQ ID NO: 85; (bc Thr at position 84 of SEQ ID NO: 85; (bf) Glu at position 85 of SEQ ID NO: 85; (bg) Cys at position 86 of SEQ ID NO: 85; (bh) Cys at position 87 of SEQ ID NO: 85; (bi) Phe at position 88 of SEQ ID NO: 85; (bj) Thr at position 89 of SEQ ID NO: 85; (bk) Asp at position 90 of SEQ ID NO: 85;(bl) Phe at position 91 of SEQ ID NO:85; and (bm) Cys at position 92 of SEQ ID NO:85. In some embodiments, the ALK7 binding protein specifically binds to ALK7 between amino acids 28-92 of SEQ ID NO:85 and contacts one or more amino acids selected from the group consisting of: (a) Cys at position 28 of SEQ ID NO:85; (b) Val at position 29 of SEQ ID NO:85; (c) Cys at position 30 of SEQ ID NO:85; (d) Leu at position 31 of SEQ ID NO:85; (e) Leu at position 32 of SEQ ID NO:85; (f) Cys at position 33 of SEQ ID NO:85; (g) Asp at position 34 of SEQ ID NO:85; (h) Ser at position 35 of SEQ ID NO:85; (i) Ser at position 36 of SEQ ID NO:85; (j) Asn at position 37 of SEQ ID NO:85; (k) Phe at position 38 of SEQ ID NO:85; (l) ... Thr at position 39 of SEQ ID NO:85; (m) Cys at position 40 of SEQ ID NO:85; (n) Gln at position 41 of SEQ ID NO:85; (o) Thr at position 42 of SEQ ID NO:85; (p) Glu at position 43 of SEQ ID NO:85; (q) Gly at position 44 of SEQ ID NO:85; (r) Ala at position 45 of SEQ ID NO:85; (s) Cys at position 46 of SEQ ID NO:85; (t) Trp at position 47 of SEQ ID NO:85; (u) Ala at position 48 of SEQ ID NO:85; (v) Ser at position 49 of SEQ ID NO:85; (w) Val at position 50 of SEQ ID NO:85; (x) Met at position 51 of SEQ ID NO:85; (y) Leu at position 52 of SEQ ID NO:85; (z) at position 39 of SEQ ID NO:85; Thr at position 53 of SEQ ID NO: 85; (aa) Asn at position 54 of SEQ ID NO: 85; (ab) Gly at position 55 of SEQ ID NO: 85; (ac) Lys at position 56 of SEQ ID NO: 85; (ad) Glu at position 57 of SEQ ID NO: 85; (ae) Gln at position 58 of SEQ ID NO: 85; (af) Val at position 59 of SEQ ID NO: 85;(ag) Ile at position 60 of SEQ ID NO: 85; (ah) Lys at position 61 of SEQ ID NO: 85; (ai) Ser at position 62 of SEQ ID NO: 85; (aj) Cys at position 63 of SEQ ID NO: 85; (ak) Val at position 64 of SEQ ID NO: 85; (al) Ser at position 65 of SEQ ID NO: 85; (am) Leu at position 66 of SEQ ID NO: 85; (an) Pro at position 67 of SEQ ID NO: 85; (ao) Glu at position 68 of SEQ ID NO: 85; (ap) Leu at position 69 of SEQ ID NO: 85; (aq) Asn at position 70 of SEQ ID NO: 85; (ar) Ala at position 71 of SEQ ID NO: 85; (as) Gln at position 72 of SEQ ID NO: 85; (at) Val at position 73 of SEQ ID NO: 85; (au) ...aq) Pro at position 66 of SEQ ID NO: 85 Phe at position 74 of SEQ ID NO: 85; (av) Cys at position 75 of SEQ ID NO: 85; (aw) His at position 76 of SEQ ID NO: 85; (ax) Ser at position 77 of SEQ ID NO: 85; (ay) Ser at position 78 of SEQ ID NO: 85; (az) Asn at position 79 of SEQ ID NO: 85; (ba) Asn at position 80 of SEQ ID NO: 85; (bb) Val at position 81 of SEQ ID NO: 85; (bc) Thr at position 82 of SEQ ID NO: 85; (bd) Lys at position 83 of SEQ ID NO: 85; (be) Thr at position 84 of SEQ ID NO: 85; (bf) Glu at position 85 of SEQ ID NO: 85; (bg) Cys at position 86 of SEQ ID NO: 85; (bh) Cys at position 87 of SEQ ID NO: 85; (bi) at position 74 of SEQ ID NO: 85; Phe at position 88 of SEQ ID NO:85; (bj) Thr at position 89 of SEQ ID NO:85; (bk) Asp at position 90 of SEQ ID NO:85; (bl) Phe at position 91 of SEQ ID NO:85; and (bm) Cys at position 92 of SEQ ID NO:85;Furthermore, it inhibits the binding of one or more ALK7 ligands (e.g., GDF1, GDF3, GDF8, activin B, activin A / B, and / or Nodal) to ALK7. In some embodiments, the ALK7-binding protein specifically binds to ALK7 between amino acids 28-92 of SEQ ID NO:85 and increases lipolysis (e.g., lipolysis in white adipocytes and / or brown adipocytes). In some embodiments, the ALK7 binding protein specifically binds to ALK7 between amino acids 28-92 of SEQ ID NO:85 and contacts one or more amino acids selected from the group consisting of: (a) Cys at position 28 of SEQ ID NO:85; (b) Val at position 29 of SEQ ID NO:85; (c) Cys at position 30 of SEQ ID NO:85; (d) Leu at position 31 of SEQ ID NO:85; (e) Leu at position 32 of SEQ ID NO:85; (f) Cys at position 33 of SEQ ID NO:85; (g) Asp at position 34 of SEQ ID NO:85; (h) Ser at position 35 of SEQ ID NO:85; (i) Ser at position 36 of SEQ ID NO:85; (j) Asn at position 37 of SEQ ID NO:85; (k) Phe at position 38 of SEQ ID NO:85; (l) ... Thr at position 39 of SEQ ID NO:85; (m) Cys at position 40 of SEQ ID NO:85; (n) Gln at position 41 of SEQ ID NO:85; (o) Thr at position 42 of SEQ ID NO:85; (p) Glu at position 43 of SEQ ID NO:85; (q) Gly at position 44 of SEQ ID NO:85; (r) Ala at position 45 of SEQ ID NO:85; (s) Cys at position 46 of SEQ ID NO:85; (t) Trp at position 47 of SEQ ID NO:85; (u) Ala at position 48 of SEQ ID NO:85; (v) Ser at position 49 of SEQ ID NO:85; (w) Val at position 50 of SEQ ID NO:85; (x) Met at position 51 of SEQ ID NO:85; (y) Leu at position 52 of SEQ ID NO:85; (z) at position 39 of SEQ ID NO:85; Thr at position 53 of SEQ ID NO:85; (aa) Asn at position 54 of SEQ ID NO:85; (ab) Gly at position 55 of SEQ ID NO:85;(ac) Lys at position 56 of SEQ ID NO: 85; (ad) Glu at position 57 of SEQ ID NO: 85; (ae) Gln at position 58 of SEQ ID NO: 85; (af) Val at position 59 of SEQ ID NO: 85; (ag) Ile at position 60 of SEQ ID NO: 85; (ah) Lys at position 61 of SEQ ID NO: 85; (ai) Ser at position 62 of SEQ ID NO: 85; (aj) Cys at position 63 of SEQ ID NO: 85; (ak) Val at position 64 of SEQ ID NO: 85; (al) Ser at position 65 of SEQ ID NO: 85; (am) Leu at position 66 of SEQ ID NO: 85; (an) Pro at position 67 of SEQ ID NO: 85; (ao) Glu at position 68 of SEQ ID NO: 85; (ap) Leu at position 69 of SEQ ID NO: 85; (aq) Lys at position 56 ... Asn at position 70 of SEQ ID NO: 85; (ar) Ala at position 71 of SEQ ID NO: 85; (as) Gln at position 72 of SEQ ID NO: 85; (at) Val at position 73 of SEQ ID NO: 85; (au) Phe at position 74 of SEQ ID NO: 85; (av) Cys at position 75 of SEQ ID NO: 85; (aw) His at position 76 of SEQ ID NO: 85; (ax) Ser at position 77 of SEQ ID NO: 85; (ay) Ser at position 78 of SEQ ID NO: 85; (az) Asn at position 79 of SEQ ID NO: 85; (ba) Asn at position 80 of SEQ ID NO: 85; (bb) Val at position 81 of SEQ ID NO: 85; (bc) Thr at position 82 of SEQ ID NO: 85; (bd) Lys at position 83 of SEQ ID NO: 85; (be) at position 70 of SEQ ID NO: 85; Thr at position 84 of SEQ ID NO: 85; (bf) Glu at position 85 of SEQ ID NO: 85; (bg) Cys at position 86 of SEQ ID NO: 85; (bh) Cys at position 87 of SEQ ID NO: 85; (bi) Phe at position 88 of SEQ ID NO: 85; (bj) Thr at position 89 of SEQ ID NO: 85; (bk) Asp at position 90 of SEQ ID NO: 85;(bl) Phe at position 91 of SEQ ID NO: 85; and (bm) Cys at position 92 of SEQ ID NO: 85; and increase lipolysis (e.g., lipolysis of white adipocytes and / or brown adipocytes).

[0032] Also provided are nucleic acids encoding the ALK7 binding protein and groups of nucleic acids. Also provided are vectors containing said nucleic acids and groups of nucleic acids, and host cells transformed with said nucleic acids and vectors. In some embodiments, said host cells are hybridomas or mammalian host cells such as NSO mouse myeloma cells, Human cells or Chinese hamster ovary (CHO) cells. Host cells are also provided, including mammalian host cells that produce ALK7-binding protein and hybridomas.

[0033] Methods for preparing ALK7-binding protein are also provided. In some embodiments, the method includes culturing host cells capable of expressing the protein under conditions suitable for expressing ALK7-binding protein and optionally isolating the expressed ALK7-binding protein. Preparation and / or isolation of ALK7-binding protein using methods disclosed herein or otherwise known in the art are also provided.

[0034] Pharmaceutical compositions comprising an ALK7-binding protein and a pharmaceutically acceptable carrier are also provided. In some embodiments, this disclosure provides methods for treating and / or improving symptoms in a subject associated with elevated ALK7 expression or ALK7-mediated signaling, or which can be treated and / or improved by reducing ALK7 signaling. In some embodiments, the methods reduce ALK7-mediated signaling in the subject.

[0035] The conditions that may be treated and / or improved in the subject using the provided methods include, but are not limited to: obesity (e.g., abdominal obesity); overweight; insulin resistance; metabolic syndrome and other metabolic diseases or conditions; lipid disorders such as low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia, or dyslipidemia; lipoprotein aberrations; decreased triglycerides; inflammation (e.g., liver inflammation and / or adipose tissue inflammation), fatty liver disease; non-alcoholic fatty liver disease; hyperglycemia; impaired glucose tolerance (IGT); hyperinsulinemia; high cholesterol (e.g., high LDL levels and hypercholesterolemia); cardiovascular diseases such as heart disease including coronary artery disease, congestive heart failure, stroke, peripheral vascular disease. Diseases, disordered fibrinolysis, atherosclerosis; arteriosclerosis and hypertension; Syndrome X; restenosis; neuropathy; retinopathy; neurodegenerative diseases; endothelial dysfunction, respiratory dysfunction, kidney disease (e.g., nephropathy); pancreatitis; polycystic ovary syndrome; elevated uric acid levels; hemochromatosis (iron overload); acanthosis nigricans (dark spots on the skin); and cancers (e.g., myeloma (multiple myeloma, plasmacytoma, focal myeloma, or extramedullary myeloma) or ovarian cancer, breast cancer, colon cancer, endometrial cancer, liver cancer, kidney cancer, pancreatic cancer, stomach cancer, uterine cancer, and / or colon cancer); and those associated with one or more of the above diseases or conditions or with overweight (e.g., BMI ≥ 25 kg / m²). 2 Or other conditions / symptoms associated with excessive body fat.

[0036] In some embodiments, the disclosed method includes administering to a subject in need a pharmaceutical composition containing an effective amount of ALK7-binding protein (e.g., an antagonist ALK7-binding protein such as an antagonist anti-ALK7 antibody). In some embodiments, the ALK7-binding protein is administered alone. In other embodiments, the ALK7-binding protein is administered as a combination therapy. In still other embodiments, the ALK7-binding protein is administered as a combination therapy according to standards of care / treatment / therapy.

[0037] Methods for blocking or reducing ALK7 activity (e.g., ligand binding and / or signaling) are also provided. In some embodiments, the method includes contacting an ALK7-binding protein with cells expressing ALK7 (e.g., differentiated white or brown adipocytes). In some cases, the method includes contacting the ALK7-binding protein with cells expressing ALK7 in the presence of GDF1, GDF3, GDF8, activin B, activin A / B, and / or Nodal. In some embodiments, the method is performed in vivo. In other embodiments, the method is performed in vitro. In some embodiments, the blocked or reduced ALK7 activity is phosphorylation of ALK7. In further embodiments, the blocked or reduced ALK7 activity is phosphorylation of Smad (e.g., Smad2 and / or Smad3). In some embodiments, this disclosure provides a method for blocking or reducing ALK7 activity in a subject, comprising administering an effective amount of ALK7-binding protein to a subject in need.

[0038] A method for blocking or reducing ALK7 activity is also provided in pathological conditions associated with ALK7 expression and / or ALK7 signaling, or in pathological conditions that can be treated and / or improved by reducing or inhibiting the activity of ALK7 ligands. In some embodiments, the method includes administering an ALK7-binding protein to a subject having increased ALK7 or ALK7 ligand expression. In some embodiments, the pathological condition is obesity, diabetes, metabolic disease, dyslipidemia; cardiovascular disease, type 2 diabetes, inflammatory or pulmonary disease, fatty liver disease, neurological disease, and liver or kidney disease.

[0039] In one embodiment, this disclosure provides a method of treating or improving overweight or overweight-related conditions, comprising administering an effective amount of an ALK7-binding protein (e.g., an antagonist ALK7-binding protein such as an antagonist anti-ALK7 antibody) to an overweight subject. In one embodiment, the condition being treated or improved is obesity. In another embodiment, the condition being treated or improved is a member selected from the group consisting of: dyslipidemia, hyperlipidemia, hypercholesterolemia, low HDL serum levels, high LDL serum levels (e.g., LDL-C ≥100 mg / dL, ≥130 mg / dL, ≥160 mg / dL), and hypertriglyceridemia (e.g., TG ≥150 mg / dL, ≥160 mg / dL, ≥170 mg / dL). In another embodiment, the condition being treated or improved is hypertension. In another embodiment, the condition being treated or improved is diabetes. In one embodiment, the administered ALK7-binding protein is an ALK7 antagonist. In one embodiment, the applied antagonist ALK7 binding protein is an anti-ALK7 antibody or an ALK7 binding antibody fragment. In another embodiment, the applied antagonist ALK7 binding protein is an anti-ALK7 antibody or an ALK7 binding antibody fragment disclosed herein. In one embodiment, the applied ALK7 binding protein comprises the VH and VL pairs disclosed in Table 1A. In another embodiment, the applied ALK7 binding protein cross-blocks the binding of an antibody to ALK7 comprising the VH and VL sequence pairs disclosed in Table 1A or competes with said antibody for binding to ALK7. In one embodiment, the applied ALK7 binding protein comprises the VH and VL pairs disclosed in Table 1B or Table 3. In another embodiment, the applied ALK7 binding protein cross-blocks the binding of an antibody to ALK7 comprising the VH and VL sequence pairs disclosed in Table 1B or Table 3 or competes with said antibody for binding to ALK7. In one embodiment, the applied ALK7 binding protein comprises the VH and VL pairs disclosed in Table 1A, Table 1B, or Table 3. In another embodiment, the applied ALK7-binding protein cross-blocks the binding of antibodies containing the VH and VL sequence pairs disclosed in Table 1A, Table 1B, or Table 3 to ALK7 or competes with said antibodies for binding to ALK7.

[0040] In one embodiment, this disclosure provides a method of treating or improving obesity or obesity-related symptoms, comprising administering an effective amount of an ALK7-binding protein (e.g., an antagonist ALK7-binding protein such as an antagonist anti-ALK7 antibody) to an obese subject. In one embodiment, the symptom being treated or improved is hypertension, dyslipidemia (e.g., high total cholesterol or high levels of triglycerides), type 2 diabetes, coronary artery disease, stroke, gallbladder disease, osteoarthritis, sleep disorders, breathing problems, cancer (e.g., myeloma (multiple myeloma, plasmacytoma, focal myeloma, or extramedullary myeloma) or ovarian cancer, breast cancer, colon cancer, endometrial cancer, liver cancer, kidney cancer, pancreatic cancer, gastric cancer, uterine cancer, and / or colon cancer), obesity-related gallbladder disease, obesity-related inflammation, obesity-induced sleep apnea, fatty degeneration (fatty liver), glucagonoma, arteriosclerosis, or heart failure. In some embodiments, subjects administering ALK7 binding protein are at risk of developing the following conditions: hypertension, dyslipidemia (e.g., high total cholesterol or high triglyceride levels), type 2 diabetes, coronary artery disease, stroke, gallbladder disease, osteoarthritis, sleep disorders, breathing problems, cancer (e.g., myeloma (multiple myeloma, plasmacytoma, focal myeloma, or extramedullary myeloma) or ovarian cancer, breast cancer, colon cancer, endometrial cancer, liver cancer, kidney cancer, pancreatic cancer, stomach cancer, uterine cancer, or colon cancer), obesity-related gallbladder disease, obesity-related inflammation, obesity-induced sleep apnea, fatty degeneration, glucagonoma, arteriosclerosis, or heart failure. In one embodiment, the administered ALK7 binding protein is an ALK7 antagonist. In one embodiment, the administered antagonist ALK7 binding protein is an anti-ALK7 antibody or an ALK7 binding antibody fragment. In another embodiment, the administered antagonist ALK7 binding protein is an anti-ALK7 antibody or an ALK7 binding antibody fragment disclosed herein. In one embodiment, the applied ALK7 binding protein comprises the VH and VL pairs disclosed in Table 1A. In another embodiment, the applied ALK7 binding protein cross-blocks the binding of an antibody to ALK7 comprising the VH and VL sequence pairs disclosed in Table 1A or competitively binds to ALK7 with said antibody. In one embodiment, the applied ALK7 binding protein comprises the VH and VL pairs disclosed in Table 3. In another embodiment, the applied ALK7 binding protein cross-blocks the binding of an antibody to ALK7 comprising the VH and VL sequence pairs disclosed in Table 3 or competitively binds to ALK7 with said antibody. In one embodiment, the applied ALK7 binding protein comprises the VH and VL pairs disclosed in Table 1A, Table 1B, or Table 3. In another embodiment, the applied ALK7 binding protein cross-blocks the binding of an antibody to ALK7 comprising the VH and VL sequence pairs disclosed in Table 1A, Table 1B, or Table 3 or competitively binds to ALK7 with said antibody.

[0041] In one embodiment, this disclosure provides a method of treating or improving type 2 diabetes or symptoms associated with type 2 diabetes, comprising administering an effective amount of an ALK7-binding protein (e.g., an antagonist ALK7-binding protein such as an antagonist anti-ALK7 antibody) to a diabetic subject. In one embodiment, this disclosure provides a method of treating or improving symptoms associated with type 2 diabetes. In another embodiment, the symptoms are selected from the group consisting of: eye conditions (e.g., glaucoma, cataracts, and retinopathy), cardiovascular diseases (e.g., hypertension, atherosclerosis, myocardial infarction, and stroke), hyperglycemia, peripheral neuropathy, and kidney diseases (e.g., nephropathy). In another embodiment, the subject is at risk of developing type 2 diabetes or symptoms associated with type 2 diabetes. In another embodiment, the subject is at risk of developing: eye conditions (e.g., glaucoma, cataracts, and retinopathy), cardiovascular diseases (e.g., hypertension, atherosclerosis, myocardial infarction, disordered fibrinolysis, and stroke), hyperglycemia, peripheral neuropathy, or kidney diseases (e.g., nephropathy). In one embodiment, the applied ALK7 binding protein is an ALK7 antagonist. In one embodiment, the applied antagonist ALK7 binding protein is an anti-ALK7 antibody or an ALK7 binding antibody fragment. In another embodiment, the applied antagonist ALK7 binding protein is an anti-ALK7 antibody or an ALK7 binding antibody fragment disclosed herein. In one embodiment, the applied ALK7 binding protein comprises the VH and VL pairs disclosed in Table 1A. In one embodiment, the applied ALK7 binding protein comprises the VH and VL pairs disclosed in Table 3. In another embodiment, the applied ALK7 binding protein cross-blocks the binding of antibodies comprising the VH and VL sequence pairs disclosed in Table 1B or Table 3 to ALK7 or competitively binds to ALK7 with said antibodies.

[0042] In one embodiment, this disclosure provides a method of treating or improving a metabolic disease or condition or a symptom associated with a metabolic disease or condition, comprising administering an effective amount of an ALK7 binding protein (e.g., an antagonist ALK7 binding protein such as an antagonist anti-ALK7 antibody) to a subject in need. In one embodiment, the symptom being treated or improved is an alteration in lipid, lipoprotein, or apolipoprotein metabolism. In another embodiment, the metabolic symptom is high plasma triglyceride levels, hypertension, dyslipidemia, high fasting blood glucose, or low HDL cholesterol levels. In another embodiment, the symptom being treated or improved is atherosclerosis, arteriosclerosis, or endothelial dysfunction. In one embodiment, the symptom being treated or improved is chronic inflammation. In another embodiment, the symptom being treated or improved is non-alcoholic fatty liver disease (e.g., fatty liver and / or NASH). In one embodiment, the administered ALK7 binding protein is an ALK7 antagonist. In one embodiment, the administered antagonist ALK7 binding protein is an anti-ALK7 antibody or an ALK7 binding antibody fragment. In another embodiment, the applied antagonist ALK7-binding protein is an anti-ALK7 antibody or an ALK7-binding antibody fragment disclosed herein. In one embodiment, the applied ALK7-binding protein comprises the VH and VL pairs disclosed in Table 1A. In another embodiment, the applied ALK7-binding protein cross-blocks the binding of an antibody to ALK7 comprising the VH and VL sequence pairs disclosed in Table 1A or competes with said antibody for binding to ALK7. In one embodiment, the applied ALK7-binding protein comprises the VH and VL pairs disclosed in Table 1B or Table 3. In another embodiment, the applied ALK7-binding protein cross-blocks the binding of an antibody to ALK7 comprising the VH and VL sequence pairs disclosed in Table 1B or Table 3 or competes with said antibody for binding to ALK7.

[0043] In one embodiment, this disclosure provides a method of treating or improving insulin resistance or symptoms associated with insulin resistance, comprising administering an effective amount of an ALK7-binding protein (e.g., an antagonist ALK7-binding protein such as an antagonist anti-ALK7 antibody) to a subject in need. In another embodiment, the symptom being treated or improved is associated with impaired glucose tolerance or hyperglycemia. In another embodiment, the symptom being treated or improved is associated with hypertension or atherosclerosis. In another embodiment, the symptom being treated or improved is a member selected from the group consisting of: dyslipidemia, hyperlipidemia, hypercholesterolemia, low HDL serum levels, high LDL serum levels (e.g., LDL-C ≥100 mg / dL, ≥130 mg / dL, ≥160 mg / dL), and hypertriglyceridemia (e.g., TG ≥150 mg / dL, ≥160 mg / dL, ≥170 mg / dL). In one embodiment, the administered ALK7-binding protein is an ALK7 antagonist. In one embodiment, the applied antagonist ALK7 binding protein is an anti-ALK7 antibody or an ALK7 binding antibody fragment. In another embodiment, the applied antagonist ALK7 binding protein is an anti-ALK7 antibody or an ALK7 binding antibody fragment disclosed herein. In one embodiment, the applied ALK7 binding protein comprises the VH and VL pairs disclosed in Table 1A. In another embodiment, the applied ALK7 binding protein cross-blocks the binding of antibodies to ALK7 comprising the VH and VL sequence pairs disclosed in Table 1A or competes with said antibodies for binding to ALK7. In one embodiment, the applied ALK7 binding protein comprises the VH and VL pairs disclosed in Table 1B or Table 3. In another embodiment, the applied ALK7 binding protein cross-blocks the binding of antibodies to ALK7 comprising the VH and VL sequence pairs disclosed in Table 1B or Table 3 or competes with said antibodies for binding to ALK7.

[0044] In one embodiment, this disclosure provides a method of treating or improving a disease or condition of the eye, nervous system, kidney, lung, and / or liver, or a related symptom, comprising administering an effective amount of ALK7 binding protein (e.g., an antagonist ALK7 binding protein such as an antagonist anti-ALK7 antibody) to a subject in need. In one embodiment, the symptom being treated or improved is inflammation. In one embodiment, the symptom being treated or improved is kidney disease (e.g., diabetic nephropathy, arteriosclerosis of the renal arteries), or kidney failure. In another embodiment, the symptom being treated or improved is chronic inflammation. In another embodiment, the symptom being treated or improved is inflammation of adipose tissue. In another embodiment, the symptom being treated or improved is liver inflammation. In another embodiment, the symptom being treated or improved is NAFLD (e.g., fatty liver and / or NASH). In some embodiments, the subject administering the ALK7 binding protein is at risk of developing a disease or condition of the kidney, lung, or liver. In some embodiments, the subject administering the ALK7 binding protein is at risk of developing kidney disease. In some embodiments, the subject administering the ALK7 binding protein is at risk of developing kidney disease. In one embodiment, the subject is at risk of developing chronic inflammation. In one embodiment, the subject is at risk of developing inflammation of adipose tissue. In another embodiment, the subject is at risk of developing liver inflammation. In one embodiment, the administered ALK7 binding protein is an ALK7 antagonist. In one embodiment, the administered antagonist ALK7 binding protein is an anti-ALK7 antibody or an ALK7 binding antibody fragment. In another embodiment, the administered antagonist ALK7 binding protein is an anti-ALK7 antibody or an ALK7 binding antibody fragment disclosed herein. In one embodiment, the administered ALK7 binding protein comprises the VH and VL pairs disclosed in Table 1A. In another embodiment, the administered ALK7 binding protein cross-blocks antibodies that bind to ALK7 or competitively bind to ALK7 with the VH and VL sequence pairs disclosed in Table 1A. In one embodiment, the administered ALK7 binding protein comprises the VH and VL pairs disclosed in Table 1B or Table 3. In another embodiment, the applied ALK7-binding protein cross-blocking antibody includes the VH and VL sequence pairs disclosed in Table 1B or Table 3 binding to ALK7 or competing with the antibody for binding to ALK7.

[0045] In one embodiment, this disclosure provides a method of treating or improving cardiovascular disease or condition or symptoms associated with cardiovascular disease or condition, comprising administering an effective amount of ALK7 binding protein (e.g., an antagonist ALK7 binding protein such as an antagonist anti-ALK7 antibody) to a subject in need. In one embodiment, the condition being treated or improved is coronary artery disease, congestive heart failure, restenosis, stroke, peripheral vascular disease, microvascular disease, disordered fibrinolysis, or atherosclerosis. In one embodiment, the subject administering the ALK7 binding protein is at risk of developing coronary artery disease, congestive heart failure, restenosis, stroke, peripheral vascular disease, microvascular disease, or atherosclerosis. In one embodiment, the condition being treated or improved is hypertension (e.g., blood pressure >130 / 80 mmHg at rest). In one embodiment, the subject administering the ALK7 binding protein is at risk of developing hypertension. In one embodiment, the condition being treated or improved is atherosclerosis. In one embodiment, the subject administering the ALK7 binding protein is at risk of developing atherosclerosis. In one embodiment, the applied ALK7 binding protein is an ALK7 antagonist. In one embodiment, the applied antagonist ALK7 binding protein is an anti-ALK7 antibody or an ALK7 binding antibody fragment. In another embodiment, the applied antagonist ALK7 binding protein is an anti-ALK7 antibody or an ALK7 binding antibody fragment disclosed herein. In one embodiment, the applied ALK7 binding protein comprises the VH and VL pairs disclosed in Table 1A. In another embodiment, the applied ALK7 binding protein cross-blocks the binding of an antibody to ALK7 comprising the VH and VL sequence pairs disclosed in Table 1A or competitively binds to ALK7 with said antibody. In one embodiment, the applied ALK7 binding protein comprises the VH and VL pairs disclosed in Table 1B. In another embodiment, the applied ALK7 binding protein cross-blocks the binding of an antibody to ALK7 comprising the VH and VL sequence pairs disclosed in Table 1B or competitively binds to ALK7 with said antibody. In one embodiment, the applied ALK7 binding protein comprises the VH and VL pairs disclosed in Table 3. In another embodiment, the applied ALK7-binding protein cross-blocking antibody includes the VH and VL sequence pairs disclosed in Table 3 binding to ALK7 or competing with the antibody for binding to ALK7. Attached Figure Description

[0046] Figure 1The amount of fat change in high-fat diet (HFD) mice treated with TBS and ALK7 mAb is shown. Changes in fat mass are relative to baseline before ALK7 Ab or TBS treatment. Treatment with ALK7 mAb (i.e., J02, K02, G05, CO3, and L02) significantly reduced fat mass in HFD mice. * indicates p > 0.001 relative to HFD + TBS.

[0047] Figure 2 The amount of change in lean body mass in high-fat diet (HFD) mice treated with TBS and ALK7 mAb is shown. The amount of change in lean body mass is relative to baseline before ALK7 Ab or TBS treatment. Treatment with ALK7 mAb (i.e., J02, K02, G05, CO3, and L02) did not change lean body mass in HFD mice. Detailed Implementation

[0048] This disclosure provides isolated and / or recombinant ALK7-binding proteins. In some embodiments, the ALK7-binding protein specifically binds to ALK7. In other embodiments, the ALK7-binding protein is an anti-ALK7 antibody. Nucleic acid encoding the ALK7-binding protein, a vector containing said nucleic acid, and a host cell are also provided, as well as methods for preparing and using the ALK7-binding protein. The provided ALK7-binding protein has uses for diagnosing, treating, and / or improving diseases or symptoms associated with increased ALK7 expression and / or signaling. Such uses include, but are not limited to, prevention and / or improvement of obesity (e.g., abdominal obesity); overweight; insulin resistance; metabolic syndrome and other metabolic diseases or conditions; lipid disorders such as low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia, or dyslipidemia; lipoprotein aberrations; reduced triglycerides; inflammation (e.g., liver inflammation and / or adipose tissue inflammation), fatty liver disease; non-alcoholic fatty liver disease; hyperglycemia; impaired glucose tolerance (IGT); hyperinsulinemia; high cholesterol (e.g., high LDL levels and hypercholesterolemia); cardiovascular diseases such as heart disease including coronary artery disease, congestive heart failure, stroke, peripheral vascular disease. Diseases, atherosclerosis; arteriosclerosis and hypertension; Syndrome X; restenosis; neuropathy; retinopathy; neurodegenerative diseases; endothelial dysfunction, respiratory dysfunction, kidney disease (e.g., nephropathy); pancreatitis; polycystic ovary syndrome; elevated uric acid levels; hemochromatosis (iron overload); acanthosis nigricans (dark spots on the skin); and cancers (e.g., myeloma (multiple myeloma, plasmacytoma, focal myeloma, or extramedullary myeloma) or ovarian cancer, breast cancer, colon cancer, endometrial cancer, liver cancer, kidney cancer, pancreatic cancer, stomach cancer, uterine cancer, and / or colon cancer); and those associated with one or more of the above diseases or conditions or with overweight (e.g., 25 kg / m²). 2(BMI) or other conditions / symptoms associated with excessive body fat.

[0049] definition

[0050] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. For example, *Concise Dictionary of Biomedicine and Molecular Biology*, Juo, Pei-Show, 2nd edition, 2002, CRC Press; *The Dictionary of Cell and Molecular Biology*, 3rd edition, 1999, Academic Press; and *The Oxford Dictionary of Biochemistry and Molecular Biology*, Revised, 2000, Oxford University Press, provide a general interpretation of many of the terms used in this disclosure for those skilled in the art. The headings provided herein are not intended to limit the various embodiments which can be obtained by referring to the entire specification. Furthermore, terms that will be defined below are more fully defined by referring to the full text of the specification.

[0051] Unless the context in which the terms are used explicitly specifies otherwise, the terms “an,” “a,” and “the” include plural indicators. The terms “an” (or “a type”), “an or more,” and “at least one” are used interchangeably herein. Furthermore, when used herein, “and / or” is considered to refer to a specific disclosure of each of two or more specified features or components having or not having the other. Thus, the term “and / or” as used herein, such as in phrases like “A and / or B,” is intended to include “A and B,” “A or B,” “A” (alone), and “B” (alone). Similarly, the term “and / or” as used herein, such as in phrases like “A, B, and / or C,” is intended to cover each of the following embodiments: 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 (alone); B (alone); and C (alone).

[0052] The term “comprise” generally means to include, that is, to allow the presence of one or more features or components. Wherever embodiments are described in the language “comprising” throughout this document, other similar embodiments described in the terms “consisting of” and / or “substantially consisting of” are also provided.

[0053] The terms “about” and “approximately” used in conjunction with numerical values ​​throughout the specification and claims refer to a range of accuracy familiar and acceptable to those skilled in the art. Generally, such a range of accuracy is ±10%. Optionally and specifically in biological systems, the terms “about” and “approximately” may mean a value on the order of preferably ≤5 times and more preferably ≤2 times the given value.

[0054] The range of numbers includes numbers within a defined range.

[0055] ALK7 binding proteins are proteins that specifically bind to ALK7, preferably to the extracellular domain of ALK7.

[0056] The terms “ALK7” and “ALK7 receptor” are used interchangeably and refer to ALK7 (also referred to in the literature as ACVRLK7, activin A receptor, type I, ACVR-1C, activin receptor-like kinase 7, and EC 2.7.11). A reference sequence for human ALK7 is provided in NCBI reference sequence NP_001104501.1. The provided ALK7 binding protein binds to the extracellular domain of human ALK7 corresponding to the amino acid sequence of SEQ ID NO:86. A reference sequence for rat ALK7 is provided in NCBI reference sequence P70539. In some embodiments, the provided ALK7 binding protein binds to the extracellular domain of rat ALK7 corresponding to the amino acid sequence of SEQ ID NO:87.

[0057] The terms “compete” or “competes” when used in the context of ALK7 binding proteins (e.g., neutralizing antibodies) refer to competition between antigen-binding proteins, as determined by an assay in which the tested antigen-binding protein (e.g., an anti-ALK7 antibody or its ALK7 binding fragment) prevents or inhibits the specific binding of a reference antigen-binding protein (e.g., a ligand or reference antibody) to a common antigen (e.g., the extracellular domain of ALK7 or a fragment thereof). A variety of competitive binding assays can be used, such as: solid-phase direct or indirect radioimmunoassays (RIA) (see, for example, Moldenhauer et al., Scand. J. Immunol. 32:77-82 (1990) and Morel et al., Molec. Immunol. 25:7-15 (1988)), solid-phase direct or indirect enzyme immunoassays (EIA), solid-phase direct biotin-avidin EIA (see, for example, Cheung et al., Virology 176:546-552 (1990) and Kirkland et al., J. Immunol. 137:3614-3619 (1986)), and sandwich competitive assays (see, for example, Stahli et al., Methods in Enzymology 92:242-253 (1983)). Typically, this assay involves using purified antigens bound to a solid surface or cell carrying either an unlabeled test antigen-binding protein or a labeled reference antigen-binding protein.

[0058] Competitive inhibition can be measured by determining the amount of a marker bound to a solid surface or cell in the presence of the test antigen-binding protein. Typically, an excess of the test antigen-binding protein is present. Antigen-binding proteins identified by competitive assays (competitive antigen-binding proteins) include ALK7-binding proteins that bind to the same epitope as a reference ALK7-binding protein, as well as ALK7-binding proteins that bind to a neighboring epitope sufficiently close to the epitope bound by the reference ALK7-binding protein to create steric hindrance. Typically, when an excess of a competitive ALK7-binding protein is present, it will inhibit the specific binding of the reference ALK7-binding protein to ALK7 by at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%. In some cases, the competitive antigen-binding protein inhibits the specific binding of the reference ALK7-binding protein by at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.

[0059] When used in the context of ALK7 proteins, the term "epitope" refers to an ALK7 protein determinant (e.g., human ALK7 or mouse ALK7) capable of binding to an ALK7-binding protein (e.g., an antibody) of this disclosure. Epitopes typically consist of chemically active surface groups of a molecule (such as amino acids or sugar side chains) and generally possess specific three-dimensional structural features, as well as specific charge features. The difference between conformational and non-conformational epitopes is that binding to conformational epitopes is lost in the presence of denaturing solvents, while binding to non-conformational epitopes is not lost. ALK7 epitopes bound by ALK7-binding proteins can be identified using techniques known in the art.

[0060] The antigen-binding proteins disclosed herein, such as anti-ALK7 binding antibodies and their ALK7-binding fragments, variants, or derivatives, can be described or designated according to one or more epitopes or one or more portions of an antigen, such as a target polysaccharide that they recognize or specifically bind to. For example, a portion of ALK7 that specifically interacts with the antigen-binding domain of an ALK7-binding protein disclosed herein is an "epitaph." Epitopes can be formed from consecutive or discontinuous amino acids juxtaposed by the ternary folding of a protein. Epitopes formed from consecutive amino acids are generally retained upon exposure to denaturing solvents, while epitopes formed by ternary folding are generally lost upon treatment with denaturing solvents. Epitope determinants may include chemically active surface groups of a molecule (such as amino acids, sugar side chains, phosphoryl groups, or sulfonyl groups) and may have specific three-dimensional structural features and / or specific charge features. Epitopes typically comprise 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, or 35 amino acids with a unique spatial configuration. Epitopes can be routinely determined using methods known in the art.

[0061] The terms “inhibit,” “block,” “reduce,” “lower,” “suppress,” “antagonize,” and “neutralize” are used interchangeably and refer to any statistically significant reduction in activity (e.g., ALK7 ligand binding and / or ALK7 signaling), including complete blockade of activity. For example, “inhibition,” “suppression,” or “antagonism” can refer to a reduction in activity of approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to a control.

[0062] In some implementations, the terms "reduction," "inhibition," or "antagonism" can refer to the ability of an ALK7-binding protein, such as an antibody or its ALK7-binding fragment, to statistically significantly (e.g., p-value less than or equal to 0.05) reduce the phosphorylation of one or more Smads (e.g., Smad2 and / or Smad3) induced by contacting cells expressing ALK7 and ActrIIA / B with ALK7 ligands (such as GDF1, GDF3, GDF8, activin B, activin A / B, and / or Nodal). Cells expressing ALK7 can be naturally occurring cells or cell lines, or can be recombinantly generated by introducing nucleic acids encoding ALK7 into host cells. In one embodiment, an ALK7-binding protein, such as an ALK7 antibody or an ALK7-binding fragment thereof, antagonizes (reduces) ALK7 ligand-mediated phosphorylation 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 about 100%, as determined, for example, by Western blotting followed by detection with an antiphosphotyrosine antibody, or by an ELISA (e.g., P-Smad ELISA) or Smad-dependent reporter gene assay performed using techniques described herein or otherwise known in the art. In one embodiment, the ALK7-binding protein antagonizes (reduces) ALK7-mediated inhibition of lipolysis in adipocytes. In one embodiment, the ALK7-binding protein is an ALK7 antagonist and antagonizes ALK7-mediated lipolysis inhibition in white adipocytes by 5% to 100%, 10% to 95%, 10% to 90%, 10% to 85%, 10% to 80%, 10% to 75%, 10% to 70%, 10% to 75%, 10% to 70%, 10% to 60%, 10% to 55%, 10% to 50%, or 10% to 45%, as determined in a lipolysis assay. In another embodiment, the ALK7-binding protein reduces or decreases ALK7-mediated lipolysis inhibition in white adipocytes by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or about 100%, as determined in a lipolysis assay. In some embodiments, the lipolysis assay is performed in the presence of one or more ALK7 ligands. In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal.

[0063] In one embodiment, the ALK7-binding protein is an ALK7 antagonist and antagonizes ALK7-mediated lipolysis inhibition in white and / or brown adipocytes by 5% to 100%, 10% to 95%, 10% to 90%, 10% to 85%, 10% to 80%, 10% to 75%, 10% to 70%, 10% to 75%, 10% to 60%, 10% to 55%, 10% to 50%, or 10% to 45%, as determined in a lipolysis assay. In another embodiment, the ALK7-binding protein reduces or decreases ALK7-mediated lipolysis inhibition in white and / or brown adipocytes by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or about 100%, as determined in a lipolysis assay. In some embodiments, the lipolysis assay is performed in the presence of one or more ALK7 ligands. In other embodiments, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal.

[0064] The terms “increase,” “enhance,” and “agonist” are used interchangeably and refer to any statistically significant increase in activity (e.g., ALK7 ligand binding and / or ALK7 signaling). For example, “increase” or “enhancement” can refer to an increase of approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% in activity compared to a control.

[0065] In some embodiments, ALK7 binding increases lipolysis in cells. In some embodiments, the ALK7-binding protein increases lipolysis in cells by at least 5% to 100%, 10% to 95%, 10% to 90%, 10% to 85%, 10% to 80%, 10% to 75%, 10% to 70%, 10% to 75%, 10% to 60%, 10% to 55%, 10% to 50%, or 10% to 45%, as determined in a lipolysis assay. In some embodiments, the ALK7-binding protein increases lipolysis in adipocytes. In some embodiments, the ALK7-binding protein increases lipolysis in adipocytes by at least 5% to 100%, 10% to 95%, 10% to 90%, 10% to 85%, 10% to 80%, 10% to 75%, 10% to 70%, 10% to 75%, 10% to 70%, 10% to 60%, 10% to 55%, 10% to 50%, or 10% to 45%, as determined in a lipolysis assay. In some embodiments, the lipolysis assay is performed in the presence of one or more ALK7 ligands. In other embodiments, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein increases lipolysis in white or brown adipocytes.

[0066] In some embodiments, ALK7-binding protein increases lipolysis in white adipocytes. In some embodiments, ALK7-binding protein increases lipolysis in white adipocytes by at least 5% to 100%, 10% to 95%, 10% to 90%, 10% to 85%, 10% to 80%, 10% to 75%, 10% to 70%, 10% to 75%, 10% to 60%, 10% to 55%, 10% to 50%, or 10% to 45%, as determined in a lipolysis assay. In some embodiments, the lipolysis assay is performed in the presence of one or more ALK7 ligands. In other embodiments, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal.

[0067] In some embodiments, ALK7-binding proteins increase lipolysis in brown adipocytes. In some embodiments, ALK7-binding proteins increase lipolysis in brown adipocytes by at least 5% to 100%, 10% to 95%, 10% to 90%, 10% to 85%, 10% to 80%, 10% to 75%, 10% to 70%, 10% to 75%, 10% to 60%, 10% to 55%, 10% to 50%, or 10% to 45%, as determined in a lipolysis assay. In some embodiments, the lipolysis assay is performed in the presence of one or more ALK7 ligands. In other embodiments, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal.

[0068] In some embodiments, ALK7-binding proteins increase lipolysis in white and brown adipocytes. In some embodiments, ALK7-binding proteins increase lipolysis in white and brown adipocytes by at least 5% to 100%, 10% to 95%, 10% to 90%, 10% to 85%, 10% to 80%, 10% to 75%, 10% to 70%, 10% to 75%, 10% to 60%, 10% to 55%, 10% to 50%, or 10% to 45%, as determined in a lipolysis assay. In some embodiments, the lipolysis assay is performed in the presence of one or more ALK7 ligands. In other embodiments, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal.

[0069] In another embodiment, the ALK7-binding protein increases lipolysis in white adipocytes by at least 5% to 100%, 10% to 95%, 10% to 90%, 10% to 85%, 10% to 80%, 10% to 75%, 10% to 70%, 10% to 75%, 10% to 60%, 10% to 55%, 10% to 50%, or 10% to 45%, as determined using standard techniques and conditions in a lipolysis assay performed in the presence of activin B (50 ng / ml) (e.g., as described in the examples herein). In another embodiment, the ALK7-binding protein reduces or decreases ALK7-mediated lipolysis inhibition in white adipocytes by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% or about 100%, as determined using standard techniques and conditions in a lipolysis inhibition assay. The lipolysis assay was performed in the presence of activin B (50 ng / ml) (e.g., as described in the examples herein).

[0070] In another embodiment, the ALK7 binding protein increases lipolysis in white and / or brown adipocytes by at least 5% to 100%, 10% to 95%, 10% to 90%, 10% to 85%, 10% to 80%, 10% to 75%, 10% to 70%, 10% to 75%, 10% to 70%, 10% to 60%, 10% to 55%, 10% to 50%, or 10% to 45%, as determined using standard techniques and conditions in a lipolysis assay performed in the presence of activin B (50 ng / ml) (e.g., as described in the examples herein). In another embodiment, the ALK7-binding protein reduces or decreases ALK7-mediated lipolysis inhibition in white adipocytes by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or about 100%, as determined using standard techniques and conditions in the lipolysis inhibition assay. The lipolysis assay is performed in the presence of activin B (50 ng / ml) (e.g., as described in the examples herein).

[0071] In some embodiments, ALK7-binding protein increases glycerol production in adipocytes. In some embodiments, ALK7-binding protein increases glycerol production in adipocytes by at least 5% to 100%, 10% to 95%, 10% to 90%, 10% to 85%, 10% to 80%, 10% to 75%, 10% to 70%, 10% to 75%, 10% to 60%, 10% to 55%, 10% to 50%, or 10% to 45%, as determined in a lipolysis assay. In some embodiments, the lipolysis assay is performed in the presence of one or more ALK7 ligands. In some embodiments, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, ALK7-binding protein increases glycerol production in white or brown adipocytes.

[0072] The terms “antibody” and “immunoglobulin” are used interchangeably herein and include both full-length antibodies and their antigen-binding fragments or single chains. A typical antibody consists of at least two heavy chains (H) and two light chains (L) linked together by disulfide bonds. Each heavy chain contains a heavy chain variable region (VH) and a heavy chain constant region. The heavy chain constant region contains three domains: CHI, CH2, and CH3. Each light chain contains a light chain variable region (VL) and a light chain constant region. The light chain constant region contains 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 consists of three CDRs and four FWs arranged in the following order from the amino terminus to the carboxyl terminus: FW1, CDR1, FW2, CDR2, FW3, CDR3, FW4. The variable regions of the heavy and light chains contain binding domains that interact with the antigen. The constant region of an antibody can mediate the binding of an immunoglobulin to a host tissue or factor, including various immune system cells (e.g., effector cells) or the first component (Clq) of the classical complement system. Exemplary antibodies include typical antibodies, scFvs, and combinations thereof, wherein the scFv is covalently linked (e.g., via peptide bonds or via chemical linkers) to the N-terminus or C-terminus of the heavy and / or light chains of the typical antibody, or intercalated within the heavy and / or light chains of the typical antibody.

[0073] The terms "antibody" and "immunoglobulin" encompass complete polyclonal antibodies, complete monoclonal antibodies, antibody fragments (such as Fab, Fab', F(ab')2, and Fv fragments), single-chain Fv (scFv) derivatives and mutants, multispecific antibodies such as bispecific antibodies, chimeric antibodies, humanized antibodies, human antibodies, fusion proteins containing the antigenic determinant of an antibody, and any other modified immunoglobulin molecule containing an antigen recognition site, provided that the antibody exhibits the desired binding activity. Antibodies can be any of the five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM (designated α, δ, ε, γ, and μ, respectively, based on the identification of their heavy chain constant domains), or their subclasses (isotypes) (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2). Different classes of immunoglobulins have different and well-known subunit structures and three-dimensional conformations. Antibodies can be naked antibodies or conjugated to other molecules such as toxins, radioisotopes, etc. The term "IgG" refers to polypeptides belonging to a class of antibodies encoded by the immunoglobulin γ gene, which is essentially identified. In humans, this class includes IgG1, IgG2, IgG3, and IgG4. In mice, this class includes IgG1, IgG2a, IgG2b, and IgG3.

[0074] The terms “ALK7 antibody,” “ALK7-bound antibody,” or “anti-ALK7 antibody” refer to antibodies that can bind to ALK7 with sufficient affinity, such that the antibodies can be used as therapeutic agents or diagnostic agents targeting ALK7, respectively.

[0075] When used in the context of the ALK7 protein, "specific binding" generally means the ability of a binding protein, such as an antibody, to bind to ALK7 (e.g., human ALK7, preferably the extracellular domain of ALK7) with a greater affinity than the binding protein binds to an unrelated control protein. In some embodiments, the control protein is egg white lysozyme. Preferably, the binding protein binds to ALK7 with an affinity at least 100, 500, or 1000 times that for the control protein. Preferably, the binding protein has an affinity ≤1 x 10⁻⁶ for human ALK7. -7 M or ≤1X10 -8 The binding affinity is measured using a binding assay known in the art. In some embodiments, the binding affinity is measured using a radioimmunoassay (RIA) or... (For example, using ALK7 as the analyte and ALK7 binding protein as the ligand, or vice versa) to measure.

[0076] In some implementations, the ALK7-binding protein (e.g., an anti-ALK7 antibody) binds to unrelated, non-ALK7 proteins to less than about 10% of the binding between the ALK7-binding protein and ALK7, as, for example, by radioimmunoassay (RIA). (Using recombinant ALK7 as the analyte and ALK7-binding protein as the ligand, or vice versa), kinetic exclusion assay Or measured by other binding assays known in the art. In some embodiments, the ALK7 binding protein is a dissociation constant (K0) having a value of ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, ≤0.1 nM, ≤10 pM, ≤1 pM, or ≤0.1 pM. D () full-length antibody or ALK7-binding antibody fragment.

[0077] The term "antigen-binding antibody fragment" (e.g., "ALK7-binding antibody fragment") refers to a fragment containing all or a portion of the antigen-binding variable region (e.g., CDR3) of a complete antibody. It is known that the antigen-binding function of an antibody can be performed by a fragment of a full-length antibody. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments, linear antibodies, single-chain antibodies, and multispecific antibodies formed from one or more antibody fragments. In some embodiments, this disclosure provides an ALK7-binding antibody fragment, wherein the antibody fragment is a Fab fragment, Fab' fragment, F(ab')2 fragment, Fv fragment, dimeric or single-chain antibody molecule.

[0078] The Fc region comprises a polypeptide containing the constant region of an antibody excluding the first constant region immunoglobulin domain. Therefore, Fc refers to the last two constant regions of the immunoglobulin domains of IgA, IgD, and IgG, and the last three constant regions of the immunoglobulin domains of IgE and IgM, along with the flexible hinge N-terminus of these domains. For IgA and IgM, Fc may include the J chain. For IgG, Fc contains the immunoglobulin domains Cγ2 and Cγ3, and the hinge between Cγ1 and Cγ2. While the boundaries of the Fc region may vary, the generally defined human IgG heavy chain Fc region contains residues C226 or P230 at its C-terminus, numbered according to the EU index as listed 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 alone or in the case of a whole antibody, antibody fragment, or Fc fusion protein. Polymorphism has been observed at several different Fc positions (including, but not limited to, positions 270, 272, 312, 315, 356 and 358 via EU index numbers), and therefore subtle differences may exist between the presented sequences and those in the prior art.

[0079] "Monoclonal antibody" refers to a homogeneous group of antibodies involved in the highly specific recognition and binding of a single antigenic determinant or epitope. This contrasts with polyclonal antibodies, which typically consist of different antibodies targeting different antigenic determinants. The term "monoclonal antibody" encompasses full-length and complete monoclonal antibodies, as well as antibody fragments containing antibody moieties (such as Fab, Fab', F(ab')2, and Fv), single-chain (scFv) mutants, and fusion proteins), and any other modified immunoglobulin molecules containing antigen recognition sites. Monoclonal antibodies can be prepared in any number of ways, including but not limited to hybridomas, phage selection, recombinant expression, and transgenic animals.

[0080] The term "chimeric antibody" refers to an antibody whose amino acid sequence of an immunoglobulin molecule is derived from two or more species. Typically, the variable regions of both the light and heavy chains correspond to the variable regions of an antibody derived from one mammalian species (e.g., mouse, rat, rabbit, etc.) that has the desired antigen-binding specificity, affinity, and / or ability, while the constant regions are sequence-homogeneous with those of an antibody derived from another species (typically human) to avoid triggering an immune response in said species.

[0081] The term "humanized antibody" refers to an antibody derived from a non-human (e.g., mouse) immunoglobulin that has been engineered to contain a smaller, preferably minimal, non-human (e.g., mouse) sequence. Typically, a humanized antibody is a human immunoglobulin in which residues from the CDR are replaced by residues from the CDR of a non-human species (e.g., mouse, rat, rabbit, or hamster) having the desired antigen-binding specificity, affinity, and / or capability (Jones, Nature 321:522-525 (1986); Riechmann, Nature 332:323-327 (1988); Verhoeyen, Science 239:1534-1536 (1988)). In some cases, the Fv framework region (FW) residues of a human immunoglobulin are replaced by corresponding residues from an antibody derived from a non-human species having the desired antigen-binding specificity, affinity, and / or capability. Humanized antibodies can be further modified by substitution of additional residues within the Fv framework region and / or within the replaced non-human residues to improve and optimize antibody specificity, affinity, and / or potency. Generally, humanized antibodies will substantially contain at least one and typically two or three variable domains containing all or substantially all CDR regions corresponding to non-human immunoglobulins, and all or substantially all FR regions being those of the human immunoglobulin common sequence. Humanized antibodies may also contain at least a portion (Fc) of immunoglobulin constant regions or domains, typically a portion of human immunoglobulins. Examples of methods for generating humanized antibodies are described in U.S. Patent Nos. 5,225,539 and 5,639,641.

[0082] The term "human antibody" refers to an antibody produced by humans or an antibody having an amino acid sequence corresponding to an antibody produced by humans, prepared using any technique known in the art. The term "human antibody" includes full-length antibodies, fragments thereof, and / or antibodies containing at least one human heavy chain and / or light chain polypeptide, such as antibodies containing mouse light chains and human heavy chain polypeptides.

[0083] "Antagonist," "blocking," or "neutralizing" binding proteins are binding proteins that inhibit or reduce the activity of the antigen they bind to, such as ALK7. In some embodiments, antagonist ALK7 binding proteins reduce or inhibit the polymerization of ALK7 and ActRII receptors (e.g., ActRIIA or ActRIIB), GDF1, GDF3, GDF8, activin B, activin A / B, and / or Nodal. In some embodiments, antagonist ALK7 binding proteins substantially or completely inhibit ALK7 activity. In some embodiments, ALK7 activity is reduced by 10%, 20%, 30%, 50%, 70%, 80%, 90%, 95%, or 100%. In some embodiments, antagonist ALK7 binding proteins are anti-ALK7 antibodies, such as full-length antibodies or ALK7-binding antibody fragments. In another embodiment, the antagonist anti-ALK7 antibody inhibits or reduces the activity of ALK7 by at least 10%, 20%, 30%, 50%, 70%, 80%, 90%, 95%, or even 100%.

[0084] "Binding affinity" generally refers to the strength of the sum 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 the intrinsic binding affinity that reflects a 1:1 interaction between the members of a binding pair (e.g., antibody and antigen). The affinity of molecule X for its partner Y can generally be determined by the dissociation constant (K). D Affinity can be measured by commonly used methods known in the art, including those described herein, and can be used for the purposes of this disclosure.

[0085] "Efficacy" is a measure of the drug activity of a compound, expressing the amount of compound required to produce a given strength of action. It refers to the amount of compound required to achieve a defined biological effect; the smaller the dose required, the more potent the drug. Unless otherwise stated, efficacy is usually expressed as IC50 in nM. 50 Value. IC 50 This is the median inhibitory concentration of ALK7-binding proteins (e.g., anti-ALK7 antibodies). In functional assays, IC50 represents the median inhibitory concentration of ALK7-binding proteins. 50 It is the concentration that reduces the biological response by 50% of its maximum. In ligand-receptor binding studies, IC50... 50 It is a concentration that reduces the ligand-receptor binding level by 50%. IC 50The improvement in potency of the antibody or other binding protein provided herein compared to a reference anti-ALK7 antibody or other ALK7 binding protein can be at least 2, 4, 6, 8, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, or at least 180 times.

[0086] "Antibody-dependent cell-mediated cytotoxicity" or "ADCC" refers to a form of cytotoxicity in which secreted Ig binding to Fc receptors (FcRs) present on certain cytotoxic cells (e.g., natural killer (NK) cells, neutrophils, and macrophages) enables these cytotoxic effector cells to specifically bind to target cells carrying antigens and subsequently kill the target cells with cytotoxins. Specific, high-affinity IgG antibodies directed to the surface of target cells "arm" the cytotoxic cells and are absolutely necessary for this type of killing. Target cell lysis occurs extracellularly, requiring direct cell-to-cell contact and not involving complement. It is conceivable that other proteins containing Fc regions, besides antibodies, with the ability to specifically bind to target cells carrying ALK7, specifically Fc fusion proteins, would be able to achieve cell-mediated cytotoxicity. For simplicity, cell-mediated cytotoxicity resulting from the activity of Fc fusion proteins is also referred to herein as ADCC activity.

[0087] The isolated ALK7-binding proteins (e.g., ALK7 antibodies, including ALK7 binding fragments, variants, and derivatives thereof), polynucleotides, vectors, cells, or compositions are proteins (e.g., antibodies), polynucleotides, vectors, cells, or compositions that are not found in nature. Isolated proteins, polynucleotides, vectors, cells, or compositions include those that have been purified to the point that they no longer exist in the form they are found in nature. In some embodiments, the isolated proteins, polynucleotides, vectors, cells, or compositions are substantially pure. The isolated proteins and isolated nucleic acids do not contain, or are substantially free of, substances they naturally associate with, such as other polypeptides or nucleic acids that they are present with in their natural environment or in the environment in which they are prepared (when such preparation is performed by recombinant DNA techniques practiced in vitro or in vivo) (e.g., cell cultures). Proteins and nucleic acids can be formulated with diluents or adjuvants and are still used for practical purposes of separation—for example, if used to coat microtiter plates used in immunoassays, proteins will typically be mixed with gelatin or other carriers, or when used for diagnostic or therapeutic purposes, proteins will be mixed with pharmaceutically acceptable carriers or diluents.

[0088] The terms “subject,” “individual,” “animal,” “patient,” and “mammal” refer to any subject, specifically a mammalian subject, for whom diagnosis, prognosis, or treatment is desired. Mammal subjects include, but are not limited to, humans, non-human primates, livestock, farm animals, rodents, etc., who will be recipients of a particular treatment.

[0089] The term "pharmaceutical composition" refers to a formulation in which the biological activity of the active ingredient is permitted and which does not contain any additional components at concentrations that would have unacceptable toxicity to a subject administering the composition. Such a composition may be sterile.

[0090] An “effective amount” of a polypeptide (e.g., antigen-binding protein, including antibodies) disclosed herein is an amount sufficient to perform the stated purpose. Depending on the stated purpose, the “effective amount” may be determined empirically and in a conventional manner. The term “therapeutic effective amount” refers to an amount of polypeptide (e.g., antigen-binding protein, including antibodies) or other medicine that is effective in “treating” a disease or condition in a subject (e.g., a mammal, such as a human) and provides some improvement or benefit to a subject having said disease or condition. Thus, a “therapeutic effective” amount is an amount that provides some relief, reduction, and / or decrease in at least one clinical symptom of an ALK7-mediated disease or condition. Clinical symptoms associated with diseases or conditions treatable by the methods disclosed herein are well known. Furthermore, the therapeutic effect need not be complete or curative, as long as it provides some benefit to the subject. In some embodiments, the term “therapeutic effective” refers to an amount of therapeutic agent capable of reducing ALK7 activity in a subject in need. The actual amount administered, as well as the rate and duration of administration, will depend on the nature and severity of the subject being treated. Treatment prescriptions, such as the determination of dosage, are within the responsibility of general practitioners and other physicians. The appropriate dosage of antibodies and their antigen-binding fragments is generally known; see, Ledermann et al., Int. J. Cancer 47:659-664 (1991); Bagshawe et al., Ant. Immun. and Radiopharm. 4:915-922 (1991).

[0091] "Sufficient amount" or "sufficient amount" to achieve a specific outcome in a subject with an ALK7-mediated disease or symptom refers to the amount of a therapeutic agent (e.g., an antigen-binding protein, including antibodies, as disclosed herein) that is effective in producing the desired effect (optionally a therapeutic effect, i.e., by administering a therapeutically effective amount)). In some embodiments, this specific outcome is a reduction in ALK7 activity in the desired subject.

[0092] The term "label" refers to a detectable compound or composition that is directly or indirectly conjugated to a portion, such as an anti-ALK7 antibody, to generate a "labeled" portion. The label itself may be detectable (e.g., radioisotope labeling or fluorescent labeling), or, in the case of enzyme labeling, catalyze a chemical change in the detectable substrate compound or composition.

[0093] Terms such as “treating” or “treatment,” “to treat” or “ameliorating” and “to ameliorate” refer to: (a) therapeutic measures that cure, slow, alleviate, and / or prevent the progression of a diagnosed pathological condition or symptom; and (b) preventive or preventative measures that prevent and / or slow the development of a targeted disease or symptom. Therefore, subjects requiring treatment include those who already have the disease or symptom; those who are at risk of developing the disease or symptom; and those who are taking precautions against the disease or symptom. In some embodiments, a subject is considered successfully “treated” according to the methods provided herein if the subject shows complete, partial, or transient improvement or elimination of symptoms, for example, associated with the disease or symptom. In some embodiments, this disclosure provides a method for treating diseases, conditions, or symptoms selected from: obesity (e.g., abdominal obesity); insulin resistance; metabolic syndrome and other metabolic diseases or symptoms; lipid disorders such as low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia, or dyslipidemia; lipoprotein aberrations; decreased triglycerides; inflammation (e.g., liver inflammation and / or adipose tissue inflammation), fatty liver disease; non-alcoholic fatty liver disease; hyperglycemia; impaired glucose tolerance (IGT); hyperinsulinemia; high cholesterol (e.g., high LDL levels and hypercholesterolemia); cardiovascular diseases such as heart disease including coronary artery disease, congestive heart failure, stroke, etc. Peripheral vascular disease, atherosclerosis; arteriosclerosis and hypertension; Syndrome X; restenosis; neuropathy; retinopathy; neurodegenerative disease; endothelial dysfunction, respiratory dysfunction, kidney disease (e.g., nephropathy); pancreatitis; polycystic ovary syndrome; elevated uric acid levels; hemochromatosis (iron overload); acanthosis nigricans (dark spots on the skin); and cancer (e.g., myeloma (multiple myeloma, plasmacytoma, focal myeloma, or extramedullary myeloma) or ovarian cancer (e.g., epithelial ovarian cancer), breast cancer, colon cancer, endometrial cancer, liver cancer, kidney cancer, pancreatic cancer, stomach cancer, uterine cancer, or colon cancer); and with one or more of the above diseases or conditions or with overweight (e.g., 25 kg / m²). 2 (BMI) or other conditions / symptoms associated with excessive body fat.

[0094] As used herein, “in combination with” or “combination therapy” refers to any form of administration that ensures the effectiveness of the additional therapy (e.g., second, third, fourth, etc.) in the body (e.g., multiple compounds are effective simultaneously in the subject, which may include the synergistic effect of these compounds). Effectiveness may not be related to measurable concentrations of the agent in the blood, serum, or plasma. For example, different therapeutic compounds may be administered simultaneously or sequentially in the same formulation or in separate formulations and according to different schedules. Thus, a subject receiving such treatment may benefit from the combined effect of different therapies. One or more ALK7-binding proteins described herein may be administered simultaneously, before, or after one or more other additional agents and / or supportive therapies. Generally, each therapeutic agent will be administered at a specific dose and / or according to a schedule determined for that particular agent. The specific combination employed in the regimen will take into account the compatibility of the antagonist of this disclosure with the therapy and / or the desired outcome.

[0095] Unless otherwise indicated, the methods and techniques of this disclosure are generally performed according to known conventional methods and as described in the various general and more specific references cited and discussed throughout this disclosure. See, for example, Sambrook et al., Molecular Cloning: A Laboratory Manual, 3rd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (2001), and 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 (1990), all of which are incorporated herein by reference.

[0096] The terms “cancer,” “tumor,” “cancerous,” and “malignant” refer to or describe a physiological condition in mammals characterized by unregulated cell growth. Examples of cancer include, but are not limited to, carcinomas including adenocarcinoma, lymphoma, blastoma, melanoma, sarcoma, and leukemia. More specific examples of such cancers include squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, Hodgkin's lymphoma and non-Hodgkin's lymphoma, pancreatic cancer, glioblastoma, glioma, cervical cancer, ovarian cancer, liver cancer such as hepatocellular carcinoma and hepatocellular carcinoma, bladder cancer, breast cancer (including hormone-mediated breast cancer, see, for example, Innes et al., Br.J. Cancer 94:1057-1065 (2006)), colon cancer, colorectal cancer, endometrial cancer, myeloma (such as multiple myeloma), salivary gland cancer, kidney cancer such as renal cell carcinoma and Wilms' tumor, basal cell carcinoma, melanoma, prostate cancer, vulvar cancer, thyroid cancer, testicular cancer, esophageal cancer, various types of head and neck cancers, and mucinous-derived cancers such as mucinous ovarian cancer, bile duct cancer (liver), and renal papillary carcinoma. In a specific embodiment, the cancer is breast cancer, endometrial cancer, or uterine cancer. In another embodiment, the cancer is myeloma (e.g., multiple myeloma, plasmacytoma, focal myeloma, and extramedullary myeloma) or endometrial cancer, gastric cancer, liver cancer, colon cancer, kidney cancer, or pancreatic cancer.

[0097] The terms “polynucleotide” and “nucleic acid” are used interchangeably and are intended to cover both singular and plural nucleic acids, and refer to isolated nucleic acid molecules or constructs, such as messenger RNA (mRNA), complementary DNA (cDNA), or plasmid DNA (pDNA). In some embodiments, the polynucleotide contains conventional phosphodiester bonds or unconventional bonds (e.g., amide bonds, such as those present in peptide nucleic acids (PNA)). The term “nucleic acid” refers to any one or more nucleic acid fragments, such as DNA, cDNA, or RNA fragments, present in the polynucleotide. When applied to nucleic acids or polynucleotides, the term “isolated” refers to nucleic acid molecules, DNA, or RNA that have been removed from their native environment; for example, recombinant polynucleotides encoding antigen-binding proteins contained in a vector are considered isolated for the purposes of this disclosure. Further examples of isolated polynucleotides include recombinant polynucleotides maintained in heterologous host cells or purified (partially purified or substantially purified) from other polynucleotides in solution form. Isolated RNA molecules include in vivo or in vitro RNA transcripts of the polynucleotides of this disclosure. Isolated polynucleotides or nucleic acids according to this disclosure also include such molecules produced synthetically. In addition, polynucleotides or nucleic acids may include regulatory elements such as promoters, enhancers, ribosome binding sites, or transcription termination signals.

[0098] The term "vector" refers to a construct capable of being delivered to a host cell and expressing one or more genes or sequences of interest in some implementation schemes. Examples of vectors include, but are not limited to, viral vectors, naked DNA or RNA expression vectors, plasmids, granules or phage vectors, DNA or RNA expression vectors associated with cationic condensers, DNA or RNA expression vectors encapsulated in liposomes, and certain eukaryotic cells (such as production cells).

[0099] The term "host cell" refers to a cell or group of cells that carries or is capable of carrying recombinant nucleic acids. Host cells can be prokaryotic (e.g., *Escherichia 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 any type of animal cell, such as insect cells (e.g., Sf-9) or mammalian cells (e.g., HEK293F, CHO, COS-7, NIH-3T3, NSO, etc.). (and hybridoma). In another embodiment, the host cell is a CHO cell selected from the group consisting of: CHO-K, CHO-0, CHO-Lec10, CHO-Lec13, CHO-Lec1, CHO Pro. - 5 and CHO dhfr - In the specific implementation plan, the host cell is a hybridoma.

[0100] The terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein to refer to polymers having amino acids of any length. Polymers may be linear or branched, may contain modified amino acids, and may be interspersed with non-amino acids. The term also covers amino acid polymers that are naturally occurring or modified by interference; for example, disulfide bond formation, glycosylation, esterification, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeled component. Within the definition, also included, for example, are one or more analogues containing amino acids (including, for example, non-natural amino acids, etc.) and other modified polypeptides known in the art. It should be understood that because the ALK7 binding protein provided in some embodiments is antibody-based, the ALK7 binding protein may be present as a single chain or an associated chain.

[0101] “Recombinant” polypeptides, proteins, or antibodies refer to polypeptides, proteins, or antibodies produced by recombinant DNA technology. For the purposes of this disclosure, recombinant polypeptides, proteins, and antibodies expressed in host cells are considered to be isolated, and natural or recombinant polypeptides that have been isolated, fractionated, or partially or substantially purified by any suitable technique are also considered to be isolated.

[0102] This disclosure also includes fragments, variants, or derivatives of polypeptides, and any combinations thereof. When referring to polypeptides and proteins, the term "fragment" includes any polypeptide or protein that retains at least some of the properties of a reference polypeptide or protein. Fragments of polypeptides include proteolytic fragments as well as deletion fragments.

[0103] The term "variant" refers to an antibody or polypeptide sequence that differs from the parent antibody or polypeptide sequence due to at least one amino acid modification. Variants of antibodies or polypeptides include fragments, and also include antibodies or polypeptides with altered amino acid sequences due to amino acid substitutions, deletions, or insertions. Variants can be naturally occurring or non-naturally occurring. Non-naturally occurring variants can be generated using mutagenesis techniques known in the art. Variant polypeptides may contain conserved or non-conserved amino acid substitutions, deletions, or additions.

[0104] When applied to antibodies or peptides, the term "derivative" refers to an antibody or peptide that has been modified to exhibit additional characteristics not present on the natural antibody or peptide. Examples of "derivative" antibodies are fusions or conjugates with a second peptide or another molecule (e.g., a polymer, such as PEG, a chromophore, or a fluorophore) or atom (e.g., a radioisotope).

[0105] The term "amino acid substitution" refers to replacing an amino acid residue present in a parental sequence with another amino acid residue. Amino acids can be substituted in the parental sequence, for example, through chemical peptide synthesis or through known recombination methods. Therefore, references to "substitution at position X" or "substitution at position X" mean that the amino acid residue present at position X is replaced by a substitute amino acid residue. In some embodiments, the substitution pattern may be described according to the diagram AXY, where A is a single-letter code corresponding to the naturally present amino acid residue at position X, and Y is the substituted amino acid residue. In other embodiments, the substitution pattern may be described according to the diagram XY, where Y is a single-letter code corresponding to the amino acid residue that replaces the naturally present amino acid residue at position X.

[0106] "Conservative amino acid substitution" is a substitution in which an 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), non-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), β-branched side chains (e.g., Thr, Val, Ile), and aromatic side chains (e.g., Tyr, Phe, Trp, His). Therefore, if an amino acid residue in a polypeptide is replaced by another amino acid residue from the same side chain family, the substitution is considered conserved. In another embodiment, a string of amino acid residues can be conservatively substituted with structurally similar amino acid strings that differ in sequence and / or composition from members of the side chain family.

[0107] Non-conservative substitutions include substitutions in which (a) a residue having a positively charged side chain (e.g., Arg, His, or Lys) substitutes for or is substituted for a negatively charged residue (e.g., Glu or Asp), (b) a hydrophilic residue (e.g., Ser or Thr) substitutes for or is substituted for a hydrophobic residue (e.g., Ala, Leu, Ile, Phe, or Val), (c) Cys or Pro substitutes for or is substituted for any other residue, or (d) a residue having a bulky hydrophobic or aromatic side chain (e.g., Val, His, Ile, or Trp) substitutes for or is substituted for a residue having a smaller side chain (e.g., Ala or Ser) or a residue without a side chain (e.g., Gly).

[0108] Other substitutions are readily identifiable. For example, for the amino acid alanine, the substitution can be obtained from any of D-Ala, Gly, β-Ala, L-Cys, and D-Cys. For lysine, the substitution can be any of D-Lys, Arg, D-Arg, homo-Arg, Met, D-Met, ornithine, or D-ornithine. Typically, substitutions in functionally important regions of a polypeptide that are expected to induce property changes are those where (a) a polar residue (e.g., Ser or Thr) substitutes for (or is substituted for) a hydrophobic residue (e.g., Leu, Ile, Phe, or Ala); (b) a Cys residue substitutes for (or is substituted for) any other residue; (c) a residue with a positively charged side chain (e.g., Lys, Arg, or His) substitutes for (or is substituted for) a residue with a negatively charged side chain (e.g., Glu or Asp); or (d) a residue with a bulky side chain (e.g., Phe) substitutes for (or is substituted for) a residue without such a side chain (e.g., Gly). The likelihood that one of the aforementioned non-conserved substitutions can alter the functional properties of a protein is also related to the position of the substitution relative to the functionally important region of the protein: some non-conserved substitutions may have little or no effect on biological properties accordingly.

[0109] The term "amino acid insertion" refers to the introduction of a new amino acid residue between two amino acid residues present in the parent sequence. Amino acid residues can be inserted into the parent sequence, for example, through chemical peptide synthesis or through recombination methods known in the art. Therefore, the phrase "insertion between positions X and Y" or "insertion between Kabat positions X and Y" (e.g., cysteine ​​amino acid residue insertion between positions 239 and 240), where X and Y correspond to the positions of amino acid residues, refers to the insertion of an amino acid residue between positions X and Y, and also refers to the insertion of a codon encoding the amino acid residue between the codons encoding the amino acid residue at positions X and Y.

[0110] The term "sequence identity percentage" or "identity percentage" between two polynucleotide or polypeptide sequences refers to the number of identical matching positions shared by the sequences within 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 location in both the target and reference sequences where the same nucleotide or amino acid is present. Gaps present in the target sequence are not counted because gaps are not nucleotides or amino acids. Similarly, gaps present in the reference sequence are not counted because only nucleotides or amino acids from the target sequence are counted, not those from the reference sequence. The sequence identity percentage is calculated by determining the number of positions in both sequences where the same amino acid residue or nucleic acid base appears to obtain 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 obtain the sequence identity percentage. The comparison of sequences between two sequences and the determination of the sequence identity percentage can be performed using readily available software programs. Suitable software programs are available from various sources and can be used to align both protein and nucleotide sequences. A suitable program for determining the percentage of sequence identity is bl2seq, which is part of the BLAST program suite available from the U.S. National Center for Biotechnology Information (NCBI) BLAST website (blast.ncbi.nlm.nih.gov). Bl2seq performs comparisons between two sequences using either 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 are, for example, Needle, Stretcher, Water, or Matcher, which are part of the EMBOSS suite of bioinformatics programs and are also available from the European Institute for Bioinformatics (EBI) at www.ebi.ac.uk / Tools / psa.

[0111] The structure used to carry a CDR or a set of CDRs is typically an antibody heavy or light chain sequence or a major portion thereof, wherein the CDR or set of CDRs is located at the position corresponding to the CDR or CDR set of the naturally occurring VH and VL antibody variable domains encoded by rearranged immunoglobulin genes. The structure and position of immunoglobulin variable domains and their CDRs can be readily determined by those skilled in the art using procedures, and known variable domain residue numbering systems such as Chothia, Chothia+, and Kabat can be conventionally determined by reference to Kabat (Kabat et al., Sequences of Proteins of Immunological Interest. 4th edition USDHHS. 1987, and tools available on the Internet (e.g., at bioinf.org.uk / abysis / sequence_input / key_annotation / key_annotation.html; and immuno.bme.nwu.edu)), which are incorporated herein by reference in their entirety.

[0112] CDRs can also be carried by other scaffolds, such as fibronectin, cytochrome B, albumin (e.g., ALBUdAb (Domantis / GSK) and ALB-Kunitz (Dyax)), and unstructured repeat sequences of 3 or 6 amino acids (e.g., Technology and (Technology) and sequences containing elastin-like repeat sequence domains (see, for example, U.S. Patent Application No. 61 / 442,106, which is incorporated herein by reference in its entirety).

[0113] Essentially, the CDR amino acid sequences listed herein can be carried as CDRs in human variable domains or their main components. Essentially, the HCDR3 sequences listed herein represent embodiments of the present disclosure, and each of these can be carried as HCDR3 in human heavy chain variable domains or their main components.

[0114] The variable domains used in this disclosure can be obtained from any germline or rearranged human variable domain, or can be synthetic variable domains based on a known common sequence of human variable domains. A CDR sequence (e.g., CDR3) can be introduced into all components of a variable domain lacking a CDR (e.g., CDR3) using recombinant DNA technology.

[0115] For example, Marks et al. (Bio / Technology 10:779-783 (1992); which is incorporated herein by reference in its entirety) provide a method for generating all components of an antibody variable domain, wherein a common primer directed at or adjacent to the 5' end of the variable domain is used to bind to a common primer of the third frame region of the human VH gene to provide all components of a VH variable domain lacking CDR3. Marks et al. also describe how all these components can be combined with the CDR3 of a specific antibody. Using similar techniques, the CDR3-derived sequences of this disclosure can be shuffled with all components of a VH or VL domain lacking CDR3, and the shuffled complete VH or VL domain can be combined with a homologous VL or VH domain to provide an antigen-binding protein. All components can then be displayed in a suitable host system, such as the phage display system in International Application Publication No. WO92 / 01047 or any of the subsequent extensive literature (including Kay et al., (1996) Phage Display of Peptides and Proteins: A Laboratory Manual, San Diego: Academic Press), allowing for the selection of suitable antigen-binding proteins. All components can consist of more than 104 individual members, for example, 10 6 Up to 10 8 Or 10 10 Any of the components. 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 International Application Publication No. WO92 / 01047, each of which is incorporated herein by reference in its entirety. Similar truncation or combination techniques have also been disclosed by Stemmer (Nature 370:389-391 (1994), which is incorporated herein by reference in its entirety), who describes techniques related to β-lactamase genes but observed that the methods could be used to generate antibodies.

[0116] It is claimed that if an ALK7-binding protein binds to ALK7 to such an extent that it partially blocks the binding of a reference molecule to ALK7, then the ALK7-binding protein (e.g., an anti-ALK7 antibody) "competes" with the reference molecule to bind to ALK7. The ability of proteins to competitively bind to ALK7 and thus interfere with, block, or "cross-block" each other's binding to ALK7 can be determined by any standard competitive binding assay known in the art (including, for example, competitive ELISA assays, surface plasmon resonance (SPR) assays). Biosensor, Piscataway, NJ) or as determined by the method described by Scatchard et al. (Ann. NY Acad. Sci. 51:660-672 (1949)). It is claimed that the ALK7-binding protein can competitively inhibit the binding of a reference molecule to ALK7 by, for example, at least 90%, at least 80%, at least 70%, at least 60%, or at least 50%. According to some embodiments, the ALK7-binding protein competitively inhibits the binding of a reference molecule to ALK7 by at least 90%, at least 80%, at least 70%, at least 60%, or at least 50%. According to other embodiments, the ALK7-binding protein competitively inhibits the binding of a reference molecule to ALK7 by at least 90%, at least 80%, at least 70%, at least 60%, or at least 50%.

[0117] ALK7 binding protein

[0118] A protein that specifically binds to ALK7 is provided. In some embodiments, an antagonist ALK-7 binding protein is provided. In some embodiments, the ALK7 binding protein is an antibody. In other embodiments, the antibody is an antagonist anti-ALK7 antibody.

[0119] As used herein, the term "ALK7" refers to a family of activin receptor-like kinase-7 proteins from any species, as well as variants derived from such ALK7 proteins through mutagenesis or other modifications. References to ALK7 herein are understood to refer to any of the currently identified forms. Members of the ALK7 family are typically transmembrane proteins, consisting of a ligand-binding extracellular domain with a cysteine-rich region, a transmembrane domain, and a cytoplasmic domain with predicted serine / threonine kinase activity. Various naturally occurring isotypes of human ALK7 exist. The sequence of the canonical human ALK7 isotype 1 precursor protein (NCBIRef Seq NP_660302.2) is as follows:

[0120]

[0121] The 481TISQLCVKED CKA (SEQ ID NO:85) signal peptide is indicated by a single underline and the extracellular domain is indicated in bold.

[0122] In some embodiments, the ALK7-binding protein binds ALK7 with an affinity of at least 100, 500, or 1000 times that of a control protein that is not a member of the TGF-β receptor family. In some embodiments, the ALK7-binding protein binds ALK7 and has a dissociation constant (K0) of <1 μM, <100 nM, <10 nM, <1 nM, <0.1 nM, <10 pM, <1 pM, or <0.1 pM. DIn some implementations, the ALK7 binding protein has a K+ level for human ALK7 in the ranges of ≤1 μM and ≥0.1 pM, ≤100 μM and ≥0.1 pM, or ≤100 μM and ≥1 pM. D .

[0123] In some implementation schemes, the use of The analysis determined the ability of an ALK7-binding protein (e.g., an anti-ALK7 antibody) to competitively bind to the ALK7 protein versus to block the binding of the reference ALK7-binding protein to the ALK7 protein. Instruments (e.g., 3000) In another embodiment of operation according to the manufacturer's recommendations, the ALK7-Fc fusion protein is captured in CM5 by previously attached anti-niFc IgG. The chip is coated with ALK7. Typically, 200-800 resonant units of ALK7-Fc (dimer) are attached to the chip (the binding level is easily given as a measurable amount, but can be easily saturated by the concentration of the test reagents used).

[0124] Two ALK7-binding proteins (designated A* and B*) whose ability to compete with or block each other is to be evaluated are mixed in a suitable buffer at a 1:1 molar ratio of binding sites to produce a test mixture. When calculating concentrations on a binding site basis, the molecular weight of the ALK7-binding protein is considered to be the total molecular weight of the ALK7-binding protein divided by the number of ALK7 binding sites on that ALK7-binding protein. The concentration of each ALK7-binding protein (i.e., A* and B*) in the test mixture should be high enough to facilitate capture on... The binding sites for this ALK7-binding protein on the ALK7-Fc molecule on the chip are saturated. The A* and B* ALK7-binding proteins in the mixture are at the same molar concentration (on a binding basis), and said concentration is typically between 1.00 and 1.5 μmol (on a binding site basis). Separate solutions containing only ALK7-binding protein A* and only ALK7-binding protein B* are also prepared. The ALK7-binding proteins A* and B* in these solutions should be in the same buffer and at the same concentration, as in the test mixture. The test mixture is then coated onto the ALK7-Fc... The chip is then passed over, and the total amount of binding is recorded. The chip is then treated in a way that removes the bound ALK7-binding protein without damaging the ALK7-Fc coating. Typically, this is done by treating the chip with 30 mM HCl for 60 seconds. A solution of ALK7-binding protein A* alone is then passed over the ALK7-Fc-coated surface, and the amount of binding is recorded. The chip is treated again to remove the bound antibody without damaging the ALK7-Fc coating. A solution of ALK7-binding protein B* alone is then passed over the ALK7-Fc-coated surface, and the amount of binding is recorded. Next, the maximum theoretical binding of a mixture of ALK7-binding protein A* and ALK7-binding protein B* is calculated, and this is the sum of the bindings of each ALK7-binding protein when passed individually over the ALK7 surface. If the actual recorded binding of the mixture is less than this theoretical maximum, the two ALK7-binding proteins compete with / block each other. Therefore, in general, blocking ALK7-binding proteins is achieved at the above... The protein that binds to ALK7 in the blocking assay is such that, during the assay and in the presence of a second ALK7 binding protein, the recorded binding is between 80% and 0.1% of the maximum theoretical binding of the two combined ALK7 binding proteins (as defined above) (e.g., 80% > 4%), specifically between 75% and 0.1% of the maximum theoretical binding (e.g., 75% to 4%), and more specifically between 70% and 0.1% of the maximum theoretical binding (e.g., 70% to 4%).

[0125] The above-mentioned This assay is an exemplary assay used to determine whether two ALK7-binding proteins, such as anti-ALK7 antibodies, compete with each other to bind to ALK7 or block each other's ALK7 binding. In rare cases, a particular ALK7-binding protein may not bind to CM5 via anti-Fc IgG. The ALK7-Fc of the chip (this can occur when the relevant binding site on ALK7 is masked or disrupted by the ALK7-Fc bond). In such cases, blocking can be determined using a labeled version of ALK7, such as C-terminal His-labeled ALK7. In this particular form, the anti-His antibody will be linked to... The chip is then passed through, and the His-tagged ALK7 is captured by the anti-His antibody. Cross-blocking analysis is performed essentially as described above, except that after each chip regeneration cycle, fresh His-tagged ALK7 is loaded back onto the surface coated with the anti-His antibody. Furthermore, various other known combinations of tags and tag-binding proteins can be used for this blocking assay (e.g., HA tag with anti-HA antibody; FLAG tag with anti-FLAG antibody; biotin tag with streptoin). The following is a general description of the ELISA assay used to determine whether or not an ALK7-binding protein blocks or is able to block the binding of a reference ALK7-binding protein to ALK7.

[0126] In some implementations, ELISA is used to determine the ability of an ALK7-binding protein (e.g., an anti-ALK7 antibody) to competitively bind to ALK7 against a reference ALK7-binding protein (e.g., an anti-ALK7 antibody or an ALK7 ligand). The general principle of this assay is to coat the wells of an ELISA plate with a reference ALK7-binding protein (e.g., an anti-ALK7 antibody). An excess of a second potential blocking test ALK7-binding protein (i.e., not bound to the ELISA plate) is added in solution. A limited amount of ALK7 (or optionally ALK7-Fc) is then added to the wells. The coated reference ALK7-binding protein and the test ALK7-binding protein in solution compete to bind a limited number of ALK7 (or ALK7-Fc) molecules. The plate is washed to remove ALK7 not bound by the coated reference ALK7-binding protein and also to remove the test solution phase ALK7-binding protein and any complexes formed between the test solution phase ALK7-binding protein and ALK7. The amount of bound ALK7 is then measured using an appropriate ALK7 assay reagent. A solution-based test ALK7 binding protein capable of blocking the binding of a coated reference ALK7 binding protein to ALK7 will result in a reduction in the number of ALK7 molecules that the coated reference ALK7 binding protein can bind relative to the number of ALK7 molecules that the coated reference ALK7 binding protein can bind in the absence of a second solution-based test ALK7 binding protein. The background signal used for the assay is defined as the signal obtained in wells containing a coated reference ALK7 binding protein, a solution-based test ALK7 binding protein, an ALK7-only buffer (i.e., no ALK7), and an ALK7 assay reagent. The positive control signal used for the assay is defined as the signal obtained in wells containing a coated reference ALK7 binding protein, a solution-only test ALK7 binding protein buffer (i.e., no solution-based test ALK7 binding protein), and an ALK7 and ActRII receptor (e.g., ActRIIA or ActRIIB) assay reagent. The ELISA assay is performed in a manner such that a positive control signal has at least three times the background signal. As a control for method artifacts, the cross-blocking assay can be performed in the manner described above, and can also be reversed, in which the ALK7 binding protein is tested as the coated antibody and the reference ALK7 binding protein is used as the solution phase antibody.

[0127] In some embodiments, the ALK7-binding protein binds ALK7 with an affinity of at least 100, 500, or 1000 times that of a control protein that is not a member of the TGF-β receptor family. In other embodiments, the ALK7-binding protein binds ALK7 with an affinity of at least 100, 500, or 1000 times that of a control protein that is not a member of the TGF-β receptor family. In some embodiments, the ALK7-binding protein binds ALK7 and has a dissociation constant (Km) of <1 μM, <100 nM, <10 nM, <1 nM, <0.1 nM, <10 pM, <1 pM, or <0.1 pM. D In some implementations, the ALK7 binding protein has a K+ level for human ALK7 in the ranges of ≤1 μM and ≥0.1 pM, ≤100 μM and ≥0.1 pM, or ≤100 μM and ≥1 pM. D .

[0128] In some embodiments, a cell-based lipolysis inhibition assay is used to determine the ability of an ALK7-binding protein (e.g., an antagonist anti-ALK7 antibody) to reduce (inhibit) ALK7-mediated lipolysis inhibition in mammalian white adipocytes. In some embodiments, the lipolysis inhibition assay is performed using mature white adipocytes (e.g., human, mouse, or rat) to determine the ability of an ALK7-binding protein (e.g., an anti-ALK7 antibody) to reduce ALK7 activity. Kits, reagents, and methods for performing the lipolysis assay are commercially available and are known in the art. In specific embodiments, the lipolysis inhibition assay is performed as provided in the examples herein. In other embodiments, the assay is performed according to the instructions and reagents provided in commercially available lipolysis assay kits (e.g., BioAssay Systems, EnzyChrom). TM Fat breakdown assay kits, catalog number EAPL-200; Abcam, catalog number ab185433; Zen-Bio, catalog number LIP-1-NCL1; BioVision, catalog number K577-100; Sigma-Aldrich, catalog number MAK211; and AdipoLyze... TM Lipolysis assay, Lonza, catalog number 193339).

[0129] In some embodiments, the ALK7-binding protein is an ALK7 antagonist and increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-binding protein increases lipolysis in mature white adipocytes by 5% to 100%, 10% to 95%, 10% to 90%, 10% to 85%, 10% to 80%, 10% to 75%, 10% to 70%, 10% to 65%, 10% to 60%, 10% to 55%, 10% to 50%, or 10% to 45%, as determined using standard techniques and conditions in a lipolysis inhibition assay performed in the presence of activin B (50 ng / ml) (e.g., as described in the examples herein). In other embodiments, the ALK7-binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-binding protein increases lipolysis in mature white adipocytes by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% or about 100%, as determined using standard techniques and conditions in a lipolysis inhibition assay performed in the presence of activin B (50 ng / ml) (e.g., as described in the examples herein).

[0130] Pharmacokinetic parameters dependent on ALK7 signaling can be measured as endpoints for in vivo assays of ALK7-binding proteins to identify those that neutralize ALK7 and provide therapeutic benefit. ALK7 neutralizing binders are defined as those that cause a statistically significant change in these pharmacokinetic parameters compared to animal treatment with the drug. Such in vivo assays can be performed in any suitable mammal (e.g., mouse, rat, or monkey).

[0131] In some embodiments, the ALK7-binding protein is an antibody that specifically binds to ALK7. In other embodiments, the ALK7-binding protein is a full-length anti-ALK7 antibody. In still other embodiments, the antibody is a monoclonal antibody, recombinant antibody, human antibody, humanized antibody, chimeric antibody, bispecific antibody, multispecific antibody, or an ALK7-binding antibody fragment thereof.

[0132] In some embodiments, the anti-ALK7 antibody is an ALK7-binding antibody fragment. In some embodiments, the ALK7-binding antibody fragment is: Fab, Fab', F(ab')2, Fv fragment, bispecific or single-chain antibody molecule. In other embodiments, the ALK7 antibody is Fd, single-chain Fv (scFv), disulfide-linked Fv, V-NAR domain, IgNar, endosome, IgGΔCH2, microantibody, F(ab')3, tetrasome, trisome, bispecific, single-domain antibody, DVD-Ig, Fcab, mAb. 2 、(scFv)2、scFv-Fc or double scFv.

[0133] In another embodiment, the ALK7 binding protein is an antibody comprising VH and VL. In some embodiments, the anti-ALK7 antibody further comprises a heavy chain constant region or a fragment thereof. In some embodiments, the antibody comprises a heavy chain immunoglobulin constant region selected from the group consisting of: (a) a human IgA constant region or a fragment thereof; (b) a human IgD constant region or a fragment thereof; (c) a human IgE constant domain or a fragment thereof; (d) a human IgG1 constant region or a fragment thereof; (e) a human IgG2 constant region or a fragment thereof; (f) a human IgG3 constant region or a fragment thereof; (g) a human IgG4 constant region or a fragment thereof; and (h) a human IgM constant region or a fragment thereof. In some embodiments, the ALK7 binding protein comprises a heavy chain constant region or a fragment thereof, such as a human IgG constant region or a fragment thereof. In another embodiment, the ALK7 binding protein comprises a heavy chain immunoglobulin constant domain having or having been mutated to have altered effector function and / or half-life.

[0134] In specific implementations, the ALK7 binding protein is an antibody containing a mutated IgG1 heavy chain constant region with reduced 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; U.S. Application Publication 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.

[0135] In some embodiments, the heavy chain constant region or a fragment thereof includes one or more amino acid substitutions relative to the wild-type IgG constant domain, wherein the modified IgG has a reduced ADCC compared to IgG having the wild-type IgG constant domain. Examples of Fc sequence engineered modifications contained in the provided antibody with reduced ADCC include modifications corresponding to one or more of the following: IgG1-K326W, E333S; IgG2-E333S; IgG1-N297A; IgG1-L234A, L235A; IgG2-V234A, G237A; IgG4-L235A, G237A, E318A; IgG4-S228P, L236E; IgG2-EU sequence. Columns 118-260; IgG4-EU sequences 261-447; 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 based on the EU index as in Kabat.

[0136] In some implementations, the ALK7 binding protein includes a heavy chain immunoglobulin constant domain that has been mutated to have reduced CDC activity. In specific implementations, the ALK7 binding protein is an antibody containing a mutated IgG1 heavy chain constant region that reduces CDC activity (see, for example, WO97 / 11971 and WO07 / 106585; US Application Publication 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 engineered Fc sequence modifications in anti-ALK7 antibodies that reduce CDC include modifications corresponding to one or more of the following: IgG1-S239D, A330L, I332E; IgG2 EU sequence 118-260; IgG4-EU sequence 261-447; IgG2-H268Q, V309L, A330S, A331S; IgG1-C226S, C229S, E233P, L234V, L235A; IgG1-L234F, L235E, P331S; and IgG1-C226S, P230S.

[0137] In another embodiment, the heavy chain constant region or a fragment thereof comprises one or more amino acid substitutions relative to the wild-type IgG constant domain, wherein the modified IgG has an increased half-life compared to the half-life of IgG having the wild-type IgG constant domain. For example, the IgG constant domain may contain one or more amino acid substitutions at positions 251-257, 285-290, 308-314, 385-389, and 428-436, wherein the amino acid position numbering is based on the EU index as listed in Kabat. In some embodiments, the IgG constant domain may contain one or more of the following: an amino acid substitution at Kabat position 252 with Tyr, Phe, Trp, or Thr; an amino acid substitution at Kabat position 254 with 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 the wild-type human IgG constant domain, including an amino acid substitution with Tyr at Kabat position 252, an amino acid substitution with Thr at Kabat position 254, and an amino acid substitution with Glu at Kabat position 256.

[0138] In another embodiment, the ALK7 binding protein is an antibody containing the light chain immunoglobulin constant region. In yet another embodiment, the antibody contains the human Igκ constant region or the human Igλ constant region.

[0139] In some embodiments, the ALK7-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 the VH and VL pairs disclosed in Table 1A. In another embodiment, the ALK7-binding protein comprises a set of CDRs, wherein the CDRs are present in the VH and VL pairs selected from the group consisting of: (a) the VH sequence of SEQ ID NO:4 and the VL sequence of SEQ ID NO:13; (b) the VH sequence of SEQ ID NO:22 and the VL sequence of SEQ ID NO:31; (c) the VH sequence of SEQ ID NO:40 and the VL sequence of SEQ ID NO:49; and (d) the VH sequence of SEQ ID NO:58 and the VL sequence of SEQ ID NO:67; and wherein the protein binds ALK7.

[0140] In some embodiments, the ALK7-binding protein comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, wherein said CDRs are present in the VH and VL pairs disclosed in Table 1B. In another embodiment, the ALK7-binding protein comprises a set of CDRs, wherein said CDRs are present in the VH and VL pairs selected from the group consisting of: (a) the VH sequence of SEQ ID NO:152 and the VL sequence of SEQ ID NO:98; (b) the VH sequence of SEQ ID NO:159 and the VL sequence of SEQ ID NO:110; and (c) the VH sequence of SEQ ID NO:165 and the VL sequence of SEQ ID NO:171; and wherein said protein binds ALK7.

[0141] In some embodiments, the ALK7 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 the VH and VL pairs disclosed in Table 3. In another embodiment, the ALK7 binding protein comprises a set of CDRs, wherein the CDRs are present in VH and VL pairs selected from the group consisting of: (a) the VH sequence of SEQ ID NO:91 and the VL sequence of SEQ ID NO:98; (b) the VH sequence of SEQ ID NO:105 and the VL sequence of SEQ ID NO:110; (c) the VH sequence of SEQ ID NO:117 and the VL sequence of SEQ ID NO:124; (d) the VH sequence of SEQ ID NO:128 and the VL sequence of SEQ ID NO:135; and (d) the VH sequence of SEQ ID NO:140 and the VL sequence of SEQ ID NO:148; and wherein the protein binds ALK7.

[0142] In some embodiments, the ALK7 binding protein comprises a set of CDRs: (a) VH-CDR1, VH-CDR2, and VH-CDR3 or (b) VL-CDR1, VL-CDR2, and VL-CDR3, wherein the CDR set 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 compared to the reference CDR set disclosed herein. In another embodiment, the ALK7 binding protein comprises a set of CDRs, wherein the CDR set 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 compared to the reference CDR set in the VH or VL sequences disclosed in Table 1A.

[0143] In some embodiments, the ALK7 binding protein comprises a set of CDRs: (a) VH-CDR1, VH-CDR2, and VH-CDR3 or (b) VL-CDR1, VL-CDR2, and VL-CDR3, wherein the CDR set 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 compared to the reference CDR set disclosed herein. In another embodiment, the ALK7 binding protein comprises a set of CDRs, wherein the CDR set 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 compared to the reference CDR set in the VH or VL sequences disclosed in Table 1B.

[0144] In some embodiments, the ALK7 binding protein comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, wherein the CDR set 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 compared to the reference CDR set disclosed herein. In another embodiment, the ALK7 binding protein comprises a set of CDRs, wherein the CDR set 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 compared to the reference CDR set in the VH and VL sequence pairs disclosed in Table 3.

[0145] In another embodiment, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, wherein the CDR set 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 compared to the reference CDR set, wherein: (a)(i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:1; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:2; (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:3; (iv) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:10; (v) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:11; and (vi) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:10. (b)(i) VH-CDR1 contains the amino acid sequence of SEQ ID NO:19; (ii) VH-CDR2 contains the amino acid sequence of SEQ ID NO:20; (iii) VH-CDR3 contains the amino acid sequence of SEQ ID NO:21; (iv) VL-CDR1 contains the amino acid sequence of SEQ ID NO:28; (v) VL-CDR2 contains the amino acid sequence of SEQ ID NO:29; and (vi) VL-CDR3 contains the amino acid sequence of SEQ ID NO:30; (c)(i) VH-CDR1 contains the amino acid sequence of SEQ ID NO:37; (ii) VH-CDR2 contains the amino acid sequence of SEQ ID NO:38; (iii) VH-CDR3 contains the amino acid sequence of SEQ ID NO:39; (iv) VL-CDR1 contains the amino acid sequence of SEQ ID NO:46; (v) VL-CDR2 contains the amino acid sequence of SEQ ID NO:47; and (vi) VL-CDR3 contains the amino acid sequence of SEQ ID NO:12. The amino acid sequence of NO:48; or (d)(i)VH-CDR1 contains the amino acid sequence of SEQ ID NO:55; (ii)VH-CDR2 contains the amino acid sequence of SEQ ID NO:56; (iii)VH-CDR3 contains the amino acid sequence of SEQ ID NO:57; (iv)VL-CDR1 contains the amino acid sequence of SEQ ID NO:64; (v)VL-CDR2 contains the amino acid sequence of SEQ ID NO:65; and (vi)VL-CDR3 contains the amino acid sequence of SEQ ID NO:66; and wherein said protein binds to ALK7.In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of a complex containing ALK7, the type II receptor (e.g., ActRIIA or ActRIIB), and one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8) on the surface of cells expressing ALK7 and type II receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with one or more type II receptors; and (c) competitively binding to ALK7 with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8). (d) Reduce phosphorylation of ALK7 in cells expressing ALK7 and type II receptors (e.g., ActRIIA or ActRIIB) in the presence of one or more TGF-β superfamily ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal); (e) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal); (f) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal); K (determined by analysis) D The ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0146] In another embodiment, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, wherein the CDR set 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 compared to the reference CDR set, wherein: (a)(i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:37; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:56; (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:90; (iv) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:95; (v) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:96; and (vi) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:95. (b)(i) VH-CDR1 contains the amino acid sequence of SEQ ID NO: 156; (ii) VH-CDR2 contains the amino acid sequence of SEQ ID NO: 157; (iii) VH-CDR3 contains the amino acid sequence of SEQ ID NO: 184; (iv) VL-CDR1 contains the amino acid sequence of SEQ ID NO: 107; (v) VL-CDR2 contains the amino acid sequence of SEQ ID NO: 108; and (vi) VL-CDR3 contains the amino acid sequence of SEQ ID NO: 109; and (c)(i) VH-CDR1 contains the amino acid sequence of SEQ ID NO: 1; (ii) VH-CDR2 contains the amino acid sequence of SEQ ID NO: 163; (iii) VH-CDR3 contains the amino acid sequence of SEQ ID NO: 164; (iv) VL-CDR1 contains the amino acid sequence of SEQ ID NO: 167; (v) VL-CDR2 contains the amino acid sequence of SEQ ID NO: 97; The amino acid sequence of NO:168; and (vi)VL-CDR3 contains the amino acid sequence of SEQ ID NO:169; and said protein binds to ALK7.In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of a complex containing ALK7, the type II receptor (e.g., ActRIIA or ActRIIB), and one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8) on the surface of cells expressing ALK7 and type II receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with one or more type II receptors; and (c) competitively binding to ALK7 with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8). (d) Reduce phosphorylation of ALK7 in cells expressing ALK7 and type II receptors (e.g., ActRIIA or ActRIIB) in the presence of one or more TGF-β superfamily ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal); (e) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal); (f) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal); K (determined by analysis) D The ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0147] In another embodiment, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, wherein the CDR set 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 compared to the reference CDR set, wherein: (a)(i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:88; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:89; (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:90; (iv) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:95; (v) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:96; and (vi) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:95. (b)(i) VH-CDR1 contains the amino acid sequence of SEQ ID NO: 102; (ii) VH-CDR2 contains the amino acid sequence of SEQ ID NO: 103; (iii) VH-CDR3 contains the amino acid sequence of SEQ ID NO: 104; (iv) VL-CDR1 contains the amino acid sequence of SEQ ID NO: 107; (v) VL-CDR2 contains the amino acid sequence of SEQ ID NO: 108; and (vi) VL-CDR3 contains the amino acid sequence of SEQ ID NO: 109; (c)(i) VH-CDR1 contains the amino acid sequence of SEQ ID NO: 114; (ii) VH-CDR2 contains the amino acid sequence of SEQ ID NO: 115; (iii) VH-CDR3 contains the amino acid sequence of SEQ ID NO: 116; (iv) VL-CDR1 contains the amino acid sequence of SEQ ID NO: 121; (v) VL-CDR2 contains the amino acid sequence of SEQ ID NO: 97; (b)(i) VH-CDR1 contains the amino acid sequence of SEQ ID NO: 102; (ii) VH-CDR2 contains the amino acid sequence of SEQ ID NO: 103; (iii) VH-CDR3 contains the amino acid sequence of SEQ ID NO: 116; (iv) VL-CDR1 contains the amino acid sequence of SEQ ID NO: 121; (v) VL-CDR2 contains the amino acid sequence of SEQ ID NO: 97; (iv) VL-CDR1 contains the amino acid sequence of SEQ ID NO: 121; (v) VL-CDR2 contains the amino acid sequence of SEQ ID NO: 97; (iv) VH ... (vi) VL-CDR3 contains the amino acid sequence of SEQ ID NO:122; (d)(i) VH-CDR1 contains the amino acid sequence of SEQ ID NO:125; (ii) VH-CDR2 contains the amino acid sequence of SEQ ID NO:126; (iii) VH-CDR3 contains the amino acid sequence of SEQ ID NO:127; (iv) VL-CDR1 contains the amino acid sequence of SEQ ID NO:132; (v) VL-CDR2 contains the amino acid sequence of SEQ ID NO:133; and (vi) VL-CDR3 contains the amino acid sequence of SEQ ID NO:134.Alternatively, (e)(i) VH-CDR1 contains the amino acid sequence of SEQ ID NO:137; (ii) VH-CDR2 contains the amino acid sequence of SEQ ID NO:138; (iii) VH-CDR3 contains the amino acid sequence of SEQ ID NO:139; (iv) VL-CDR1 contains the amino acid sequence of SEQ ID NO:145; (v) VL-CDR2 contains the amino acid sequence of SEQ ID NO:146; and (vi) VL-CDR3 contains the amino acid sequence of SEQ ID NO:147; and wherein said protein binds to ALK7. In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of a complex containing ALK7, the type II receptor (e.g., ActRIIA or ActRIIB), and one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8) on the surface of cells expressing ALK7 and type II receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with one or more type II receptors; and (c) competitively binding to ALK7 with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8). (d) Reduce phosphorylation of ALK7 in cells expressing ALK7 and type II receptors (e.g., ActRIIA or ActRIIB) in the presence of one or more TGF-β superfamily ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal); (e) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal); (f) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal); K (determined by analysis) DThe ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0148] In another embodiment, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, wherein: (a)(i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:1; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:2; (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:3; (iv) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:10; (v) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:11; and (vi) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:12; (b)(i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:19; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:20; and (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:12. (iv) VL-CDR1 contains the amino acid sequence of SEQ ID NO:21; (v) VL-CDR2 contains the amino acid sequence of SEQ ID NO:29; and (vi) VL-CDR3 contains the amino acid sequence of SEQ ID NO:30; (c)(i) VH-CDR1 contains the amino acid sequence of SEQ ID NO:37; (ii) VH-CDR2 contains the amino acid sequence of SEQ ID NO:38; (iii) VH-CDR3 contains the amino acid sequence of SEQ ID NO:39; (iv) VL-CDR1 contains the amino acid sequence of SEQ ID NO:46; (v) VL-CDR2 contains the amino acid sequence of SEQ ID NO:47; and (vi) VL-CDR3 contains the amino acid sequence of SEQ ID NO:48; or (d)(i) VH-CDR1 contains the amino acid sequence of SEQ ID NO:55; (ii) VH-CDR2 contains the amino acid sequence of SEQ ID NO:56; (iii) VH-CDR3 contains the amino acid sequence of SEQ ID NO:21. (iv) VL-CDR1 contains the amino acid sequence of SEQ ID NO: 57; (v) VL-CDR2 contains the amino acid sequence of SEQ ID NO: 65; and (vi) VL-CDR3 contains the amino acid sequence of SEQ ID NO: 66; and wherein the protein binds ALK7.

[0149] In another embodiment, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, wherein: (a)(i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO: 37; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO: 56; (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO: 90; (iv) VL-CDR1 comprises the amino acid sequence of SEQ ID NO: 95; (v) VL-CDR2 comprises the amino acid sequence of SEQ ID NO: 96; and (vi) VL-CDR3 comprises the amino acid sequence of SEQ ID NO: 97; (b)(i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO: 156; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO: 157; and (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO: 97. (iv) VL-CDR1 contains the amino acid sequence of SEQ ID NO:107; (v) VL-CDR2 contains the amino acid sequence of SEQ ID NO:108; and (vi) VL-CDR3 contains the amino acid sequence of SEQ ID NO:109; and (c)(i) VH-CDR1 contains the amino acid sequence of SEQ ID NO:1; (ii) VH-CDR2 contains the amino acid sequence of SEQ ID NO:163; (iii) VH-CDR3 contains the amino acid sequence of SEQ ID NO:1164; (iv) VL-CDR1 contains the amino acid sequence of SEQ ID NO:107; (v) VL-CDR2 contains the amino acid sequence of SEQ ID NO:168; and (vi) VL-CDR3 contains the amino acid sequence of SEQ ID NO:169; and wherein the protein binds ALK7.

[0150] In another embodiment, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, wherein: (a)(i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO: 88; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO: 89; (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO: 90; (iv) VL-CDR1 comprises the amino acid sequence of SEQ ID NO: 95; (v) VL-CDR2 comprises the amino acid sequence of SEQ ID NO: 96; and (vi) VL-CDR3 comprises the amino acid sequence of SEQ ID NO: 97; (b)(i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO: 102; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO: 103; and (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO: 88. (iv) VL-CDR1 contains the amino acid sequence of SEQ ID NO: 104; (v) VL-CDR2 contains the amino acid sequence of SEQ ID NO: 108; and (vi) VL-CDR3 contains the amino acid sequence of SEQ ID NO: 109; (c)(i) VH-CDR1 contains the amino acid sequence of SEQ ID NO: 114; (ii) VH-CDR2 contains the amino acid sequence of SEQ ID NO: 115; (iii) VH-CDR3 contains the amino acid sequence of SEQ ID NO: 116; (iv) VL-CDR1 contains the amino acid sequence of SEQ ID NO: 121; (v) VL-CDR2 contains the amino acid sequence of SEQ ID NO: 122; and (vi) VL-CDR3 contains the amino acid sequence of SEQ ID NO: 123; (d)(i) VH-CDR1 contains the amino acid sequence of SEQ ID NO: 125; (ii) VH-CDR2 contains the amino acid sequence of SEQ ID NO: 109; (iii) VH-CDR3 contains the amino acid sequence of SEQ ID NO:126; (iv) VL-CDR1 contains the amino acid sequence of SEQ ID NO:132; (v) VL-CDR2 contains the amino acid sequence of SEQ ID NO:133; and (vi) VL-CDR3 contains the amino acid sequence of SEQ ID NO:134; or (e) (i) VH-CDR1 contains the amino acid sequence of SEQ ID NO:137; (ii) VH-CDR2 contains the amino acid sequence of SEQ ID NO:138; (iii) VH-CDR3 contains the amino acid sequence of SEQ ID NO:139;(iv) VL-CDR1 contains the amino acid sequence of SEQ ID NO:145; (v) VL-CDR2 contains the amino acid sequence of SEQ ID NO:146; and (vi) VL-CDR3 contains the amino acid sequence of SEQ ID NO:147; and wherein said protein binds ALK7.

[0151] In some embodiments, the ALK7-binding protein specifically binds to ALK7 and comprises a set of CDRs having 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 compared to the reference CDR set, wherein: (a)(i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:1; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:2; (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:3; (iv) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:10; (v) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:11; and (vi) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:12; and wherein said protein binds to ALK7. In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of a complex containing ALK7, type II receptor (e.g., ActRIIA or ActRIIB), and activin B on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with ActRIIA or ActRIIB; (c) competitively binding to ALK7 with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8); and (d) reducing... (e) Reduced phosphorylation of ALK7 in cells expressing ALK7 and ActRII receptors (e.g., ActRIIA or ActRIIB) in the presence of GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal; (f) Reduced phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal); K (determined by analysis) DThe ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0152] In some embodiments, the ALK7-binding protein specifically binds to ALK7 and comprises a set of CDRs having 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 compared to a reference CDR set, wherein: (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:19; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:20; (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:21; (iv) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:28; (v) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:29; and (vi) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:30; and wherein said protein binds to ALK7. In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of a complex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB), and activin B on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with one or more type II receptors; (c) competitively binding to ALK7 with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8); and (d) reducing the formation of a complex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB), and activin B on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; ... and (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8). (e) Phosphorylation of ALK7 in cells expressing ALK7 and ActRII receptors (e.g., ActRIIA or ActRIIB) in the presence of DF1, GDF3, GDF8, activin B, activin AB and / or Nodal; (e) Reduction of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal); (f) Phosphorylation of Smad (e.g., at ≤1 nM and ≥1 pM, e.g., by means of DF1, GDF3, GDF8, activin B, activin AB and / or Nodal) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal); K (determined by analysis) DThe ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0153] In some embodiments, the ALK7-binding protein specifically binds to ALK7 and comprises a set of CDRs having 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 compared to a reference CDR set, wherein: (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:37; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:38; (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:39; (iv) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:46; (v) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:47; and (vi) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:48; and wherein said protein binds to ALK7. In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of complexes containing ALK7, type II receptors (e.g., ActRIIA or ActRIIB), and one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8) on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with one or more type II receptors; and (c) binding with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8). (d) Competitive binding to ALK7 with GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal; (e) Reducing phosphorylation of ALK7 in cells expressing ALK7 and ActRII receptors (e.g., ActRIIA or ActRIIB) in the presence of GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal; (f) Reducing phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal); (c) Phosphorylation of Smad (e.g., Smad2 and / or Smad3) at ≤1 nM and ≥1 pM (e.g., as by...). K (determined by analysis) DThe ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0154] In some embodiments, the ALK7-binding protein specifically binds to ALK7 and comprises a set of CDRs having 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 compared to a reference CDR set, wherein: (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:55; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:56; (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:57; (iv) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:64; (v) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:65; and (vi) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:66; and wherein said protein binds to ALK7. In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of complexes containing ALK7, type II receptors (e.g., ActRIIA or ActRIIB), and one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8) on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with one or more type II receptors; and (c) binding with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8). (d) Competitive binding to ALK7 with GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal; (e) Reducing phosphorylation of ALK7 in cells expressing ALK7 and ActRII receptors (e.g., ActRIIA or ActRIIB) in the presence of GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal; (f) Reducing phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal); (c) Phosphorylation of Smad (e.g., Smad2 and / or Smad3) at ≤1 nM and ≥1 pM (e.g., as by...). K (determined by analysis) DThe ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0155] In some embodiments, the ALK7-binding protein specifically binds to ALK7 and comprises a set of CDRs having 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 compared to the reference CDR set, wherein: (a)(i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:88; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:89; (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:90; (iv) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:95; (v) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:96; and (vi) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:97; and wherein said protein binds to ALK7. In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of a complex containing ALK7, type II receptor (e.g., ActRIIA or ActRIIB), and activin B on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with ActRIIA or ActRIIB; (c) competitively binding to ALK7 with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8); and (d) reducing... (e) Reduced phosphorylation of ALK7 in cells expressing ALK7 and ActRII receptors (e.g., ActRIIA or ActRIIB) in the presence of GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal; (f) Reduced phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal); K (determined by analysis) DThe ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0156] In some embodiments, the ALK7-binding protein specifically binds to ALK7 and comprises a set of CDRs having 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 compared to a reference CDR set, wherein: (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO: 102; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO: 103; (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO: 104; (iv) VL-CDR1 comprises the amino acid sequence of SEQ ID NO: 107; (v) VL-CDR2 comprises the amino acid sequence of SEQ ID NO: 108; and (vi) VL-CDR3 comprises the amino acid sequence of SEQ ID NO: 109; and wherein said protein binds to ALK7. In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of a complex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB), and activin B on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with one or more type II receptors; (c) competitively binding to ALK7 with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8); and (d) reducing the formation of a complex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB), and activin B on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; ... and (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8). (e) Phosphorylation of ALK7 in cells expressing ALK7 and ActRII receptors (e.g., ActRIIA or ActRIIB) in the presence of DF1, GDF3, GDF8, activin B, activin AB and / or Nodal; (e) Reduction of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal); (f) Phosphorylation of Smad (e.g., at ≤1 nM and ≥1 pM, e.g., by means of DF1, GDF3, GDF8, activin B, activin AB and / or Nodal) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal); K (determined by analysis) DThe ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0157] In some embodiments, the ALK7-binding protein specifically binds to ALK7 and comprises a set of CDRs having 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 compared to a reference CDR set, wherein: (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO: 114; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO: 115; (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO: 116; (iv) VL-CDR1 comprises the amino acid sequence of SEQ ID NO: 121; (v) VL-CDR2 comprises the amino acid sequence of SEQ ID NO: 122; and (vi) VL-CDR3 comprises the amino acid sequence of SEQ ID NO: 123; and wherein said protein binds to ALK7. In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of complexes containing ALK7, type II receptors (e.g., ActRIIA or ActRIIB), and one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8) on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with one or more type II receptors; and (c) binding with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8). (d) Competitive binding to ALK7 with GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal; (e) Reducing phosphorylation of ALK7 in cells expressing ALK7 and ActRII receptors (e.g., ActRIIA or ActRIIB) in the presence of GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal; (f) Reducing phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal); (c) Phosphorylation of Smad (e.g., Smad2 and / or Smad3) at ≤1 nM and ≥1 pM (e.g., as by...). K (determined by analysis) DThe ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0158] In some embodiments, the ALK7-binding protein specifically binds to ALK7 and comprises a set of CDRs having 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 compared to a reference CDR set, wherein: (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:125; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:126; (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:127; (iv) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:132; (v) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:133; and (vi) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:134; and wherein said protein binds to ALK7. In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of complexes containing ALK7, type II receptors (e.g., ActRIIA or ActRIIB), and one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8) on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with one or more type II receptors; and (c) binding with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8). (d) Competitive binding to ALK7 with GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal; (e) Reducing phosphorylation of ALK7 in cells expressing ALK7 and ActRII receptors (e.g., ActRIIA or ActRIIB) in the presence of GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal; (f) Reducing phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal); (c) Phosphorylation of Smad (e.g., Smad2 and / or Smad3) at ≤1 nM and ≥1 pM (e.g., as by...). K (determined by analysis) DThe ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0159] In some embodiments, the ALK7-binding protein specifically binds to ALK7 and comprises a set of CDRs having 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 compared to a reference CDR set, wherein: (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:137; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:138; (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:139; (iv) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:145; (v) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:146; and (vi) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:147; and wherein said protein binds to ALK7. In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of complexes containing ALK7, type II receptors (e.g., ActRIIA or ActRIIB), and one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8) on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with one or more type II receptors; and (c) binding with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8). (d) Competitive binding to ALK7 with GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal; (e) Reducing phosphorylation of ALK7 in cells expressing ALK7 and ActRII receptors (e.g., ActRIIA or ActRIIB) in the presence of GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal; (f) Reducing phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal); (c) Phosphorylation of Smad (e.g., Smad2 and / or Smad3) at ≤1 nM and ≥1 pM (e.g., as by...). K (determined by analysis) DThe ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0160] In some embodiments, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein the CDR set 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 compared to the reference CDR set, wherein: (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:37; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:38; and (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:39 or 57; and the protein binds to ALK7. In another embodiment, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein: (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:37; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:38; and (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:39; and the protein binds to ALK7. In another embodiment, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein the CDR set 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 compared to the reference CDR set, wherein: (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:37; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:38; and (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:39; and the protein binds to ALK7. In another embodiment, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein the CDR set 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 compared to the reference CDR set, wherein: (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:37; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:38; and (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:57; and the protein binds to ALK7.In another embodiment, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein: (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:37; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:38; and (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:57; and the protein binds to ALK7. In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of complexes containing ALK7, type II receptors (e.g., ActRIIA or ActRIIB), and one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8) on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with one or more type II receptors; and (c) binding with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8). (d) Competitive binding to ALK7 with GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal in the presence of ALK7 and ActRII receptors (e.g., ActRIIA or ActRIIB); (e) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal); (f) Phosphorylation of Smad (e.g., Smad2 and / or Smad3) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal); (c) Phosphorylation of Smad (e.g., Smad2 and / or Smad3) with ≤1 nM and ≥1 pM (e.g., as by). K (determined by analysis) DThe ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0161] In some embodiments, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein the CDR set 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 compared to the reference CDR set, wherein: (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:1; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:2; and (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:3; and the protein binds to ALK7. In some embodiments, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein: (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:1; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:2; and (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:3; and the protein binds to ALK7. In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of complexes containing ALK7, type II receptors (e.g., ActRIIA or ActRIIB), and one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8) on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with one or more type II receptors; and (c) interacting with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3). (d) Competing with GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal to bind to ALK7; (e) Reducing phosphorylation of ALK7 in cells expressing ALK7 and ActRII receptors (e.g., ActRIIA or ActRIIB) in the presence of GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal; (f) Reducing phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal); (c) Phosphorylation of Smad (e.g., Smad2 and / or Smad3) at ≤1 nM and ≥1 pM (e.g., as by... K (determined by analysis) DThe ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0162] In some embodiments, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein the CDR set 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 compared to the reference CDR set, wherein: (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:19; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:20; and (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:21; and the protein binds to ALK7. In some embodiments, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein: (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:19; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:20; and (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:21; and the protein binds to ALK7. In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of complexes containing ALK7, type II receptors (e.g., ActRIIA or ActRIIB), and one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8) on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with one or more type II receptors; and (c) interacting with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3). (d) Competing with GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal to bind to ALK7; (e) Reducing phosphorylation of ALK7 in cells expressing ALK7 and ActRII receptors (e.g., ActRIIA or ActRIIB) in the presence of GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal; (f) Reducing phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal); (c) Phosphorylation of Smad (e.g., Smad2 and / or Smad3) at ≤1 nM and ≥1 pM (e.g., as by... K (determined by analysis) DThe ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0163] In another embodiment, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein the CDR set 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 compared to the reference CDR set, wherein: (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:37; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:38; and (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:39; and the protein binds to ALK7. In another embodiment, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:37; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:38; and (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:39; and the protein binds to ALK7. In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of complexes containing ALK7, type II receptors (e.g., ActRIIA or ActRIIB), and one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8) on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with one or more type II receptors; and (c) interacting with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3). (d) Competing with GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal to bind to ALK7; (e) Reducing phosphorylation of ALK7 in cells expressing ALK7 and ActRII receptors (e.g., ActRIIA or ActRIIB) in the presence of GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal; (f) Reducing phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal); (c) Phosphorylation of Smad (e.g., Smad2 and / or Smad3) at ≤1 nM and ≥1 pM (e.g., as by... K (determined by analysis) DThe ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0164] In another embodiment, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein the CDR set 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 compared to the reference CDR set, wherein: (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:55; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:56; and (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:57; and the protein binds to ALK7. In another embodiment, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:55; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:56; and (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:57; and the protein binds to ALK7. In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of complexes containing ALK7, type II receptors (e.g., ActRIIA or ActRIIB), and one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8) on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with one or more type II receptors; and (c) interacting with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3). (d) Competing with GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal to bind to ALK7; (e) Reducing phosphorylation of ALK7 in cells expressing ALK7 and ActRII receptors (e.g., ActRIIA or ActRIIB) in the presence of GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal; (f) Reducing phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal); (c) Phosphorylation of Smad (e.g., Smad2 and / or Smad3) at ≤1 nM and ≥1 pM (e.g., as by... K (determined by analysis) DThe ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0165] In some embodiments, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein the CDR set 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 compared to the reference CDR set, wherein: (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:88; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:89; and (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:90; and the protein binds to ALK7. In some embodiments, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein: (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:88; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:89; and (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:90; and the protein binds to ALK7. In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of complexes containing ALK7, type II receptors (e.g., ActRIIA or ActRIIB), and one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8) on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with one or more type II receptors; and (c) interacting with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3). (d) Competing with GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal to bind to ALK7; (e) Reducing phosphorylation of ALK7 in cells expressing ALK7 and ActRII receptors (e.g., ActRIIA or ActRIIB) in the presence of GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal; (f) Reducing phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal); (c) Phosphorylation of Smad (e.g., Smad2 and / or Smad3) at ≤1 nM and ≥1 pM (e.g., as by... K (determined by analysis) DThe ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0166] In some embodiments, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein the CDR set 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 compared to the reference CDR set, wherein: (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:102; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:103; and (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:104; and the protein binds to ALK7. In some embodiments, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein: (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:102; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:103; and (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:104; and the protein binds to ALK7. In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of complexes containing ALK7, type II receptors (e.g., ActRIIA or ActRIIB), and one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8) on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with one or more type II receptors; and (c) interacting with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3). (d) Competing with GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal to bind to ALK7; (e) Reducing phosphorylation of ALK7 in cells expressing ALK7 and ActRII receptors (e.g., ActRIIA or ActRIIB) in the presence of GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal; (f) Reducing phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal); (c) Phosphorylation of Smad (e.g., Smad2 and / or Smad3) at ≤1 nM and ≥1 pM (e.g., as by... K (determined by analysis) DThe ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0167] In another embodiment, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein the CDR set 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 compared to the reference CDR set, wherein: (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO: 114; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO: 115; and (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO: 116; and the protein binds to ALK7. In another embodiment, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO: 114; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO: 115; and (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO: 116; and the protein binds to ALK7. In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of complexes containing ALK7, type II receptors (e.g., ActRIIA or ActRIIB), and one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8) on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with one or more type II receptors; and (c) interacting with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3). (d) Competing with GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal to bind to ALK7; (e) Reducing phosphorylation of ALK7 in cells expressing ALK7 and ActRII receptors (e.g., ActRIIA or ActRIIB) in the presence of GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal; (f) Reducing phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal); (c) Phosphorylation of Smad (e.g., Smad2 and / or Smad3) at ≤1 nM and ≥1 pM (e.g., as by... K (determined by analysis) DThe ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0168] In another embodiment, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein the CDR set 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 compared to the reference CDR set, wherein: (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:125; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:126; and (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:127; and the protein binds to ALK7. In another embodiment, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:125; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:126; and (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:127; and the protein binds to ALK7. In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of complexes containing ALK7, type II receptors (e.g., ActRIIA or ActRIIB), and one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8) on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with one or more type II receptors; and (c) interacting with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3). (d) Competing with GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal to bind to ALK7; (e) Reducing phosphorylation of ALK7 in cells expressing ALK7 and ActRII receptors (e.g., ActRIIA or ActRIIB) in the presence of GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal; (f) Reducing phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal); (c) Phosphorylation of Smad (e.g., Smad2 and / or Smad3) at ≤1 nM and ≥1 pM (e.g., as by... K (determined by analysis) DThe ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0169] In another embodiment, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein the CDR set 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 compared to the reference CDR set, wherein: (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:137; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:138; and (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:139; and the protein binds to ALK7. In another embodiment, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:137; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:138; and (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:139; and the protein binds to ALK7. In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of complexes containing ALK7, type II receptors (e.g., ActRIIA or ActRIIB), and one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8) on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with one or more type II receptors; and (c) interacting with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3). (d) Competing with GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal to bind to ALK7; (e) Reducing phosphorylation of ALK7 in cells expressing ALK7 and ActRII receptors (e.g., ActRIIA or ActRIIB) in the presence of GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal; (f) Reducing phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB and / or Nodal); (c) Phosphorylation of Smad (e.g., Smad2 and / or Smad3) at ≤1 nM and ≥1 pM (e.g., as by... K (determined by analysis) DThe ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0170] In some embodiments, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VL-CDR1, VL-CDR2, and VL-CDR3, wherein the CDR set 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 compared to the reference CDR set, wherein: (i) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:10; (ii) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:11; and (iii) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:12; and wherein the protein binds to ALK7. In some embodiments, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VL-CDR1, VL-CDR2, and VL-CDR3, wherein: (i) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:10; (ii) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:11; and (iii) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:12; and wherein said protein binds to ALK7. In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of a complex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB), and one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8) on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with one or more type II receptors; and (c) competitively binding to ALK7 with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8). (d) Reduce phosphorylation of ALK7 in cells expressing ALK7 and type II receptors (e.g., ActRIIA or ActRIIB) in the presence of one or more TGF-β superfamily ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); (e) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); (f) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); K (determined by analysis) DThe ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0171] In some embodiments, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VL-CDR1, VL-CDR2, and VL-CDR3, wherein the CDR set 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 compared to the reference CDR set, wherein: (i) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:28; (ii) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:29; and (iii) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:30; and wherein the protein binds to ALK7. In some embodiments, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VL-CDR1, VL-CDR2, and VL-CDR3, wherein: (i) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:28; (ii) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:29; and (iii) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:30; and wherein said protein binds to ALK7. In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of a complex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB), and one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8) on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with one or more type II receptors; and (c) competitively binding to ALK7 with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8). (d) Reduce phosphorylation of ALK7 in cells expressing ALK7 and type II receptors (e.g., ActRIIA or ActRIIB) in the presence of one or more TGF-β superfamily ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); (e) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); (f) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); K (determined by analysis) DThe ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0172] In some embodiments, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VL-CDR1, VL-CDR2, and VL-CDR3, wherein the CDR set 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 compared to the reference CDR set, wherein: (i) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:46; (ii) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:47; and (iii) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:48; and wherein the protein binds to ALK7. In some embodiments, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VL-CDR1, VL-CDR2, and VL-CDR3, wherein: (i) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:46; (ii) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:47; and (iii) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:48; and wherein said protein binds to ALK7. In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of a complex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB), and one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8) on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with one or more type II receptors; and (c) competitively binding to ALK7 with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8). (d) Reduce phosphorylation of ALK7 in cells expressing ALK7 and type II receptors (e.g., ActRIIA or ActRIIB) in the presence of one or more TGF-β superfamily ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); (e) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); (f) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); K (determined by analysis) DThe ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0173] In some embodiments, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VL-CDR1, VL-CDR2, and VL-CDR3, wherein the CDR set 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 compared to the reference CDR set, wherein: (i) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:64; (ii) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:65; and (iii) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:66; and wherein the protein binds to ALK7. In some embodiments, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VL-CDR1, VL-CDR2, and VL-CDR3, wherein: (i) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:64; (ii) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:65; and (iii) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:66; and wherein said protein binds to ALK7. In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of a complex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB), and one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8) on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with one or more type II receptors; and (c) competitively binding to ALK7 with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8). (d) Reduce phosphorylation of ALK7 in cells expressing ALK7 and type II receptors (e.g., ActRIIA or ActRIIB) in the presence of one or more TGF-β superfamily ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); (e) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); (f) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); K (determined by analysis) DThe ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0174] In some embodiments, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VL-CDR1, VL-CDR2, and VL-CDR3, wherein the CDR set 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 compared to the reference CDR set, wherein: (i) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:95; (ii) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:96; and (iii) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:97; and wherein the protein binds to ALK7. In some embodiments, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VL-CDR1, VL-CDR2, and VL-CDR3, wherein: (i) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:95; (ii) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:96; and (iii) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:97; and wherein said protein binds to ALK7. In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of a complex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB), and one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8) on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with one or more type II receptors; and (c) competitively binding to ALK7 with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8). (d) Reduce phosphorylation of ALK7 in cells expressing ALK7 and type II receptors (e.g., ActRIIA or ActRIIB) in the presence of one or more TGF-β superfamily ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); (e) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); (f) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); K (determined by analysis) DThe ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0175] In some embodiments, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VL-CDR1, VL-CDR2, and VL-CDR3, wherein the CDR set 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 compared to the reference CDR set, wherein: (i) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:107; (ii) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:108; and (iii) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:109; and wherein the protein binds to ALK7. In some embodiments, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VL-CDR1, VL-CDR2, and VL-CDR3, wherein: (i) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:107; (ii) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:108; and (iii) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:109; and wherein said protein binds to ALK7. In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of a complex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB), and one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8) on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with one or more type II receptors; and (c) competitively binding to ALK7 with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8). (d) Reduce phosphorylation of ALK7 in cells expressing ALK7 and type II receptors (e.g., ActRIIA or ActRIIB) in the presence of one or more TGF-β superfamily ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); (e) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); (f) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); K (determined by analysis) DThe ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0176] In some embodiments, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VL-CDR1, VL-CDR2, and VL-CDR3, wherein the CDR set 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 compared to the reference CDR set, wherein: (i) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:121; (ii) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:122; and (iii) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:123; and wherein the protein binds to ALK7. In some embodiments, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VL-CDR1, VL-CDR2, and VL-CDR3, wherein: (i) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:121; (ii) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:122; and (iii) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:123; and wherein said protein binds to ALK7. In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of a complex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB), and one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8) on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with one or more type II receptors; and (c) competitively binding to ALK7 with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8). (d) Reduce phosphorylation of ALK7 in cells expressing ALK7 and type II receptors (e.g., ActRIIA or ActRIIB) in the presence of one or more TGF-β superfamily ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); (e) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); (f) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); K (determined by analysis) DThe ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0177] In some embodiments, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VL-CDR1, VL-CDR2, and VL-CDR3, wherein the CDR set 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 compared to the reference CDR set, wherein: (i) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:132; (ii) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:133; and (iii) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:134; and wherein the protein binds to ALK7. In some embodiments, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VL-CDR1, VL-CDR2, and VL-CDR3, wherein: (i) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:132; (ii) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:133; and (iii) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:134; and wherein said protein binds to ALK7. In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of a complex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB), and one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8) on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with one or more type II receptors; and (c) competitively binding to ALK7 with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8). (d) Reduce phosphorylation of ALK7 in cells expressing ALK7 and type II receptors (e.g., ActRIIA or ActRIIB) in the presence of one or more TGF-β superfamily ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); (e) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); (f) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); K (determined by analysis) DThe ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0178] In some embodiments, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VL-CDR1, VL-CDR2, and VL-CDR3, wherein the CDR set 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 compared to the reference CDR set, wherein: (i) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:145; (ii) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:146; and (iii) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:147; and wherein the protein binds to ALK7. In some embodiments, the ALK7 binding protein specifically binds to ALK7 and comprises a set of CDRs: VL-CDR1, VL-CDR2, and VL-CDR3, wherein: (i) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:145; (ii) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:146; and (iii) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:147; and wherein said protein binds to ALK7. In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of a complex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB), and one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8) on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with one or more type II receptors; and (c) competitively binding to ALK7 with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8). (d) Reduce phosphorylation of ALK7 in cells expressing ALK7 and type II receptors (e.g., ActRIIA or ActRIIB) in the presence of one or more TGF-β superfamily ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); (e) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); (f) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); K (determined by analysis) DThe ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0179] In some embodiments, the ALK7 binding protein comprises the VH-CDR3 or VL-CDR3 sequence disclosed herein. In other embodiments, the ALK7 binding protein comprises the VH-CDR3 or VL-CDR3 sequence disclosed in Table 1A. In some embodiments, the ALK7 binding protein comprises both the VH-CDR3 and VL-CDR3 sequences disclosed herein. In other embodiments, the ALK7 binding protein comprises the VH-CDR3 and VL-CDR3 sequences disclosed in Table 1A. In some embodiments, the ALK7 binding protein comprises the VH-CDR3 or VL-CDR3 sequence disclosed in Table 1B. In other embodiments, the ALK7 binding protein comprises the VH-CDR3 and VL-CDR3 sequences disclosed in Table 1B. In some embodiments, the ALK7 binding protein comprises the VH-CDR3 or VL-CDR3 sequence disclosed in Table 3. In other embodiments, the ALK7 binding protein comprises the VH-CDR3 and VL-CDR3 sequences disclosed in Table 3.

[0180] In some embodiments, this disclosure provides an ALK7 binding protein comprising VH-CDR3 having the amino acid sequence of SEQ ID NO:3. In another embodiment, the ALK7 binding protein comprises VH-CDR3 having the amino acid sequence of SEQ ID NO:3 and VH-CDR2 having the amino acid sequence of SEQ ID NO:2. In yet another embodiment, the ALK7 binding protein comprises VH-CDR3 having the amino acid sequence of SEQ ID NO:3, VH-CDR2 having the amino acid sequence of SEQ ID NO:2, and VH-CDR1 having the amino acid sequence of SEQ ID NO:1. In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of a complex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB), and one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8) on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with one or more type II receptors; and (c) competitively binding to ALK7 with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8). (d) Reduce phosphorylation of ALK7 in cells expressing ALK7 and type II receptors (e.g., ActRIIA or ActRIIB) in the presence of one or more TGF-β superfamily ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); (e) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); (f) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); K (determined by analysis) DThe ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0181] In some embodiments, this disclosure provides an ALK7 binding protein comprising VH-CDR3 having the amino acid sequence of SEQ ID NO:21. In another embodiment, the ALK7 binding protein comprises VH-CDR3 having the amino acid sequence of SEQ ID NO:21 and VH-CDR2 having the amino acid sequence of SEQ ID NO:20. In yet another embodiment, the ALK7 binding protein comprises VH-CDR3 having the amino acid sequence of SEQ ID NO:21, VH-CDR2 having the amino acid sequence of SEQ ID NO:20, and VH-CDR1 having the amino acid sequence of SEQ ID NO:19. In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of a complex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB), and one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8) on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with one or more type II receptors; and (c) competitively binding to ALK7 with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8). (d) Reduce phosphorylation of ALK7 in cells expressing ALK7 and type II receptors (e.g., ActRIIA or ActRIIB) in the presence of one or more TGF-β superfamily ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); (e) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); (f) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); K (determined by analysis) DThe ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0182] In some embodiments, the ALK7 binding protein comprises VH-CDR3 having the amino acid sequence of SEQ ID NO:39. In another embodiment, the ALK7 binding protein comprises VH-CDR3 having the amino acid sequence of SEQ ID NO:39 and VH-CDR2 having the amino acid sequence of SEQ ID NO:38. In yet another embodiment, the ALK7 binding protein comprises VH-CDR3 having the amino acid sequence of SEQ ID NO:39, VH-CDR2 having the amino acid sequence of SEQ ID NO:38, and VH-CDR1 having the amino acid sequence of SEQ ID NO:37. In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of a complex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB), and one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8) on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with one or more type II receptors; and (c) competitively binding to ALK7 with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8). (d) Reduce phosphorylation of ALK7 in cells expressing ALK7 and type II receptors (e.g., ActRIIA or ActRIIB) in the presence of one or more TGF-β superfamily ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); (e) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); (f) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); K (determined by analysis) DThe ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0183] In some embodiments, the ALK7 binding protein comprises VH-CDR3 having the amino acid sequence of SEQ ID NO:57. In another embodiment, the ALK7 binding protein comprises VH-CDR3 having the amino acid sequence of SEQ ID NO:57 and VH-CDR2 having the amino acid sequence of SEQ ID NO:56. In yet another embodiment, the ALK7 binding protein comprises VH-CDR3 having the amino acid sequence of SEQ ID NO:57, VH-CDR2 having the amino acid sequence of SEQ ID NO:56, and VH-CDR1 having the amino acid sequence of SEQ ID NO:55. In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of a complex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB), and one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8) on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with one or more type II receptors; and (c) competitively binding to ALK7 with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8). (d) Reduce phosphorylation of ALK7 in cells expressing ALK7 and type II receptors (e.g., ActRIIA or ActRIIB) in the presence of one or more TGF-β superfamily ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); (e) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); (f) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); K (determined by analysis) DThe ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0184] In another embodiment, this disclosure provides an ALK7 binding protein comprising VH-CDR1 having the amino acid sequence of SEQ ID NO:1. In another embodiment, this disclosure provides an ALK7 binding protein comprising VH-CDR1 having the amino acid sequence of SEQ ID NO:1 and VH-CDR2 having the amino acid sequence of SEQ ID NO:2. In another embodiment, this disclosure provides an ALK7 binding protein comprising VH-CDR1 having the amino acid sequence of SEQ ID NO:1, VH-CDR2 having the amino acid sequence of SEQ ID NO:2, and VH-CDR3 having the amino acid sequence of SEQ ID NO:3 or SEQ ID NO:21.

[0185] In another embodiment, this disclosure provides an ALK7 binding protein comprising VH-CDR2 having the amino acid sequence of SEQ ID NO:2. In another embodiment, the ALK7 binding protein comprises VH-CDR2 having the amino acid sequence of SEQ ID NO:2 and VH-CDR1 having the amino acid sequence of SEQ ID NO:1. In another embodiment, the ALK7 binding protein comprises VH-CDR2 having the amino acid sequence of SEQ ID NO:2, VH-CDR1 having the amino acid sequence of SEQ ID NO:1, and VH-CDR3 having the amino acid sequence of SEQ ID NO:3 or SEQ ID NO:21.

[0186] In another embodiment, this disclosure provides an ALK7 binding protein comprising VH-CDR1 having the amino acid sequence of SEQ ID NO:38. In another embodiment, this disclosure provides an ALK7 binding protein comprising VH-CDR1 having the amino acid sequence of SEQ ID NO:37 and VH-CDR2 having the amino acid sequence of SEQ ID NO:38. In another embodiment, this disclosure provides an ALK7 binding protein comprising VH-CDR1 having the amino acid sequence of SEQ ID NO:37, VH-CDR2 having the amino acid sequence of SEQ ID NO:38, and VH-CDR3 having the amino acid sequence of SEQ ID NO:39 or SEQ ID NO:57.

[0187] In another embodiment, this disclosure provides an ALK7 binding protein comprising VH-CDR2 having the amino acid sequence of SEQ ID NO:38. In another embodiment, the ALK7 binding protein comprises VH-CDR2 having the amino acid sequence of SEQ ID NO:38 and VH-CDR1 having the amino acid sequence of SEQ ID NO:37. In another embodiment, the ALK7 binding protein comprises VH-CDR2 having the amino acid sequence of SEQ ID NO:38, VH-CDR1 having the amino acid sequence of SEQ ID NO:37, and VH-CDR3 having the amino acid sequence of SEQ ID NO:39 or SEQ ID NO:57.

[0188] In some embodiments, this disclosure provides an ALK7 binding protein comprising VH-CDR3 having the amino acid sequence of SEQ ID NO:90. In another embodiment, the ALK7 binding protein comprises VH-CDR3 having the amino acid sequence of SEQ ID NO:90 and VH-CDR2 having the amino acid sequence of SEQ ID NO:89. In yet another embodiment, the ALK7 binding protein comprises VH-CDR3 having the amino acid sequence of SEQ ID NO:90, VH-CDR2 having the amino acid sequence of SEQ ID NO:89, and VH-CDR1 having the amino acid sequence of SEQ ID NO:88. In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of a complex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB), and one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8) on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with one or more type II receptors; and (c) competitively binding to ALK7 with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8). (d) Reduce phosphorylation of ALK7 in cells expressing ALK7 and type II receptors (e.g., ActRIIA or ActRIIB) in the presence of one or more TGF-β superfamily ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); (e) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); (f) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); K (determined by analysis) DThe ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0189] In some embodiments, this disclosure provides an ALK7 binding protein comprising VH-CDR3 having the amino acid sequence of SEQ ID NO:104. In another embodiment, the ALK7 binding protein comprises VH-CDR3 having the amino acid sequence of SEQ ID NO:104 and VH-CDR2 having the amino acid sequence of SEQ ID NO:103. In yet another embodiment, the ALK7 binding protein comprises VH-CDR3 having the amino acid sequence of SEQ ID NO:104, VH-CDR2 having the amino acid sequence of SEQ ID NO:103, and VH-CDR1 having the amino acid sequence of SEQ ID NO:102. In another embodiment, the ALK7 binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of a complex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB), and one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8) on the surface of cells expressing ALK7 and ActRII receptors in the presence of one or more TGF-β superfamily ligands; (b) competitively binding to ALK7 with one or more type II receptors; and (c) competitively binding to ALK7 with one or more TGF-β superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3, and / or GDF8). (d) Reduce phosphorylation of ALK7 in cells expressing ALK7 and type II receptors (e.g., ActRIIA or ActRIIB) in the presence of one or more TGF-β superfamily ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); (e) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); (f) Reduce phosphorylation of Smad (e.g., Smad2 and / or Smad3) in cells expressing ALK7 and type II receptors (e.g., ActRIIA and / or ActRIIB) in the presence of one or more TGF-β ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and / or Nodal); K (determined by analysis) DThe ALK7 binding protein binds to ALK7 and (g) reduces the formation of complexes containing ALK7, a co-receptor (e.g., cripto and / or cryptic), and one or more TGF-β superfamily ligands (e.g., Nodal). In some embodiments, the ALK7 binding protein is an ALK7 antagonist (e.g., neutralizing anti-ALK7 antibodies). In other embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis in adipocytes by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7 binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60% in lipolysis assays using adipocytes (e.g., white adipocytes). In another embodiment, the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, activin B, activin A / B, and Nodal. In some embodiments, the ALK7-binding protein has two, three, or four of the above characteristics. In some embodiments, the ALK7-binding protein has at least two, at least three, or at least four of the above characteristics.

[0190] In some embodiments, the ALK7 binding protein comprises VH-CDR3 having the amino acid sequence SEQ ID NO:116. In another embodiment, the ALK7 binding protein comprises VH-CDR3 having the am...

Claims

1. An ALK7 binding protein comprising a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, wherein the sequences of the set of CDRs consist of: (i) a VH-CDR1 sequence of SEQ ID NO: 114; (ii) a VH-CDR2 sequence of SEQ ID NO: 115; (iii) a VH-CDR3 sequence of SEQ ID NO: 116; (iv) a VL-CDR1 sequence of SEQ ID NO: 121; (v) a VL-CDR2 sequence of SEQ ID NO: 122; and (vi) a VL-CDR3 sequence of SEQ ID NO: 123; wherein the protein binds ALK7, and wherein the ALK7 binding protein is an antibody.

2. The ALK7 binding protein of claim 1, wherein the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are from a heavy chain variable region (VH) and a light chain variable region (VL) of: (i) a VH sequence of SEQ ID NO: 117, and (ii) a VL sequence of SEQ ID NO:

124.

3. An ALK7 binding protein comprising a VH and VL pair, wherein the VH and VL pair consists of: (i) a VH sequence of SEQ ID NO: 117, and (ii) a VL sequence of SEQ ID NO: 124; and wherein the protein binds ALK7.

4. The ALK7 binding protein of any one of claims 1-3, wherein the ALK7 binding protein antagonizes ALK7 activity.

5. The ALK7 binding protein of any one of claims 1-3, wherein the ALK7 binding protein increases lipolysis in adipocytes.

6. The ALK7 binding protein of claim 5, which increases lipolysis in white or brown adipocytes.

7. The ALK7 binding protein of claim 5, which antagonizes ALK7-mediated inhibition of lipolysis in adipocytes.

8. The ALK7 binding protein of claim 7, which antagonizes ALK7-mediated inhibition of lipolysis in white or brown adipocytes.

9. The ALK7 binding protein of claim 5, which increases lipolysis in adipocytes by 5% to 100%.

10. The ALK7 binding protein of claim 5, which increases lipolysis in adipocytes by 10% to 95%.

11. The ALK7 binding protein of claim 5, which increases lipolysis in adipocytes by 10% to 90%.

12. The ALK7 binding protein of claim 5, which increases lipolysis in adipocytes by 10% to 85%.

13. The ALK7 binding protein of claim 5, which increases lipolysis in adipocytes by 10% to 80%.

14. The ALK7 binding protein of claim 5, which increases lipolysis in adipocytes by 10% to 75%.

15. The ALK7 binding protein of claim 5, which increases lipolysis in adipocytes by 10% to 70%.

16. The ALK7 binding protein of claim 5, which increases lipolysis in adipocytes by 10% to 65%.

17. The ALK7 binding protein of claim 5, which increases lipolysis in adipocytes by 10% to 60%.

18. The ALK7 binding protein of claim 5, which increases lipolysis in adipocytes by 10% to 55%.

19. The ALK7 binding protein of claim 5, which increases lipolysis in adipocytes by 10% to 50%.

20. The ALK7 binding protein of claim 5, which increases lipolysis in adipocytes by 10% to 45%.

21. The ALK7 binding protein of claim 5, wherein lipolysis is determined in a lipolysis assay performed in the presence of one or more ALK7 ligands.

22. The ALK7 binding protein of claim 21, wherein the lipolysis assay is performed in the presence of one or more ALK7 ligands selected from the group consisting of: GDF1, GDF3, GDF8, Activin B, Activin AB, and Nodal.

23. The ALK7 binding protein of any one of claims 1-3, wherein the binding protein has at least one feature selected from the group consisting of: (a) reducing the formation of a complex containing ALK7, a Type II receptor, and one or more TGF-beta superfamily ligands on the surface of a cell expressing ALK7 and the Type II receptor in the presence of the one or more TGF-beta superfamily ligands; (b) competing with one or more Type II receptors for binding to ALK7; (c) competing with one or more TGF-beta superfamily ligands for binding to ALK7; (d) reducing phosphorylation of ALK7 in a cell expressing ALK7 and a Type II receptor in the presence of one or more TGF-beta superfamily ligands; (e) reducing phosphorylation of Smad in a cell expressing ALK7 and a Type II receptor in the presence of one or more TGF-beta ligands; (f) Kd of < 1 nM and > 1 pM D binding to ALK7; and (g) reducing the formation of a complex containing ALK7, a co-receptor, and one or more TGF-beta superfamily ligands.

24. The ALK7 binding protein of claim 23, wherein the Type II receptor is ActRIIA or ActRIIB.

25. The ALK7 binding protein of claim 23, wherein the one or more TGF-beta superfamily ligands are selected from the group consisting of: Activin B, Activin AB, Nodal, GDF1, GDF3, and GDF8.

26. The ALK7 binding protein of claim 23, wherein the Smad is Smad2 and / or Smad3.

27. The ALK7 binding protein of claim 23, wherein the K D as determined by BIACORE® analysis.

28. The ALK7 binding protein of claim 23, wherein the co-receptor is cripto and / or a cryptic co-receptor.

29. The ALK7 binding protein of claim 23, wherein the one or more TGF-beta superfamily ligand is Nodal.

30. The ALK7 binding protein of any one of claims 1-3, wherein the ALK7 binding protein increases glycerol production in adipocytes.

31. The ALK7 binding protein of any one of claims 1-3, wherein the ALK7 binding protein is an antibody that specifically binds ALK7.

32. The ALK7 binding protein of claim 31, wherein the antibody is a monoclonal antibody, a recombinant antibody, or an ALK7 binding antibody fragment of either thereof.

33. The ALK7 binding protein of claim 31, wherein the antibody is a humanized antibody or an ALK7 binding antibody fragment thereof.

34. The ALK7 binding protein of claim 31, wherein the antibody is a human antibody, a chimeric antibody, a bispecific antibody, a multispecific antibody, or an ALK7 binding antibody fragment of either thereof.

35. The ALK7 binding protein of any one of claims 32-34, wherein the ALK7 binding antibody fragment is selected from the group consisting of a Fab fragment, a Fab' fragment, a F(ab')2 fragment, a Fv fragment, a diabody, or a single-chain antibody molecule.

36. The ALK7 binding protein of claim 31, wherein 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.

37. The ALK7 binding protein of claim 31, wherein the antibody further comprises a light chain immunoglobulin constant domain selected from the group consisting of: (a) a human Ig kappa constant domain; and (b) a human Ig lambda constant domain.

38. The ALK7 binding protein of claim 31, wherein the antibody further comprises a human IgG1 heavy chain constant domain and a human lambda light chain constant domain.

39. A nucleic acid molecule or a set of nucleic acid molecules encoding the ALK7 binding protein of any one of claims 1-38.

40. The nucleic acid molecule or a set of nucleic acid molecules of claim 39, which is a cDNA.

41. The nucleic acid molecule or a set of nucleic acid molecules of claim 39 or 40, wherein the encoded ALK7 binding protein is an antibody.

42. The nucleic acid molecule of claim 39, wherein the nucleic acid molecule is operably linked to a control sequence.

43. A vector comprising the nucleic acid molecule of any one of claims 39-42.

44. A host cell comprising the nucleic acid molecule of any one of claims 39-42 or the vector of claim 43.

45. The host cell of claim 44, wherein the host cell is a mammalian host cell.

46. The mammalian host cell of claim 45, wherein the host cell is an NSO murine myeloma cell, a PER.C6® human cell, or a Chinese hamster ovary (CHO) cell.

47. A method of making the ALK7 binding protein of any one of claims 1-38, comprising culturing the host cell of any one of claims 44-46 under suitable conditions for production of the ALK7 binding protein.

48. The method of claim 47, further comprising isolating the ALK7 binding protein secreted from the host cell.

49. An ALK7 binding protein produced using the method of claim 47 or 48.

50. A pharmaceutical composition comprising the ALK7 binding protein of any one of claims 1-38 and a pharmaceutically acceptable carrier.

51. The pharmaceutical composition of claim 50, for use in the manufacture of a medicament.

52. The pharmaceutical composition of claim 50 or 51, wherein the ALK7 binding protein further comprises a labeling moiety selected from the group consisting of green fluorescent protein (GFP), blue fluorescent protein, cyan fluorescent protein, and yellow fluorescent protein (YFP).

53. The pharmaceutical composition of claim 52, wherein the labeling moiety is GFP, which is enhanced GFP.

54. The pharmaceutical composition of claim 52, wherein the labeling moiety is blue fluorescent protein selected from the group consisting of enhanced blue fluorescent protein (EBFP), EBFP2, Azurite, and mKalama1.

55. The pharmaceutical composition of claim 52, wherein the labeling moiety is cyan fluorescent protein selected from the group consisting of enhanced cyan fluorescent protein (ECFP), Cerulean, and CyPet.

56. The pharmaceutical composition of claim 52, wherein the labeling moiety is YFP selected from the group consisting of Citrine, Venus, and YPet.

57. The pharmaceutical composition of claim 50 or 51, wherein the ALK7 binding protein further comprises a labeling moiety selected from the group consisting of an isotopic label, a magnetic label, a redox-active moiety, an optical dye, a biotinylation moiety, and a polypeptide epitope.

58. The pharmaceutical composition of claim 57, wherein the polypeptide epitope is selected from the group consisting of a biotin signaling peptide, a histidine peptide, a hemagglutinin, a Flag, and a gold-binding peptide.

59. The pharmaceutical composition of claim 50 or 51, wherein the ALK7 binding protein further comprises an effector moiety selected from the group consisting of a radioisotope, a toxin, and a therapeutic agent.

60. The pharmaceutical composition of claim 59, wherein the effector group is a therapeutic agent, the therapeutic agent being a chemotherapeutic agent.

61. Use of the ALK7 binding protein of any one of claims 1-38 and 49 or the pharmaceutical composition of any one of claims 50-60 in the manufacture of a medicament for treating obesity, diabetes, insulin resistance, or fatty liver disease in a subject.

62. The use of claim 61, wherein the diabetes is type 2 diabetes.

63. The use of claim 61, wherein the fatty liver disease is non-alcoholic fatty liver disease.

64. The use of any one of claims 61-63, wherein the ALK7 binding protein or the pharmaceutical composition is administered alone or as a combination therapy.

Images