Anti-activin e antibodies

Abstract

Provided herein are anti-Activin E antibodies having specific complementarity determining regions (CDRs) for the heavy and light chains, heavy and light chains, antigen binding fragments thereof, polynucleotides that encode the same, vectors, and host cells, and methods for treating a metabolic disorder, type 2 diabetes, obesity, an elevated triglyceride level, lipodystrophy, liver inflammation, fatty liver disease, hypercholesterolemia, an elevated liver enzyme, nonalcoholic steatohepatitis (NASH), a cardiovascular disease, cardiomyopathy, high blood pressure, and / or heart failure with the anti-Activin E antibodies disclosed herein.

Description

ANTI-ACTIVIN E ANTIBODIESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U. S. Provisional Application Serial No. 63 / 737,980, filed December 23, 2024, U. S. Provisional Application Serial No. 63 / 764,665, filed February 28, 2025, U. S. Provisional Application Serial No. 63 / 823,081, filed June 13, 2025 and U. S. Provisional Application Serial No. 63 / 907,507, filed October 29, 2025, the entire contents of which are incorporated herein by reference.TECHNICAL FIELD OF THE INVENTION

[0002] This document relates to materials and methods for treating conditions involving Activin E, and particularly to the use of anti-Activin E antibodies and binding domains thereof.REFERENCE TO A SEQUENCE LISTING

[0003] The application contains a Sequence Listing which has been submitted electronically in. XML format and is hereby incorporated by reference in its entirety. Said. XML copy, created on December 23, 2025, is named “IBIO2031WO.xml” and is 581,360 bytes in size. The sequence listing contained in this. XML file is part of the specification and is hereby incorporated by reference herein in its entirety.BACKGROUND OF THE INVENTION

[0004] Without limiting the scope of the invention, its background is described in connection with treatments targeting Activin E.

[0005] Activin E is a peptide that's part of the transforming growth factor- (TGF- ) superfamily. It's produced in the liver and plays a role in energy homeostasis and metabolic health. These include energy homeostasis in which Activin E activates thermogenesis in adipose tissue, which can improve insulin sensitivity and reduce body fat mass. In metabolic health Activin E promotes adipose SMAD2 / 3 signaling, which can reduce lipid mobilization and promote inflammation. Finally, in liver-adipose communication Activin E is a hepatokine that links the liver and adipose tissue. It is believed that disrupting Activin E signaling could be a potential therapeutic target for obesity and diabetes.

[0006] One such treatment is taught by Lotta, et al, in U. S. Patent Publication No. 20220184114, entitled, “Methods of Treating Metabolic Disorders and Cardiovascular Disease With Inhibin Subunit Beta E (INHBE) Inhibitors”. These applicants are said to teach methods of treating a subject having metabolic disorders and / or cardiovascular diseases, methods of identifying subjects having an increased risk of developing a metabolic disorder and / or a cardiovascular disease, and methods of detecting human Inhibin Subunit Beta E variant nucleic acid molecules and variant polypeptides.

[0007] Despite these advances, a need remains for novel agents, methods of making those agents, and the use of such inhibitors of Activin E activity in vitro and in vivo for treating a wide variety of diseases or conditions such as metabolic disorders and cardiovascular disease.SUMMARY OF THE INVENTION

[0008] As embodied and broadly described herein, an aspect of the present disclosure relates to an anti-Activin E antibody or antigen binding domain thereof comprising comprises: a heavy chain variable domain (VH) complementarity determining region 1 (CDR1), VH CDR2, and VH CDR3 comprising an amino acid sequence of any one of the following SEQ ID NOs: 1, 2, 3; 11, 12, 13; 21, 22, 23; 31, 32, 33; 41, 42, 43; 51, 52, 53; 61, 62, 63; 71, 72, 73; 81, 82, 83; 91, 92, 93; 101, 102, 103; 111, 112, 113; 121, 122, 123; 131, 132, 133; 141, 142, 143; 151, 152, 153; 161, 162, 163; 171, 172, 173; 181, 182, 183; 191, 192, 193; 201, 202, 203; 211, 212, 213; 221, 222, 223; 231, 232, 233; 241, 242, 243; 251, 252, 253; 261, 262, 263; 271, 272, 273; 281, 282, 283; 291, 292, 293; 301, 302, 303; 311, 312, 313; 321, 322, 323; 331, 332, 333; 341, 342, 343; 351, 352, 353; 361, 362, 363; 371, 372, 373; 381, 382, 383; 391, 392, 393; 401, 402, 403; 411, 412, 413; 421, 422, 423; 431, 432, 433; 441, 442, 443; 451, 452, 453; 461, 462, 463; 471, 472, 473; 481, 482, 483; or 491, 492, 493, respectively; and a light chain variable domain (VL) CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of any one of the following SEQ ID NOs: 4, 5, 6; 14, 15, 16; 24, 25, 26; 34, 35, 36; 44, 45, 46; 54, 55, 56; 64, 65, 66; 74, 75, 76; 84, 85, 86; 94, 95, 96; 104, 105, 106; 114, 115, 116; 124, 125, 126; 134, 135, 136; 144, 145, 146; 154, 155, 156; 164, 165, 166; 174, 175, 176; 184, 185, 186; 194, 195, 196; 204, 205, 206; 214, 215, 216; 224, 225, 226; 234, 235, 236; 244, 245, 246; 254, 255, 256; 264, 265, 266; 274, 275, 276; 284, 285, 286; 294, 295, 296; 304, 305, 306; 314, 315, 316; 324, 325, 326; 334, 335, 336; 344, 345, 346; 354, 355, 356; 364, 365, 366; 374, 375, 376; 384, 385, 386; 394, 395, 396; 404, 405, 406; 414, 415, 416; 424, 425, 426; 434, 435, 436; 444, 445, 446; 454, 455, 456; 464, 465, 466; 474, 475, 476; 484, 485, 486; or 494, 495, 496, respectively. In one aspect, antibody comprises: a VH and VL pair comprising at least 95, 96, 97, 98, 99, or 100% sequence identify to SEQ ID NOS; 7, 8; 17, 18; 27, 28; 37, 38; 47, 48; 57, 58; 67, 68; 77, 78; 87, 88; 97, 98; 107, 108; 117, 118; 127, 128; 137, 138; 147, 148; 157, 158; 167, 168; 177, 178; 187, 188; 197, 198; 207, 208; 217, 218; 227, 228; 237, 238; 247, 248; 257, 258; 267, 268; 277, 278; 287, 288; 297, 298; 307, 308; 317, 318; 327, 328; 337, 338; 347, 348; 357, 358; 367, 368; 377, 378; 387, 388; 397, 398; 407, 408; 417, 418; 427, 428; 437, 438; 447, 448; 457, 458; 467, 468; 477, 478; 487, 488; or 497, 498. In another aspect, the antibody comprises: a heavy chain and light chain variable domains are encoded by a polynucleotide or polynucleotides comprising at least 95, 96, 97, 98, 99, or 100% sequence identify to SEQ ID NOS: 9, 10; 19, 20; 29, 30; 39, 40; 49, 50; 59, 60; 69, 70; 79, 80; 89, 90; 99, 100; 109, 110; 119, 120; 129, 130; 139, 140; 149, 150; 159, 160; 169, 170; 179, 180; 189, 190; 199, 200; 209, 210; 219, 220; 229, 230; 239, 240; 249, 250; 259, 260; 269, 270; 279, 280; 289, 290; 299, 300; 309, 310; 319, 320; 329, 330; 339, 340; 349, 350; 359, 360; 369, 370; 379, 380; 389, 390; 399, 400; 409, 410; 419, 420; 429, 430; 439, 440; 449, 450; 459, 460; 469, 470; 479, 480; 489, 490; 499, 500; or 601, 602. In another aspect, the antibody is a monoclonal antibody. In another aspect, the antibody is a full-length antibody. In another aspect, the antibody is an antibody fragment selected from F(ab’)2, Fab, Fab’, Fv, or scFv. In another aspect, the antibody comprises an Fc domain selected from one of the following: human IgGl, human IgG2, human IgG3, and human IgG4.

[0009] As embodied and broadly described herein, an aspect of the present disclosure relates to a method of treating a disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody described hereinabove.

[0010] As embodied and broadly described herein, an aspect of the present disclosure relates to a single chain fragment variable (scFv) Activin E antagonist comprising: a heavy chain variable domain (VH) complementarity determining region 1 (CDR1), VH CDR2, and VH CDR3 comprising an amino acid sequence of any one of the following SEQ ID NOs: 1, 2, 3; 11, 12, 13; 21, 22, 23; 31, 32, 33; 41, 42, 43; 51, 52, 53; 61, 62, 63; 71, 72, 73; 81, 82, 83; 91, 92, 93; 101, 102, 103; 111, 112, 113; 121, 122, 123; 131, 132, 133; 141, 142, 143; 151, 152, 153; 161, 162, 163; 171, 172, 173; 181, 182, 183; 191, 192, 193; 201, 202, 203; 211, 212, 213; 221, 222, 223; 231, 232, 233; 241, 242, 243; 251, 252, 253; 261, 262, 263; 271, 272, 273; 281, 282, 283; 291, 292, 293; 301, 302, 303; 311, 312, 313; 321, 322, 323; 331, 332, 333; 341, 342, 343; 351, 352, 353; 361, 362, 363; 371, 372, 373; 381, 382, 383; 391, 392, 393; 401, 402, 403; 411, 412, 413; 421, 422, 423; 431, 432, 433; 441, 442, 443; 451, 452, 453; 461, 462, 463; 471, 472, 473; 481, 482, 483; or 491, 492, 493; and a light chain variable domain (VL) CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of any one of the following SEQ ID NOs: 4, 5, 6; 14, 15, 16; 24, 25, 26; 34, 35, 36; 44, 45, 46; 54, 55, 56; 64, 65, 66; 74, 75, 76; 84, 85, 86; 94, 95, 96; 104, 105, 106; 114, 115, 116; 124, 125, 126; 134, 135, 136; 144, 145, 146; 154, 155, 156; 164, 165, 166; 174, 175, 176; 184, 185, 186; 194, 195, 196; 204, 205, 206; 214, 215, 216; 224, 225, 226; 234, 235, 236; 244, 245, 246; 254, 255, 256; 264, 265, 266; 274, 275, 276; 284, 285, 286; 294, 295, 296; 304, 305, 306; 314, 315, 316; 324, 325, 326; 334, 335, 336; 344, 345, 346; 354, 355, 356; 364, 365, 366; 374, 375, 376; 384, 385, 386; 394, 395, 396; 404, 405, 406; 414, 415, 416; 424, 425, 426; 434, 435, 436; 444, 445, 446; 454, 455, 456; 464, 465, 466; 474, 475, 476; 484, 485, 486; or 494, 495, 496, respectively. In one aspect, the scFv comprises at least 95, 96, 97, 98, 99, or 100% amino acid sequence identify to: 501; 503; 505; 507; 509; 511; 513; 515; 517; 519; 521; 523; 525; 527; 529; 531; 533; 535; 537; 539; 541; 543; 545; 547; 549; 551; 553; 555; 557; 559; 561; 563; 565; 567; 569; 571; 573; 575; 577; 579; 581; 583; 585; 587; 589; 591; 593; 595; 597; or 599. In another aspect, the scFv comprises at least 95, 96, 97, 98, 99, or 100% nucleic sequence identify to: 502; 504; 506; 508; 510; 512; 514; 516; 518; 520; 522; 524; 526; 528; 530; 532; 534; 536; 538; 540; 542; 544; 546; 548; 550; 552; 554; 556; 558; 560; 562; 564; 566; 568; 570; 572; 574; 576; 578; 580; 582; 584; 586; 588; 590; 592; 594; 596; 598; or 600. In another aspect, the scFv is a tandem scFv.

[0011] As embodied and broadly described herein, an aspect of the present disclosure relates to a method of treating a disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody described hereinabove. In one aspect, the disease is selected from at least one of: a metabolic disorder, type 2 diabetes, obesity, an elevated triglyceride level, lipodystrophy, liver inflammation, fatty liver disease, hypercholesterolemia, an elevated liver enzyme, nonalcoholic steatohepatitis (NASH), a cardiovascular disease, cardiomyopathy, high blood pressure, or heart failure. In another aspect, the subject is human.

[0012] As embodied and broadly described herein, an aspect of the present disclosure relates to a nucleic acid comprising an anti-Activin E antibody or antigen binding domain thereof, comprising: a heavy chainvariable domain (VH) complementarity determining region 1 (CDR1), VH CDR2, and VH CDR3 comprising an amino acid sequence of any one of the following SEQ ID NOs: 1, 2, 3; 11, 12, 13; 21, 22, 23; 31, 32, 33; 41, 42, 43; 51, 52, 53; 61, 62, 63; 71, 72, 73; 81, 82, 83; 91, 92, 93; 101, 102, 103; 111, 112, 113; 121, 122, 123; 131, 132, 133; 141, 142, 143; 151, 152, 153; 161, 162, 163; 171, 172, 173; 181, 182, 183; 191, 192, 193; 201, 202, 203; 211, 212, 213; 221, 222, 223; 231, 232, 233; 241, 242, 243; 251, 252, 253; 261, 262, 263; 271, 272, 273; 281, 282, 283; 291, 292, 293; 301, 302, 303; 311, 312, 313; 321, 322, 323; 331, 332, 333; 341, 342, 343; 351, 352, 353; 361, 362, 363; 371, 372, 373; 381, 382, 383; 391, 392, 393; 401, 402, 403; 411, 412, 413; 421, 422, 423; 431, 432, 433; 441, 442, 443; 451, 452, 453; 461, 462, 463; 471, 472, 473; 481, 482, 483; or 491, 492, 493; and a light chain variable domain (VL) CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of any one of the following SEQ ID NOs: 4, 5, 6; 14, 15, 16; 24, 25, 26; 34, 35, 36; 44, 45, 46; 54, 55, 56; 64, 65, 66; 74, 75, 76; 84, 85, 86; 94, 95, 96; 104, 105, 106; 114, 115, 116; 124, 125, 126; 134, 135, 136; 144, 145, 146; 154, 155, 156; 164, 165, 166; 174, 175, 176; 184, 185, 186; 194, 195, 196; 204, 205, 206; 214, 215, 216; 224, 225, 226; 234, 235, 236; 244, 245, 246; 254, 255, 256; 264, 265, 266; 274, 275, 276; 284, 285, 286; 294, 295, 296; 304, 305, 306; 314, 315, 316; 324, 325, 326; 334, 335, 336; 344, 345, 346; 354, 355, 356; 364, 365, 366; 374, 375, 376; 384, 385, 386; 394, 395, 396; 404, 405, 406; 414, 415, 416; 424, 425, 426; 434, 435, 436; 444, 445, 446; 454, 455, 456; 464, 465, 466; 474, 475, 476; 484, 485, 486; or 494, 495, 496, respectively. In one aspect, the antibody or antigen binding domain thereof comprises a heavy chain and light chain variable domain encoding polynucleotide having at least 95, 96, 97, 98, 99, or 100% sequence identify to SEQ ID NOS: 9, 10; 19, 20; 29, 30; 39, 40; 49, 50; 59, 60; 69, 70; 79, 80; 89, 90; 99, 100; 109, 110; 119, 120; 129, 130; 139, 140; 149, 150; 159, 160; 169, 170; 179, 180; 189, 190; 199, 200; 209, 210; 219, 220; 229, 230; 239, 240; 249, 250; 259, 260; 269, 270; 279, 280; 289, 290; 299, 300; 309, 310; 319, 320; 329, 330; 339, 340; 349, 350; 359, 360; 369, 370; 379, 380; 389, 390; 399, 400; 409, 410; 419, 420; 429, 430; 439, 440; 449, 450; 459, 460; 469, 470; 479, 480; 489, 490; and 499, 500. In another aspect, the e antibody is a monoclonal, bispecific, multivalent, multi-specific, diabody, chimeric, scFv antibody, or domain thereof. In another aspect, the scFv encodes a polypeptide that comprises at least 95, 96, 97, 98, 99, or 100% amino acid sequence identify to: 501; 503; 505; 507; 509; 511; 513; 515; 517; 519; 521; 523; 525; 527; 529; 531; 533; 535; 537; 539; 541; 543; 545; 547; 549; 551; 553; 555; 557; 559; 561; 563; 565; 567; 569; 571; 573; 575; 577; 579; 581; 583; 585; 587; 589; 591; 593; 595; 597; or 599. In another aspect, the scFv comprises at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% nucleic sequence identify to: 502; 504; 506; 508; 510; 512; 514; 516; 518; 520; 522; 524; 526; 528; 530; 532; 534; 536; 538; 540; 542; 544; 546; 548; 550; 552; 554; 556; 558; 560; 562; 564; 566; 568; 570; 572; 574; 576; 578; 580; 582; 584; 586; 588; 590; 592; 594; 596; 598; or 600. In another aspect, the antibody binding domain is fused to an Fc domain of any one of the following: human IgGl, human IgG2, human IgG3, and human IgG4. In another aspect, the nucleic acid sequence is optimized for expression in a bacterial, fungal, mammalian, insect, or plant cell.

[0013] As embodied and broadly described herein, an aspect of the present disclosure relates to a vector comprising the nucleic acid described hereinabove.

[0014] As embodied and broadly described herein, an aspect of the present disclosure relates to a host cell comprising nucleic acid the vector described hereinabove.

[0015] As embodied and broadly described herein, an aspect of the present disclosure relates to a method of treating a subject having or at risk of developing a metabolic disorder, type 2 diabetes, obesity, an elevated triglyceride level, lipodystrophy, liver inflammation, fatty liver disease, hypercholesterolemia, an elevated liver enzyme, nonalcoholic steatohepatitis (NASH), a cardiovascular disease, cardiomyopathy, high blood pressure, and / or heart failure, the method comprising administering an anti-Inhibin E antibody administering an antibody, scFv, or antigen binding domain thereof described hereinabove or any the nucleic acid described hereinabove to the subject. In another aspect, the anti-Activin antibody or binding domain thereof comprises a variable heavy chain and light chain nucleic acid sequence having at least 95, 96, 97, 98, 99, or 100% sequence identify to SEQ ID NOS: 9, 10; 19, 20; 29, 30; 39, 40; 49, 50; 59, 60; 69, 70; 79, 80; 89, 90; 99, 100; 109, 110; 119, 120; 129, 130; 139, 140; 149, 150; 159, 160; 169, 170; 179, 180; 189, 190; 199, 200; 209, 210; 219, 220; 229, 230; 239, 240; 249, 250; 259, 260; 269, 270; 279, 280; 289, 290; 299, 300; 309, 310; 319, 320; 329, 330; 339, 340; 349, 350; 359, 360; 369, 370; 379, 380; 389, 390; 399, 400; 409, 410; 419, 420; 429, 430; 439, 440; 449, 450; 459, 460; 469, 470; 479, 480; 489, 490; 499, 500; or 601, 602. In another aspect, the anti-Activin antibody or binding domain thereof comprises an scFv comprising at least 95, 96, 97, 98, 99, or 100% amino acid sequence identify to: 501; 503; 505; 507; 509; 511; 513; 515; 517; 519; 521; 523; 525; 527; 529; 531; 533; 535; 537; 539; 541; 543; 545; 547; 549; 551; 553; 555; 557; 559; 561; 563; 565; 567; 569; 571; 573; 575; 577; 579; 581; 583; 585; 587; 589; 591; 593; 595; 597; or 599. In another aspect, the subject is administered a therapeutic agent that treats or inhibits metabolic disorders or cardiovascular diseases in a standard dosage amount. In another aspect, the subject is administered a therapeutic agent that treats or inhibits metabolic disorders or cardiovascular diseases that is the same as or lower than a standard dosage amount.

[0016] As embodied and broadly described herein, an aspect of the present disclosure relates to a method of treating a subject with a therapeutic agent that treats or inhibits a metabolic disorder, type 2 diabetes, obesity, an elevated triglyceride level, lipodystrophy, liver inflammation, fatty liver disease, hypercholesterolemia, an elevated liver enzyme, nonalcoholic steatohepatitis (NASH), a cardiovascular disease, cardiomyopathy, high blood pressure, or heart failure, the method comprising administering an antibody or antigen binding domain thereof described hereinabove, or any the nucleic acid described hereinabove to the subject. In one aspect, the subject is administered or continued to be administered a therapeutic agent that treats or inhibits the metabolic disorder, type 2 diabetes, obesity, an elevated triglyceride level, lipodystrophy, liver inflammation, fatty liver disease, hypercholesterolemia, an elevated liver enzyme, nonalcoholic steatohepatitis (NASH), a cardiovascular disease, cardiomyopathy, high blood pressure, or heart failure in a standard dosage amount; or the subject is administered or continued to be administered the therapeutic agent that treats or inhibits the metabolic disorder, type 2 diabetes, obesity, an elevated triglyceride level, lipodystrophy, liver inflammation, fatty liver disease, hypercholesterolemia, an elevated liver enzyme, nonalcoholic steatohepatitis (NASH), a cardiovascular disease, cardiomyopathy, high blood pressure, or heart failure in an amount that is the same as or lower than a standard dosageamount. In another aspect, the metabolic disorder is selected from at least one of: type 2 diabetes, and the therapeutic agent is chosen from metformin, insulin, glyburide, glipizide, glimepiride, repaglinide, nateglinide, thiazolidinediones, rosiglitazone, pioglitazone, sitagliptin, saxagliptin, linagliptin, exenatide, liraglutide, semaglutide, canagliflozin, dapagliflozin, and empagliflozin, or any combination thereof; obesity, and the therapeutic agent is chosen from orlistat, phentermine, topiramate, bupropion, naltrexone, and liraglutide, or any combination thereof: elevated triglyceride, and the therapeutic agent is chosen from rosuvastatin, simvastatin, atorvastatin, fenofibrate, gemfibrozil, fenofibric acid, niacin, and an omega-3 fatty acid, or any combination thereof, lipodystrophy, and the therapeutic agent is chosen from tesamorelin, metformin, poly-L-lactic acid, calcium hydroxyapatite, polymethylmethacrylate, bovine collagens, human collagens, silicone, and hyaluronic acid, or any combination thereof; liver inflammation, and the therapeutic agent is a hepatitis therapeutic or a hepatitis vaccine; fatty liver disease include, and the subject is administered bariatric surgery and / or dietary intervention; hypercholesterolemia, and the therapeutic agent is chosen from: atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin calcium, simvastatin, cholestyramine, colesevelam, and colestipol, alirocumab, evolocumab, niaspan, niacor, fenofibrate, gemfibrozil, and bempedoic, or any combination thereof; an elevated liver enzyme, and the therapeutic agent is chosen from coffee, folic acid, potassium, vitamin B6, a statin, and fiber, or any combination thereof; or nonalcoholic steatohepatitis (NASH) and the therapeutic agent is obeticholic acid, Selonsertib, Elafibranor, Cenicriviroc, GR MD 02, MGL 3196, IMM124E, arachidyl amido cholanoic acid, GS0976, Emricasan, Volixibat, NGM282, GS9674, Tropifexor, MN 001, LMB763, BI 1467335, MSDC 0602, PF 05221304, DF102, Saroglitazar, BMS986036, Lanifibranor, Semaglutide, Nitazoxanide, GRI 0621, EYP001, VK2809, Nalmefene, LIK066, MT 3995, Elobixibat, Namodenoson, Foralumab, SAR425899, Sotagliflozin, EDP 305, Isosabutate, Gemcabene, TERN 101, KBP 042, PF 06865571, DUR928, PF 06835919, NGM313, BMS 986171, Namacizumab, CER 209, ND L02 s0201, RTU 1096, DRX 065, IGNIS DGAT2Rx, INT 767, NC 001, Seladepar, PXL770, TERN 201, NV556, AZD2693, SP 1373, VK0214, Hepastem, TGFTX4, RLBN1127, GKT 137831, RYI 018, CB4209-CB4211, and JH 0920. In another aspect, the cardiovascular disease is selected from at least one of: high blood pressure, and the therapeutic agent is chosen from chlorthalidone, chlorothiazide, hydrochlorothiazide, indapamide, metolazone, acebutolol, atenolol, betaxolol, bisoprolol fumarate, carteolol hydrochloride, metoprolol tartrate, metoprolol succinate, nadolol, benazepril hydrochloride, captopril, enalapril maleate, fosinopril sodium, lisinopril, moexipril, perindopril, quinapril hydrochloride, ramipril, trandolapril, candesartan, eprosartan mesylate, irbesartan, losartan potassium, telmisartan, valsartan, amlodipine besylate, bepridil, diltiazem hydrochloride, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, verapamil hydrochloride, doxazosin mesylate, prazosin hydrochloride, terazosin hydrochloride, methyldopa, carvedilol labetalol hydrochloride, alpha methyldopa, clonidine hydrochloride, guanabenz acetate, guanfacine hydrochloride, guanadrel, guanethidine monosulfate, reserpine, hydralazine hydrochloride, and minoxidil, or any combination thereof; cardiomyopathy, and the therapeutic agent is an ACE inhibitor, an angiotensin II receptor blocker, a beta blocker, a calcium channel blocker, digoxin, an antiarrhythmic, an aldosterone blocker, a diuretic, an anticoagulant, a blood thinner, and a corticosteroid; or heart failure, andthe therapeutic agent is an ACE inhibitor, an angiotensin-2 receptor blocker, a beta blocker, a mineralocorticoid receptor antagonist, a diuretic, ivabradine, sacubitril valsartan, hydralazine with nitrate, and digoxin.BRIEF DESCRIPTION OF THE DRAWINGS

[0017] For a more complete understanding of the features and advantages of the present invention, reference is now made to the detailed description of the invention along with the accompanying figures and in which:

[0018] FIG. 1 is a graph that shows the antagonism of Activin E at 0.2 nM by the antibodies in reporter cell line.

[0019] FIG. 2 is a graph that shows the antagonism of Activin E at 0.02 nM by candidate antibodies in reporter cell line.

[0020] FIG. 3A is a graph that shows the establishment of Activin E signaling assay in differentiated human adipocytes, and FIG. 3B is a graph that shows the antagonism of Activin E signaling in human adipocytes by AVE-06-H08 at 100 nM Activin E using the antibodies disclosed herein.

[0021] FIG. 4A to 4G show a Diet Induced Obesity (DIO) mouse model study plan and results. FIG. 4A shows the DIO mouse model study plan. FIG. 4B is a graph that shows baseline and vehicle corrected change in body weight post dose. 2-way ANOVA used for statistical measures to compare mean body weight at each timepoint to the vehicle only group. FIG. 4C is a graph that shows body composition analysis of total fat mass. Statistics calculated using 2-way ANOVA, and comparing to baseline value. FIG. 4D is a graph that shows body composition analysis of total lean mass. Statistics calculated using 2-way ANOVA, and comparing to baseline value. FIG. 4E is a graph that shows weight of various fat depots at terminal end point. One-way ANOVA used for statistical analysis. FIG. 4F is a graph that shows a histological analysis of eWAT adipose tissue from terminal endpoint, measuring adipocyte minimum diameter and area. One-way ANOVA used for statistical analysis. FIG. 4G shows representative images of adipocyte histology. One-way ANOVA used for statistical analysis.

[0022] FIGS. 5A to 5F show the study design and results for weight regain prevention in DIO mice. Semaglutide dosed daily, mAbs dosed twice per week. FIG. 5B are graphs that show the baseline and vehicle-corrected body weights. Arrow indicates initiation of BIW mAb dosing. 2-way ANOVA used for statistical analysis. FIG. 5C is a graph that shows the food intake, reported on per-mouse basis. FIG. 5D is a graph that shows the terminal liver weight. FIG. 5E is a graph that shows the terminal adipose depot weights. FIG. 5F is a graph that shows the Terminal quadriceps weight.

[0023] FIG. 6A shows the study design for PK study in obese mature nonhuman primates (NHPs). FIG.6B shows the non-human primate (NHP) selection criteria. FIG. 6C shows the serum concentration of AVE-06-H08_IgG4 at various timepoints. FIG. 6D shows the average serum concentration of AVE-06-H08_IgG4 with half-life calculated using linear elimination from days 14-56.DETAILED DESCRIPTION

[0024] While the making and using of various embodiments of the present invention are discussed in detail below, it should be appreciated that the present invention provides many applicable inventive concepts that can be embodied in a wide variety of specific contexts. The specific embodiments discussed herein are merely illustrative of specific ways to make and use the invention and do not delimit the scope of the invention.

[0025] To facilitate the understanding of this invention, a number of terms are defined below. Terms defined herein have meanings as commonly understood by a person of ordinary skill in the areas relevant to the present invention. Terms such as “a”, “an” and “the” are not intended to refer to only a singular entity, but include the general class of which a specific example may be used for illustration. The terminology herein is used to describe specific embodiments of the invention, but their usage does not delimit the invention, except as outlined in the claims.

[0026] It should be understood that, unless clearly indicated, in any method described or disclosed herein that includes more than one act, the order of the acts is not necessarily limited to the order in which the acts of the method are recited, but the disclosure encompasses exemplary embodiments in which the order of the acts is so limited.

[0027] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0028] Antibodies.

[0029] As used herein, the term “antibody” refers to an intact antibody or a binding fragment thereof that binds specifically to a target antigen - anti-Activin E. Antigen binding domains or fragments are produced by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact antibodies. Antibody binding domain(s) or fragment(s) include, e.g., antigen-binding domain or fragment (Fab), F(ab’)2 (mono-specific, bi-specific, or multivalent), fragment variable (Fv) containing VH and VL sequences, single chain variable domain or fragment (scFv) containing VH and VL sequences linked together in one chain (single, tandem, or multivalent), single chain antibody fragments (scAb) or other antibody variable region domain or fragment, such as retaining antigen binding specificity such as diabodies, minibodies, or combinations thereof. An antibody substantially inhibits adhesion of a receptor to a counterreceptor when an excess of antibody reduces the quantity of receptor bound to counterreceptor by at least about 20%, 40%, 60% or 80%, and more usually greater than about 85% (as measured in an in vitro competitive binding assay). The antigen binding domain or fragment of the disclosure retain anti-Activin E antigen binding specificity. Antibodies (Abs) and immunoglobulins (Igs) are glycoproteins having the same structural characteristics. The present invention includes monoclonal antibodies and binding fragments thereof that are completely recombinant, in other words, where the complementarity determining regions (CDRs) are genetically spliced into an antibody backbone, often referred to as veneering an antibody, e.g., a human antibody framework Thus, in certain aspects, the monoclonal antibody is a fully synthesized antibody. In certainembodiments, the monoclonal antibodies (and binding fragments thereof) can be made in bacterial or eukaryotic cells, including mammalian, non-mammalian animals, yeast, insect, or plant cells.

[0030] As used herein, a “subject” may be a mammalian subject. Mammalian subjects include, humans, non-human primates, rodents, (e.g., rats, mice), lagomorphs (e.g., rabbits), ungulates (e.g., cows, sheep, pigs, horses, goats, and the like), etc. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human primate, for example a cynomolgus monkey. In some embodiments, the subject is a companion animal (e.g., cats, dogs).

[0031] As used herein, the terms “antigen binding domain” or “antibody fragment” refers to a portion of a full-length antibody, generally the antigen-binding or variable region, and include Fab, Fab’, F(ab’)2, Fv, and scFv fragments. Papain digestion of antibodies produces two identical antigen-binding fragments, called the Fab fragment, each with a single antigen-binding site, and a residual “Fc” fragment, so-called for its ability to crystallize readily. Pepsin treatment yields an F(ab’)2 fragment that has two antigen-binding fragments which are capable of cross-linking antigen, and a residual other fragment (which is termed pFc’). As used herein, “functional fragment” with respect to antibodies, refers to Fv, F(ab) and F(ab’)2 fragments.

[0032] As used herein, the “fragment variable” or “Fv” fragment is the minimum antibody fragment that contains a complete antigen recognition and binding site. This region consists of a dimer of one heavy and one light chain variable domain in a tight, non-covalent association (VH-VL dimer). It is in this configuration that the three CDRs of each variable domain interact to define an antigen-binding site on the surface of the VH-VL dimer. Collectively, the six CDRs confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.

[0033] The Fab fragment, also designated as F(ab), also contains the constant domain of the light chain and the first constant domain (CHI) of the heavy chain. Fab’ fragments differ from Fab fragments by the addition of a few residues at the carboxyl terminus of the heavy chain CHI domain including one or more cysteines from the antibody hinge region. Fab’-SH is the designation herein for Fab’ in which the cysteine residue(s) of the constant domains have a free thiol group. F(ab’) fragments are produced by cleavage of the disulfide bond at the hinge cysteines of the F(ab’)2 pepsin digestion product. Additional chemical couplings of antibody fragments are known to those of ordinary skill in the art.

[0034] Native antibodies and immunoglobulins are usually hetero tetrameric glycoproteins of about 150,000 daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Each light chain is linked to a heavy chain by at least one covalent disulfide bond, however, the number of disulfide linkages varies between the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has at one end a variable domain (VH) followed by the constant domains. Each light chain has a variable domain at one end (VL) and a constant domain at its other end. The constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain. Particular amino acid residues are believed to form an interface between the light andheavy chain variable domains (Clothia et al., J. Mol. Biol. 186, 651-66, 1985); Novotny and Haber, Proc. Natl. Acad. Sci. USA 82:4592-4596 (1985), relevant portions incorporated herein by reference.

[0035] As used herein, an “isolated” antibody is one that has been identified and separated and / or recovered from a component of the environment in which it was produced. Contaminant components of its production environment are materials, which would interfere with diagnostic or therapeutic uses for the antibody, and may include enzymes, hormones, and other proteinaceous or nonproteinaceous solutes. In certain embodiments, the antibody will be purified as measurable by at least three different methods: 1) to greater than 50% by weight of antibody as determined by the Lowry method, such as more than 75% by weight, or more than 85% by weight, or more than 95% by weight, or more than 99% by weight; 2) to a degree sufficient to obtain at least 10 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequentator, such as at least 15 residues of sequence; or 3) to homogeneity by SDS-PAGE under reducing or non-reducing conditions using, e.g., Coomasie blue or silver stain. Isolated antibody includes the antibody in situ within recombinant cells since at least one component of the antibody’s natural environment will not be present. Ordinarily, however, isolated antibody will be prepared by at least one purification step.

[0036] As used herein, the terms “antibody mutant” or “antibody variant” refer to an amino acid sequence variant of an antibody wherein one or more of the amino acid residues have been modified. Such mutants or variants necessarily have less than 100% sequence identity or similarity with the amino acid sequence having at least 75% amino acid sequence identity or similarity with the amino acid sequence of either the heavy or light chain variable domain of the antibody, such as at least 80%, or at least 85%, or at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the amino acid and nucleic acid sequences disclosed herein. Generally, the “antibody mutant” or “antibody variant” will maintain the same CDR sequences (that is, CDR sequences having 100% sequence identity to the CDRs), but will have the variances of at least 80%, or at least 85%, or at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity in the framework regions. However, the skilled artisan will recognize that 100% sequence identity of the CDRs is not required, as conservative amino acid changes can be made to the CDRs, which can then be tested for binding of Activin E as taught herein, without undue experimentation.

[0037] As used herein, the term “variable” in the context of the variable domain of antibodies, refers to the fact that certain portions of the variable domains differ extensively in sequence among antibodies and are used in the binding and specificity of each particular antibody for its particular antigen. However, the variability is not evenly distributed through the variable domains of antibodies. It is concentrated in three segments called complementarity determining regions (CDRs) also known as hypervariable regions both in the light chain and the heavy chain variable domains. There are at least two techniques for determining CDRs: (1) an approach based on cross-species sequence variability (i.e., Kabat et al., Sequences of Proteins of Immunological Interest (National Institute of Health, Bethesda, Md. 1987); and (2) an approach based on crystallographic studies of antigen- antibody complexes (Chothia, C. et al. (1989), Nature 342: 877), or both, that is Chothia plus Kabat. The more highly conserved portions of variable domains are called the framework (FR). The variable domains of native heavy and light chains each comprise four FR regions,largely adopting a -sheet configuration, connected by three CDRs, which form loops connecting, and in some cases forming part of, the P-sheet structure. The CDRs in each chain are held together in close proximity by the FR regions and, with the CDRs from the other chain, contribute to the formation of the antigen-binding site of antibodies (see Rabat et al.) The constant domains are not involved directly in binding an antibody to its cognate antigen but exhibit various effector function, such as participation of the antibody in antibody-dependent cellular toxicity.

[0038] The light chains of antibodies (immunoglobulin) from any vertebrate species can be assigned to one of two clearly distinct types, called kappa and lambda, based on the amino sequences of their constant domain. Depending on the amino acid sequences of the constant domain of their heavy chains, “immunoglobulins” can be assigned to different classes. There are at least five (5) major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG-1, IgG-2, IgG-3, and IgG4; IgA-1 and IgA-2. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.

[0039] As used herein, the term “monoclonal antibody” refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to conventional (polyclonal) antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In additional to their specificity, the monoclonal antibodies are advantageous in that they are synthesized by the hybridoma culture, uncontaminated by other immunoglobulins. The modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the presently disclosed and claimed invention may be made by the hybridoma method first described by Kohler and Milstein, Nature 256, 495 (1975), relevant portions incorporated herein by reference.

[0040] All monoclonal antibodies used in accordance with the presently disclosed and claimed invention will be either (1) the result of a deliberate immunization protocol, as described in more detail hereinbelow; or (2) the result of an immune response that results in the production of antibodies naturally in the course of a disease or cancer.

[0041] The uses of the monoclonal antibodies of the presently disclosed and claimed invention may require administration of such or similar monoclonal antibody to a subject, such as a human. However, when the monoclonal antibodies are produced in a non-human animal, such as a rodent or chicken, administration of such antibodies to a human patient will normally elicit an immune response, wherein the immune response is directed towards the antibodies themselves. Such reactions limit the duration and effectiveness of such a therapy. In order to overcome such problem, the monoclonal antibodies of the presently disclosed and claimed invention can be “humanized”, that is, the antibodies are engineered such that antigenic portions thereof are removed and like portions of a human antibody are substituted therefore,while the antibodies’ affinity for Activin E is retained. This engineering may only involve a few amino acids, or may include entire framework regions of the antibody, leaving only the complementarity determining regions of the antibody intact. Several methods of humanizing antibodies are known in the art and are disclosed in U. S. Pat. No. 6,180,370, issued to Queen et al on Jan. 30, 2001; U. S. Pat. No.6,054,927, issued to Brickell on Apr. 25, 2000; U. S. Pat. No. 5,869,619, issued to Studnicka on Feb. 9, 1999; U. S. Pat. No. 5,861,155, issued to Lin on Jan. 19, 1999; U. S. Pat. No. 5,712,120, issued to Rodriquez et al on Jan. 27, 1998; and U. S. Pat. No. 4,816,567, issued to Cabilly et al on Mar. 28, 1989, relevant portions incorporated herein by reference.

[0042] Humanized forms of antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fab, Fab’, F(ab’)2, Fv, scFv or other antigen-binding subsequences of antibodies) that are principally comprised of the sequence of a human immunoglobulin, and contain minimal sequence derived from a non-human immunoglobulin. Humanization can be performed following the method of Winter and co-workers (Jones et al., 1986; Riechmann et al., 1988; Verhoeyen et al., 1988), by substituting nonhuman (i.e., rodent, chicken) CDRs or CDR sequences for the corresponding sequences of a human antibody, see, e.g., U. S. Pat. No. 5,225,539. In some instances, Fvframework residues of the human immunoglobulin are replaced by corresponding non-human residues from the donor antibody. Humanized antibodies can also comprise residues that are found neither in the recipient antibody nor in the imported CDR or framework sequences. In general, the humanized antibody will comprise substantially all of, at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions are those of a human immunoglobulin consensus sequence. The humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.

[0043] The presently disclosed and claimed invention further includes the use of fully human monoclonal antibodies cross-reactive against Activin E. Fully human antibodies essentially relate to antibody molecules in which the entire sequence of both the light chain and the heavy chain, including the CDRs, arise from human genes. Such antibodies are termed “human antibodies” or “fully human antibodies” herein. Human monoclonal antibodies can be prepared by, e.g., the trioma technique; the human B-cell hybridoma technique (see Kozbor, et al., Hybridoma, 2:7 (1983)) and the EBV hybridoma technique to produce human monoclonal antibodies (see Cole, et al., PNAS 82:859 (1985)), or as taught herein. Human monoclonal antibodies may be utilized in the practice of the presently disclosed and claimed invention and may be produced by using human hybridomas (see Cote, et al., PNAS 80:2026 (1983)) or by transforming human B-cells with Epstein Barr Virus in vitro (see Cole, et al., 1985), relevant portions incorporated herein by reference.

[0044] In addition, human antibodies can be made by introducing human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. Upon challenge, human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire. Thisapproach is described, for example but not by way of limitation, in U. S. Pat. Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016, and in Marks et al., J Biol. Chem. 267: 16007, (1992); Lonberg et al., Nature, 368:856 (1994); Morrison, 1994; Fishwild et al., Nature Biotechnol. 14:845 (1996); Neuberger, Nat. Biotechnol. 14:826 (1996); and Lonberg and Huszar, Int Rev Immunol. 13:65 (1995), relevant portions incorporated herein by reference.

[0045] A method for producing an antibody of interest, such as a human antibody, is disclosed in U. S. Pat. No. 5,916,771, issued to Hori et al. on Jun. 29, 1999, and incorporated herein by reference. It includes introducing an expression vector that contains a nucleotide sequence encoding a heavy chain into one mammalian host cell in culture, introducing an expression vector containing a nucleotide sequence encoding a light chain into another mammalian host cell, and fusing the two cells to form a hybrid cell. The hybrid cell expresses an antibody containing the heavy chain and the light chain.

[0046] As used herein, the term “isolated”, in regard to a nucleic acid molecule or a polypeptide, means that the nucleic acid molecule or polypeptide is in a condition other than its native environment, such as apart from blood and / or animal tissue. In some embodiments, an isolated nucleic acid molecule or polypeptide is substantially free of other nucleic acid molecules or other polypeptides, particularly other nucleic acid molecules or polypeptides of animal origin. In some embodiments, the nucleic acid molecule or polypeptide can be in a highly purified form, i.e., greater than 95, 95, 97, 98, 99% or 100% purity. When used in this context, the term “isolated” does not exclude the presence of the same nucleic acid molecule or polypeptide in alternative physical forms, such as dimers or phosphorylated or derivatized forms.

[0047] As used herein, the terms “nucleic acid”, “nucleic acid molecule”, “nucleic acid sequence”, “polynucleotide”, or “oligonucleotide” can comprise a polymeric form of nucleotides of any length, can comprise DNA and / or RNA, and can be single-stranded, double-stranded, or multiple stranded. One strand of a nucleic acid also refers to its complement.

[0048] As used herein, the term “treatment” refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those already with the disorder as well as those in which the disorder is to be prevented.

[0049] As used herein, the term “disorder” refers to any condition that would benefit from treatment with the polypeptide. This includes chronic and acute disorders or diseases including those infectious or pathological conditions that predispose the mammal to the disorder in question.

[0050] An antibody or antibody fragment can be generated with an engineered sequence or glycosylation state to confer preferred levels of activity in antibody-dependent cellular cytotoxicity (ADCC), antibodydependent cellular phagocytosis (ADCP), antibody-dependent neutrophil phagocytosis (ADNP), or antibody-dependent complement deposition (ADCD) functions as measured by bead-based or cell-based assays or in vivo studies in animal models.

[0051] Alternatively, or additionally, it may be useful to combine amino acid modifications with one or more further amino acid modifications that alter complement component Clq binding and / or the complement-dependent cytotoxicity (CDC) function of the Fc region of an IL-23pl9 binding molecule. The binding polypeptide of particular interest may be one that binds to Clq and displays complement-dependent cytotoxicity. Polypeptides with pre-existing Clq binding activity, optionally further having the ability to mediate CDC may be modified such that one or both of these activities are enhanced. Amino acid modifications that alter Clq and / or modify its complement-dependent cytotoxicity function are described, for example, in W0 / 0042072, which is hereby incorporated by reference.

[0052] An Fc region of an antibody can be designed to alter the effector function, e.g., by modifying Clq binding and / or FcyR binding and thereby changing complement-dependent cytotoxicity (CDC) activity and / or antibody-dependent cell-mediated cytotoxicity (ADCC) activity. These “effector functions” are responsible for activating or diminishing a biological activity (e.g., in a subject). Examples of effector functions include, but are not limited to: Clq binding; CDC; Fc receptor binding; ADCC; phagocytosis; down-regulation of cell surface receptors (e.g., B cell receptor; BCR), etc. Such effector functions may require the Fc region to be combined with a binding domain (e.g., an antibody variable domain) and can be assessed using various assays (e.g., Fc binding assays, ADCC assays, CDC assays, etc.).

[0053] As used herein, a single chain variable fragment (scFv) refers to a fusion of the variable regions of the heavy and light chains of immunoglobulins, linked together with a short (usually serine, glycine) linker. This chimeric molecule retains the specificity of the original immunoglobulin, despite removal of the constant regions and the introduction of a linker peptide. This modification usually leaves the specificity unaltered. These molecules were created historically to facilitate phage display where it is highly convenient to express the antigen-binding domain as a single peptide. Alternatively, scFv can be created directly from subcloned heavy and light chains derived from a hybridoma or B cell. Single chain variable fragments lack the constant Fc region found in complete antibody molecules, and thus, the common binding sites (e.g., protein A / G) used to purify antibodies. These fragments can often be purified / immobilized using Protein L since Protein L interacts with the variable region of kappa light chains.

[0054] Flexible linkers generally are comprised of helix- and turn-promoting amino acid residues such as alanine, serine, and glycine. However, other residues can function as well. Phage display can be used to rapidly select tailored linkers for single-chain antibodies (scFvs) from protein linker libraries. A random linker library was constructed in which the genes for the heavy and light chain variable domains were linked by a segment encoding an 18-amino acid polypeptide of variable composition. The scFv repertoire (approx. 5 x 106different members) is displayed on filamentous phage and subjected to affinity selection with hapten. The population of selected variants exhibited significant increases in binding activity but retained considerable sequence diversity. Sequence analysis revealed a conserved proline in the linker two residues after the VH C terminus and an abundance of arginines and prolines at other positions as the only common features of the selected tethers. In certain embodiments, the antibody fragments are further modified to increase their serum half-life by using modified Fc regions or mutations to the various constant regions, as are known in the art.

[0055] In certain embodiments, the antibodies of the present invention are formulated for administration to humans. For example, the antibodies of the present invention can be included in a pharmaceutical composition formulated for an administration that is: intranasal, intrapulmonary, intrabronchial, intravenous, oral, intraadiposal, intraarterial, intraarticular, intracranial, intradermal, intralesional,intramuscular, intrapericardial, intraperitoneal, intrapleural, intravesicular, local, mucosal, parenteral, enteral, subcutaneous, sublingual, topical, transbuccal, transdermal, via inhalation, via injection, in creams, in lipid compositions, via a catheter, via a lavage, via continuous infusion, via infusion, via local delivery, or via localized perfusion, and wherein the composition is a serum, drop, gel, ointment, spray, reservoir, or mist.

[0056] As used herein, the term “antigen” refers to a molecule containing one or more epitopes (either linear, conformational or both) that will stimulate a host’s immune-system to make a humoral and / or cellular antigen-specific response. The term is used interchangeably with the term “immunogen.” Normally, a B-cell epitope will include at least about 5 amino acids but can be as small as 3-4 amino acids. A T-cell epitope, such as a cytotoxic T lymphocyte (CTL) epitope, will include at least about 7-9 amino acids, and a helper T-cell epitope at least about 12-20 amino acids. Normally, an epitope will include between about 7 and 15 amino acids, such as, 9, 10, 12 or 15 amino acids. The term includes polypeptides, which include modifications, such as deletions, additions and substitutions (generally conservative in nature) as compared to a native sequence, so long as the protein maintains the ability to elicit an immunological response, as defined herein. These modifications may be deliberate, as through site-directed mutagenesis, or may be accidental, such as through mutations of hosts, which produce the antigens.

[0057] As used herein, the term “epitope” refers to a specific amino acid sequence or molecule (such as a carbohydrate, small molecule, lipid, etc.) that when present in the proper conformation, provides a reactive site for an antibody (e.g., B cell epitope) or in the case of a peptide to a T cell receptor (e.g., T cell epitope).

[0058] Portions of a given polypeptide that include a B-cell epitope can be identified using any number of epitope mapping techniques that are known in the art. (See, e.g., Epitope Mapping Protocols in Methods in Molecular Biology, Vol. 66, Glenn E. Morris, Ed., 1996, Humana Press, Totowa, N. J.). For example, linear epitopes can be determined by, e.g., concurrently synthesizing large numbers of peptides on solid supports, the peptides corresponding to portions of the protein molecule, and reacting the peptides with antibodies while the peptides are still attached to the supports. Such techniques are known in the art and described in, e.g., U. S. Pat. No. 4,708,871; Geysen et al. (1984) Proc. Natl. Acad Sci. USA 81:3998-4002; Geysen et al. (1986) Molec. Immunol. 23:709-715.

[0059] As used herein, the term “substantially purified” refers to isolation of a substance (compound, polynucleotide, protein, polypeptide, polypeptide composition) such that the substance comprises the majority percent of the sample in which it resides. Typically, in a sample a substantially purified component comprises 50%, preferably 80%-85%, more preferably 90-95% of the sample. Techniques for purifying polynucleotides and polypeptides of interest are well-known in the art and include, for example, ion-exchange chromatography, affinity chromatography and sedimentation according to density.

[0060] The practice of the present invention employs, unless otherwise indicated, conventional methods of chemistry, biochemistry, molecular biology, immunology and pharmacology, within the skill of the art. Such techniques are explained fully in the literature. See, e.g., Remington’s Pharmaceutical Sciences, 18th Edition (Easton, Pa.: Mack Publishing Company, 1990); Methods In Enzymology (S. Colowick and N. Kaplan, eds., Academic Press, Inc.); and Handbook of Experimental Immunology, Vols. I-IV (D. M. Weirand C. C. Blackwell, eds., 1986, Blackwell Scientific Publications); Sambrook, et al., Molecular Cloning: A Laboratory Manual (2nd Edition, 1989); Short Protocols in Molecular Biology, 4th ed. (Ausubel et al. eds., 1999, John Wiley & Sons); Molecular Biology Techniques: An Intensive Laboratory Course, (Ream et al., eds., 1998, Academic Press); PCR (Introduction to Biotechniques Series), 2nd ed. (Newton & Graham eds., 1997, Springer Verlag); Fundamental Virology, Second Edition (Fields & Knipe eds., 1991, Raven Press, New York), relevant portion incorporated herein by reference.

[0061] Conservative amino acid substitutions involve replacement of the aliphatic or hydrophobic amino acids Ala, Vai, Leu and lie; replacement of the hydroxyl residues Ser and Thr; replacement of the acidic residues Asp and Glu; replacement of the amide residues Asn and Gin, replacement of the basic residues Lys, Arg, and His; replacement of the aromatic residues Phe, Tyr, and Trp, and replacement of the smallsized amino acids Ala, Ser, Thr, Met, and Gly.

[0062] The present disclosure provides methods of treating a subject having a metabolic disorder or at risk of developing a metabolic disorder, the methods comprising administering an anti-Activin E antibody, scFv, or binding fragment thereof to the subject that is antagonistic to the activity of Activin E.

[0063] The present disclosure also includes methods of treating a subject having type 2 diabetes or at risk of developing type 2 diabetes, the methods comprising administering an inhibitory anti-Activin E antibody, scFv, or binding fragment thereof to the subject.

[0064] The present disclosure also includes methods of treating a subject having obesity or at risk of developing obesity, the methods comprising administering an inhibitory anti-Activin E antibody, scFv, or binding fragment thereof to the subject.

[0065] The present disclosure also includes methods of treating a subject having elevated triglyceride level (hypertriglyceridemia) or at risk of developing elevated triglyceride level (hypertriglyceridemia), the methods comprising administering an inhibitory anti-Activin E antibody, scFv, or binding fragment thereof to the subject.

[0066] The present disclosure also includes methods of treating a subject having lipodystrophy or at risk of developing lipodystrophy, the methods comprising administering an inhibitory anti-Activin E antibody, scFv, or binding fragment thereof to the subject.

[0067] The present disclosure also includes methods of treating a subject having liver inflammation or at risk of developing liver inflammation, the methods comprising administering an inhibitory anti-Activin E antibody, scFv, or binding fragment thereof to the subject.

[0068] The present disclosure also includes methods of treating a subject having fatty liver disease or at risk of developing fatty liver disease, the methods comprising administering an inhibitory anti-Activin E antibody, scFv, or binding fragment thereof to the subject.

[0069] The present disclosure also includes methods of treating a subject having hypercholesterolemia or at risk of developing hypercholesterolemia, the methods comprising administering an inhibitory anti-Activin E antibody, scFv, or binding fragment thereof to the subject.

[0070] The present disclosure also includes methods of treating a subject having elevated liver enzymes (such as, for example, alanine transaminase (ALT) and / or aspartate transaminase (AST)) or at risk ofdeveloping elevated liver enzymes (such as, for example, ALT and / or AST), the methods comprising administering an inhibitory anti-Activin E antibody, scFv, or binding fragment thereof to the subject.

[0071] The present disclosure also includes methods of treating a subject having nonalcoholic steatohepatitis (NASH) or at risk of developing NASH, the methods comprising administering an inhibitory anti-Activin E antibody, scFv, or binding fragment thereof to the subject.

[0072] The present disclosure also includes methods of treating a subject having a cardiovascular disease or at risk of developing a cardiovascular disease, the methods comprising administering an inhibitory anti-Activin E antibody, scFv, or binding fragment thereof to the subject.

[0073] The present disclosure also includes methods of treating a subject having cardiomyopathy or at risk of developing cardiomyopathy, the methods comprising administering an inhibitory anti-Activin E antibody, scFv, or binding fragment thereof to the subject.

[0074] The present disclosure also includes methods of treating a subject having heart failure or at risk of developing heart failure, the methods comprising administering an inhibitory anti-Activin E antibody, scFv, or binding fragment thereof to the subject.

[0075] The present disclosure also includes methods of treating a subject having high blood pressure or at risk of developing high blood pressure, the methods comprising administering an inhibitory anti-Activin E antibody, scFv, or binding fragment thereof to the subject.

[0076] The present disclosure also includes methods of treating a subject with a therapeutic agent that treats or inhibits a metabolic disorder comprising administering or continuing to administer to the subject the therapeutic agent that treats or inhibits the metabolic disorder in a standard dosage amount, and administering to the subject an inhibitory anti-Activin E antibody, scFv, or binding fragment thereof.

[0077] The present disclosure also includes methods of treating a subject with a therapeutic agent that treats or inhibits a cardiovascular disease, wherein the subject is suffering from a cardiovascular disease, comprising administering or continuing to administer to the subject the therapeutic agent that treats or inhibits the cardiovascular disease in a standard dosage amount, and administering to the subject an inhibitory anti-Activin E antibody, scFv, or binding fragment thereof.

[0078] For subjects that have an increased risk of developing a metabolic disorder, such as type 2 diabetes, lipodystrophy, liver inflammation, fatty liver disease, hypercholesterolemia, elevated liver enzymes (such as, for example, ALT and / or AST), obesity, high blood pressure, and / or elevated triglyceride level (hypertriglyceridemia), and / or a cardiovascular disease, such as cardiomyopathy, heart failure, and high blood pressure. These subjects can be treated with an inhibitory anti-Activin E antibody, scFv, or binding fragment thereof of the present disclosure.

[0079] In certain embodiments of the disclosure, the metabolic disorder is type 2 diabetes, obesity, NASH, and / or elevated triglyceride level. In any of the embodiments disclosed herein, the metabolic disorder is type 2 diabetes. In any of the embodiments disclosed herein, the metabolic disorder is obesity. In any of the embodiments disclosed herein, the metabolic disorder is NASH. In any of the embodiments disclosed herein, the metabolic disorder is elevated triglyceride level. In any of the embodiments disclosed herein, the metabolic disorder is lipodystrophy. In any of the embodiments disclosed herein, the metabolic disorderis liver inflammation. In any of the embodiments disclosed herein, the metabolic disorder is fatty liver disease. In any of the embodiments disclosed herein, the metabolic disorder is hypercholesterolemia. In any of the embodiments disclosed herein, the metabolic disorder is elevated liver enzymes (such as, for example, ALT and / or AST).

[0080] In addition, other metabolic disorders / conditions associated with body fat distribution also include, but are not limited to: type 2 diabetes, hyperlipidemia or dyslipidemia (high or altered circulating levels of low-density lipoprotein cholesterol (LDL-C), triglycerides, very low-density lipoprotein cholesterol (VLDL-C), apolipoprotein B or other lipid fractions), obesity (particularly abdominal obesity), lipodystrophy (such as an inability to deposit fat in adipose depots regionally (partial lipodystrophy) or in the whole body (lipoatrophy)), insulin resistance or higher or altered insulin levels at fasting or during a glucose or insulin challenge, liver fat deposition or fatty liver disease and their complications (such as, for example, cirrhosis, fibrosis, or inflammation of the liver), higher or elevated or altered liver enzyme levels or other markers of liver damage, inflammation or fat deposition, higher blood pressure and / or hypertension, higher blood sugar or glucose or hyperglycemia, metabolic syndrome, coronary artery disease, and other atherosclerotic conditions, and the complications of each of the aforementioned conditions.

[0081] In any of the embodiments disclosed herein, the cardiovascular disease is cardiomyopathy, heart failure, or high blood pressure. In any of the embodiments disclosed herein, the cardiovascular disease is cardiomyopathy. In any of the embodiments disclosed herein, the cardiovascular disease is heart failure. In any of the embodiments disclosed herein, the cardiovascular disease is high blood pressure.

[0082] The present disclosure provides methods of treating a subject having or at risk of developing a metabolic disorder, the methods comprising administering an inhibitory anti-Activin E antibody, scFv, or binding fragment thereof to the subject.

[0083] The present disclosure also includes methods of treating a subject having or at risk of developing type 2 diabetes, the methods comprising administering an inhibitory anti-Activin E antibody, scFv, or binding fragment thereof to the subject. The present disclosure also includes methods of treating a subject having or at risk of developing obesity, the methods comprising administering an inhibitory anti-Activin E antibody, scFv, or binding fragment thereof to the subject.

[0084] The present disclosure also includes methods of treating a subject having or at risk of developing elevated triglyceride level, the methods comprising administering an inhibitory anti-Activin E antibody, scFv, or binding fragment thereof to the subject.

[0085] The present disclosure also includes methods of treating a subject having or at risk of developing NASH, the methods comprising administering an inhibitory anti-Activin E antibody, scFv, or binding fragment thereof to the subject.

[0086] The present disclosure also includes methods of treating a subject having or at risk of developing lipodystrophy, the methods comprising administering an inhibitory anti-Activin E antibody, scFv, or binding fragment thereof to the subject.

[0087] The present disclosure also includes methods of treating a subject having or at risk of developing liver inflammation, the methods comprising administering an inhibitory anti-Activin E antibody, scFv, or binding fragment thereof to the subject.

[0088] The present disclosure also includes methods of treating a subject having or at risk of developing fatty liver disease, the methods comprising administering an inhibitory anti-Activin E antibody, scFv, or binding fragment thereof to the subject.

[0089] The present disclosure also includes methods of treating a subject having or at risk of developing hypercholesterolemia, the methods comprising administering an inhibitory anti-Activin E antibody, scFv, or binding fragment thereof to the subject.

[0090] The present disclosure also includes methods of treating a subject having or at risk of developing elevated liver enzymes (such as, for example, ALT and / or AST), the methods comprising administering an inhibitory anti-Activin E antibody, scFv, or binding fragment thereof to the subject.

[0091] The present disclosure also includes methods of treating a subject having or at risk of developing a cardiovascular disease, the methods comprising administering an inhibitory anti-Activin E antibody, scFv, or binding fragment thereof to the subject.

[0092] The present disclosure also includes methods of treating a subject having or at risk of developing cardiomyopathy, the methods comprising administering an inhibitory anti-Activin E antibody, scFv, or binding fragment thereof to the subject.

[0093] The present disclosure also includes methods of treating a subject having or at risk of developing heart failure, the methods comprising administering an inhibitory anti-Activin E antibody, scFv, or binding fragment thereof to the subject.

[0094] The present disclosure also includes methods of treating a subject having or at risk of developing high blood pressure, the methods comprising administering an inhibitory anti-Activin E antibody, scFv, or binding fragment thereof to the subject.

[0095] Engineered Epitope Design. Engineered epitopes were built to embody solvent-accessible epitopes on the human Activin E protein.

[0096] Peptide scaffolds were computationally designed to support the native sequence and structure of target epitopes with the iBio Engineered Epitope machine learning engine. The design process starts with an initial set of blueprints indicating the positions of the scaffold residues to design and the positions of the epitope residues to hold fixed. The machine learning engine optimizes the scaffold residues in these initial blueprints for [1] structural match to the native epitope structure, [2] overall structural stability of the molecule, and [3] solubility of the peptide design. The number of scaffold residues in the blueprints are then iteratively removed until the machine learning engine can no longer satisfy all three of the loss functions described above. The final design is based on the blueprint that satisfies all loss functions using the minimal number of scaffold residues.

[0097] When the engineered epitopes are made by peptide synthesis the peptides are biotinylated for in-vitro selection and antibody screening assays.

[0098] In-Vitro Antibody Selections. Antibody in-vitro selections were carried out with two rounds of phage display using a previously constructed naive library of fully human scfv sequences. 5 x 10 12 virions were used as the input for each phage display round.

[0099] In the first round of selection, streptavidin-coated magnetic beads were incubated with biotinylated PSR, followed by incubation with the phage display library. Phages that bound to PSR were captured by the beads and removed using the KINGFISHER™ system, while the unbound phages were retained for subsequent positive selection. In the positive selection step, the remaining phage pool was incubated with soluble biotinylated engineered epitope or avi-tagged Activin E. After competitive incubation, streptavidin-coated magnetic beads coupled with an anti-avi-tag antibody were added to specifically capture the engineered epitope or Activin E and any bound phages. Phages were then separated using the KINGFISHER™ system, washed to remove non-specifically bound phages, eluted from the beads, and amplified in bacterial host cells for use in the second round of selection.

[0100] In the second round, another round of negative selection was performed against biotinylated PSR using the same method as in the first round. For positive selection, the amplified phage pool was incubated with soluble avi-tagged Activin E. Streptavidin-coated magnetic beads coupled to an anti-avi-tag antibody were added to specifically capture the Activin E and any bound phages. These beads were separated using the KINGFISHER™ system, washed to remove any non-specifically bound phages, and the Activin E-bound phages were eluted and amplified for subsequent characterization.

[0101] Phagemid from the round 2 selection was collected by midiprep of the transduced E. coli from the phage propagation step. ScFv inserts were transferred into a soluble mammalian expression vector to enable monoclonal screening by SPR kinetics.

[0102] Label-Free Activin E Binding Kinetics as Measured by SPR. The binding kinetics of antibodies to Activin E were measured using a CARTERRA® LSA. All steps were conducted in IX HBST (HBS-T 0.01 M HEPES, 0.15 M NaCl, and 0.1% T20 at pH 7.4) + 0.05% BSA )bovine serum albumin) kinetics buffer. Antibodies were captured on an anti-Human Fc-functionalized HC200M chip for 25 minutes, followed by six buffer injections to establish a baseline. This was followed by a series of injections of Activin E, arranged in order of increasing concentration. Each injection cycle consisted of a baseline, followed by an association phase with Activin E, and then a dissociation step in the assay buffer. This was followed by two 40-second injections of 0.1M glycine at pH 2.0 to regenerate the anti-Fc capture surface. Kinetic parameters were then calculated from the data using the LSA Kinetics software.

[0103] Antibody Expression and purification. Antibody expression plasmids were transiently introduced into an animal cell line using the EXPIFECTAMINE™ CHO Transfection Kit (ThermoFisher; Cat# A29129) to yield transfectants that produced antibody. For a host cell line, ExpiCHO-S (ThermoFisher; Cat# A29127) was used. After 6-12 days of growth post introduction of DNA, cell suspensions of ExpiCHO™ were harvested via centrifugation for 20 min at 4,000xg, and then filtered using 0.2 µm Disposable PES Filter units (FisherScientific, Cat# FB12566504). Antibody was recovered from filtrate using Protein A purification (HiTrap™ MabSelect SuRe™; Cytiva Cat# GE11-0034-93).

[0104] HEK293SBE / ALK7 SMAD Signaling Assay. HEK293 cells stably expressing a luciferase reporter gene linked to a SMAD binding element promoter (SBE) (BPS Bioscience, Cat# 60653) were transfected with human ALK7 expression plasmid (Sino Biologicals, Cat# HG10869-UT) using Lipofectamine 3000 (ThermoFisher, Cat# L3000001) as indicated in manufacturer’s instructions. The transfected cells were selected for ALK7 expression using 100 ug / mL hygromycin B (ThermoFisher, Cat# 10687010) until the mock transfection control cells have no viable cells remaining. A monoclonal cell population was isolated from the polyclonal pool of ALK7 stable cells via limiting dilution then tested for ALK7 expression and activity. The resulting HEK293SBE / ALK7 reporter cell line was cultured in MEM media (Cytiva, Cat# SH30024.01) supplemented with 10% FBS (Millipore Sigma, Cat# F4135), 1% non-essential amino acids (Gibco, Cat# 11140-050), 1 mM Na pyruvate (Gibco, Cat#l 1360-070), 1% Penicillin / Streptomycin (Corning, Cat# 30-002-CI), 400 pg / mL of Geneticin (Gibco, Cat#10131035) and 100 ug / mL hygromycin B.

[0105] To determine SMAD 2 / 3 activation, the HEK293SBE / ALK7 cells were seeded in white, clear bottom 384-well plate (Greiner Bio-One, Cat#781098) at 3000 cells / well using Assay Media consisting of MEM media supplemented with 0.5% FBS (Gibco, Cat# 26400044), 1% non-essential amino acids, 1 mM Na pyruvate, and 1% Penicillin / Streptomycin. 18-24 hours following plating, the cells were treated with the indicated antibodies at final dose range of 0.001-66.67 nM after an one hour, 37°C / 5% CO2, antibody pre-incubation with either 0.02 nM Activin E (qKine, Cat# Qk067), 5 nM Myostatin (PeproTech, Cat#120-00), 5 nM GDF-11 (PeproTech, Cat# 120- 11), 1 nM Activin A (PeproTech, Cat#120-14E), or 1 nM Activin C (R& D Systems, Cat# 1629-AC) final concentration for each ligand. Following 18 hours of antibody / ligand incubation, 1 volume of ONE-Step Luciferase reagent (BPS Bioscience, Cat# 60690) was added to cells and plates were shaken for 15 minutes at room temperature to facilitate lysis according to manufacturer’s instructions. After 15 minutes, luminescence was read on a SpectraMax ID5 (Molecular Devices) with 1000 ms integration time. GraphPad Prism 10.2.2 was used to calculate IC50 values, generate graphs, and perform statistical analysis.

[0106] pSmad2 assay. Primary human visceral preadipocyte cells were purchased from Lonza (Cat# PT-5005). The cells were cultured in PMG-2 preadipocyte growth media -2 bulletkit (Lonza, Cat# PT-8002), Cell passage 3rd- 10thwere used for this experiment.

[0107] To evaluate the activins induced pSmads protein in differentiated adipocytes, preadipocyte cells were seeded at 10,000 cells per well in a 96-well plate (Coming, high throughput content imaging, cat #4680) and incubated overnight in a cell culture incubator. Cell samples were then treated with differentiation media (Lonza, Cat#PT-3004) to induced preadipocyte differentiate into adipocytes. Adipocytes post differentiation 4days-6days were used for this assay.

[0108] To induce Smad2 protein phosphorylation, Adipocytes post differentiation 4days-6days were treated with the indicated antibodies at a final dose range of 0.27-200 nM after a one-hour pre-incubation at room temperature with either Activin E, or Activin C, at a final concentration of 100nM for each ligand. Cell samples were incubated in a cell culture incubator at 37°C with 5% CO2 for 30 minutes. After incubation, the samples were washed twice with lx PBS and then fixed with 4% paraformaldehyde(Thermo Scientific, Cat# J19943. K2) for 30 minutes at room temperature. The samples were then washed twice with lx PBS and blocked with blocking buffer (2% FBS, 0.2% Triton X-100 in lx PBS) for 1 hour at room temperature. Prepare the anti-pSmad2 antibody by diluting the stock antibody 1:100 and DAPI 1: 10000 in antibody dilution buffer (2% FBS, 0.01% Triton X-100 in lx PBS). Remove the blocking buffer and add 25 pL / well of the antibody solution. Incubate the samples for 1 hour at room temperature. Remove the antibody solution and wash the samples twice with lx.

[0109] PBS. The samples are now ready for imaging. Acquire images of the samples using a 20x objective on the IMAGEEXPRESS® (Molecular Devices). Analyze the samples using custom analysis with IMAGEEXPRESS® software. GraphPad Prism 10.2.2 was used to calculate EC50 values and generate graphs.

[0110] Exemplary Anti-Activin E Antibodies - CDR Sequences.

[0111] Provided herein are sequences for exemplary Anti-Activin E antibodies of the disclosure. Included are complementarity determining region (CDR) sequences and the variable heavy and light domain sequences (VH, VL) that constitute the Activin E antigen binding domains of the disclosure. The discovery of these antibodies is detailed in the Examples section.

[0112] As referred below, a light chain variable (VL) domain CDR1 region is referred to as CDR-L1; a VL CDR2 region is referred to as CDR-L2; a VL CDR3 region is referred to as CDR-L3; a heavy chain variable (VH) domain CDR1 region is referred to as CDR-H1; a VH CDR2 region is referred to as CDR-H2; and a VH CDR3 region is referred to as CDR-H3. Table 1 provides exemplary CDR combinations of antibodies of the disclosure.

[0113] Table 1: Exemplary Activin E antagonist antibody, scFv, or antigen binding domain complementarity determining regions (CDR) combinations (heavy chain CDR - hCDRl-3, light chain 1CDR1-3).Clone ID hCDRl hCDR2 hCDR3 1CDR1 1CDR2 1CDR3 AVE-01- GFAFNNY ISGSGTSK AKPRPGSIFWG QSISSY AAS QQSYGS D07 A AGPFDY PT SEQ ID 1 2 3 4 5 6 NO AVE-01- GFTFGASA ISGLGRTT ARVAPGAYAY QNIGHY DAS QQSYSTP B08 AMDY PT SEQ ID 11 12 13 14 15 16 NO AVE-02- GFNFRSYV ISDVGRR AKAEILGDYA ESIGNY AAS QQSYSTP A03 T YMDY T SEQ ID 21 22 23 24 25 26 NO AVE-02- GFAFSAYA ITESGAA ARGLLASYTG QSISSY ATS QQRDNA B04 T DV PWT SEQ ID 31 32 33 34 35 36 NO AVE-06- GFDFSSFA ITGSGGTI ASASSYYEPG QAIKNY AGS QQTYSTP B07 DP LT SEQ ID 41 42 43 44 45 46NOAVE-06- GFPFSSHG ITGSGRST ASDYRDAPGT QSISSY DAS QQSYSTP F07 FDV V SEQ ID 51 52 53 54 55 56 NO AVE-06- GFPFASHA ITGSGRST ASDYRDAPGT QSISSY DAS QQSYSTP A08 FDV V SEQ ID 61 62 63 64 65 66 NO AVE-06- GFDFSKFA ISGSGGTI ASASSYYEPG QAIKNY DAS QQSYSTP D08 DP V SEQ ID 71 72 73 74 75 76 NO AVE-06- GFDFSKFA ISGSGGTI ASDSSYYEPG QAIKNY AGS QQTYSTP G08 DP LT SEQ ID 81 82 83 84 85 86 NO AVE-06- GFDFSKFA ITRGSETT ATLGLGYYYY QPISSY SAS QQSYNA H08 FDV PPT SEQ ID 91 92 93 94 95 96 NO AVE-06- GFPFASHA ITGSGRST ASASSYYEPG QTISSF AAT QQSYHT A09 DP RS SEQ ID 101 102 103 104 105 106 NO AVE-06- GLTFSNFA IRGSGAT ARSREAYGFD QSISSY AAS QQSYSTP B09 T YT SEQ ID 111 112 113 114 115 116 NO AVE-06- GFTFSHYS ISGSGSAT ASDRYLTFDV QSISTH AAS QQSHRT D09 PLI SEQ ID 121 122 123 124 125 126 NO AVE-06- GFDFSKFA ISGSGGTI ASASSYYEPG QAIKNY AGS QQTYSTP F09 DP LT SEQ ID 131 132 133 134 135 136 NO AVE-06- GFSFDNYG ISSSGGSA ARGVVPGGFD QSINNY AAS QQSRTTP G09 WT SEQ ID 141 142 143 144 145 146 NO AVE-06- GFDFSKFA ITGTSGA ARDIRVRRSS QTIGIY SAS QQSYSTP C10 T WAMDP HIT SEQ ID 151 152 153 154 155 156 NO AVE-06- GFDFSKFA ISGSGGTI ASASSYYEPG QAIKNY AGS QQTYSTP G10 DP LT SEQ ID 161 162 163 164 165 166 NO AVE-06- GFTFTNYA ISGSGGTI ASASSYYEPG QAIKNY AGS QQTYSTP H10 DP LT SEQ ID 171 172 173 174 175 176 NO AVE-06- GFDFSKFA ISGSGGTI ASASSYYEPG QAIKNY AGS QQTYSTP Bll DP LT SEQ ID 181 182 183 184 185 186NOAVE-06- GIRFSSYA ISGSGGTI ASASSYYEPG QAIKNY AGS QQTYSTP Ell DP LT SEQ ID 191 192 193 194 195 196 NO AVE-06- GFDFSKFV ISGSGGTI ASASSYYEPG QAIKNY AGS QQTYSTP Hll DP LT SEQ ID 201 202 203 204 205 206 NO AVE-06- GFDFSKFA ISGSGGTI ASASSYYEPG QAIKNY AGS QQNYST A12 DP PFA SEQ ID 211 212 213 214 215 216 NO AVE-06- GFDFSKFA ISGSGGTI ASASSYYEPG QAIKNY AGS QQTYSTP B12 DP LT SEQ ID 221 222 223 224 225 226 NO AVE-06- GFDFSKFA ISGSGGTI ASASSYYEPG QAIKNY AGS QQNYST C12 DP PLT SEQ ID 231 232 233 234 235 236 NO AVE-06- GFPFSSHG ISGSGATT ARGQPYYGFD HSIASY RAS QQTYSIP E12 WT SEQ ID 241 242 243 244 245 246 NO AVE-06- GFDFSKFA ISGSGGTI ASASSYYEPG QAIKNY GAS QQSESTP G12 DP LT SEQ ID 251 252 253 254 255 256 NO AVE-07- GFALTDFA ISVSGGV ARSRSYYAGA APVGRY AAS QQSYSA A01 G FDV VT SEQ ID 261 262 263 264 265 266 NO AVE-07- GFTFGSYA IGTTDRY ARSRSYYAGA QTLRNY AAS QQRFSPP B01 T FDV WT SEQ ID 271 272 273 274 275 276 NO AVE-07- GYTFSNFA ITGSGVR ARSRSYYAGA QSIGSS AAS QQSDNN C01 T FDV PWT SEQ ID 281 282 283 284 285 286 NO AVE-07- GFTFNNA ISSSGGYT ARSRSYYAGA APVGRY AAS QQAYSIP D01 W FDV IT SEQ ID 291 292 293 294 295 296 NO AVE-07- GFSVRDFA ITGTDRTP ARSRSYYAGA QNIFSY AAS QQTHSIP E01 FDV QT SEQ ID 301 302 303 304 305 306 NO AVE-07- GFTFSSHN IGGGGRT ARAAPGAYAY QRISTY GAS QQTYSTP F01 T ALDY PT SEQ ID 311 312 313 314 315 316 NO AVE-07- GFSVRDFA IRISGGGT ARAAPGAYAY QRISTY SAS QQNYRT C02 ALDY PPT SEQ ID 321 322 323 324 325 326NOAVE-07- GFTFSNYA ITSSASKT ARTRYLERFA QSISSY AAS QQSFTAP F02 GGLDI LT SEQ ID 331 332 333 334 335 336 NO AVE-07- GLTFSNYT ISGTGGST ARSRSYYAGA VSISTF AAS QQSLRTP G02 FDV IT SEQ ID 341 342 343 344 345 346 NO AVE-07- GFPFSSFV LSGSGDIT ARAAPGAYAY QSVSTY AAS QQSYRT H03 ALDY PPT SEQ ID 351 352 353 354 355 356 NO AVE-07- GLTFNAY LTGSGAS ARSRSYYAGA RTVTSY GAS QQSYRT D04 A T FDV PPT SEQ ID 361 362 363 364 365 366 NO AVE-07- GFSVRDFA IHRTGGG ARSRSYYAGA QNIGNY AAS QQSYSTS E06 T FDV T SEQ ID 371 372 373 374 375 376 NO AVE-07- GFDFRSYP ISGGGGS ARSRSYYAGA QKIARY AAS QQAYSIP F06 T FDV IT SEQ ID 381 382 383 384 385 386 NO AVE-07- GFRFSNYA ISGGGGR ARGYGAEYFD QPISRY DAS QQSHSIP A07 T P WT SEQ ID 391 392 393 394 395 396 NO AVE-07- GFRFSNYA ISGGGGR ARGYGAEYFD QPISRH SAS QQSYDR E07 T P TWT SEQ ID 401 402 403 404 405 406 NO AVE-07- GFRFSNYA ISGGGGR ARGYGAEYFD QRIATY AAS QQSYSIP D08 T P LT SEQ ID 411 412 413 414 415 416 NO AVE-07- GFTVSRDY ISTGGGST AKPRPYSIAWF QTISIY AAS QQNYSV E08 ADPFDY PPT SEQ ID 421 422 423 424 425 426 NO AVE-07- GFPFSNNA ISGSYGTT ARVADGAAA QPISRY DAS QQSHSIP H08 YAMDY WT SEQ ID 431 432 433 434 435 436 NO AVE-07- GFRFSNYA ISGGGGR ARGYGAEYFD QPISRY AAS QQSYNP C10 T P PLT SEQ ID 441 442 443 444 445 446 NO AVE-07- GFTFPHSA IAGRGGS ARVADGGAA QNIITY GAS QQSFSTP Dll P YAFDY LT SEQ ID 451 452 453 454 455 456 NO AVE-07- GFRFSNYA ISGGGGR ARGYGAEYFD QPISRY DAS QQSHSIP Fll T P WT SEQ ID 461 462 463 464 465 466NOAVE-07- GFTFPHSA VTGSGSP ARVAGGAYG QSISSY DAS QQSFSNL Gll T YAMDY YT SEQ ID 471 472 473 474 475 476 NO AVE-07- GFPFSVYA FGGSGHS ARVAAGSYAY QNIITY GAS QQSFSTP F12 P AMDY LT SEQ ID 481 482 483 484 485 486 NO AVE-07- GFRFSNYA ISGGGGR ARGYGAEYFD QPISRY DAS QQSFSTP G12 T P LT SEQ ID 491 492 493 494 495 496NO

[0114] In some embodiments, provided herein is an anti-Activin E antibody, wherein the antibody comprises the amino acid sequences of the following three VH CDR1-3: SEQ ID NOS: 1, 2, 3; 11, 12, 13; 21, 22, 23; 31, 32, 33; 41, 42, 43; 51, 52, 53; 61, 62, 63; 71, 72, 73; 81, 82, 83; 91, 92, 93; 101, 102, 103; 111, 112, 113; 121, 122, 123; 131, 132, 133; 141, 142, 143; 151, 152, 153; 161, 162, 163; 171, 172, 173; 181, 182, 183; 191, 192, 193; 201, 202, 203; 211, 212, 213; 221, 222, 223; 231, 232, 233; 241, 242, 243; 251, 252, 253; 261, 262, 263; 271, 272, 273; 281, 282, 283; 291, 292, 293; 301, 302, 303; 311, 312, 313; 321, 322, 323; 331, 332, 333; 341, 342, 343; 351, 352, 353; 361, 362, 363; 371, 372, 373; 381, 382, 383; 391, 392, 393; 401, 402, 403; 411, 412, 413; 421, 422, 423; 431, 432, 433; 441, 442, 443; 451, 452, 453; 461, 462, 463; 471, 472, 473; 481, 482, 483; or 491, 492, 493; and / or comprises the amino acid sequences of the following three VL CDR1-3 SEQ ID NO: 4, 5, 6; 14, 15, 16; 24, 25, 26; 34, 35, 36; 44, 45, 46; 54, 55, 56; 64, 65, 66; 74, 75, 76; 84, 85, 86; 94, 95, 96; 104, 105, 106; 114, 115, 116; 124, 125, 126; 134, 135, 136; 144, 145, 146; 154, 155, 156; 164, 165, 166; 174, 175, 176; 184, 185, 186; 194, 195, 196; 204, 205, 206; 214, 215, 216; 224, 225, 226; 234, 235, 236; 244, 245, 246; 254, 255, 256; 264, 265, 266; 274, 275, 276; 284, 285, 286; 294, 295, 296; 304, 305, 306; 314, 315, 316; 324, 325, 326; 334, 335, 336; 344, 345, 346; 354, 355, 356; 364, 365, 366; 374, 375, 376; 384, 385, 386; 394, 395, 396; 404, 405, 406; 414, 415, 416; 424, 425, 426; 434, 435, 436; 444, 445, 446; 454, 455, 456; 464, 465, 466; 474, 475, 476; 484, 485, 486; or 494, 495, 496.

[0115] Exemplary Anti-Activin E antibodies - Variable Region Sequences.

[0116] The term variable domain and variable region are used interchangeably and refer to the portions of the light and heavy chains of an antibody that include the complementarity determining regions and framework regions (FRs).

[0117] In some embodiments, an anti-Activin E antibody of the disclosure comprises the combination of VH / VL variable chain amino acid sequences of any one of the combinations listed in Table 2.

[0118] Table 2: Exemplary Variable Heavy Chain and Variable Light Chain Amino Acid Sequences of Anti-Activin E antibodies.ClonelD VH AA VL AAAVE-01-D07 EVQLLESGGGLVQPGGSLRLSCAASGFAF DIQMTQSPSSLSASVGDRVTIT NNYAMTWVRQAPGKGLEWVSVISGSGT CRASQSISSYLHWYQQKPGKASKYYADSVKGRFTISRDNSKNTLYLQMN PKLLIYAASSLQSGVPSRFSGSSLRAEDTAVYYCAKPRPGSIFWGAGPFD GSGTDFTLTISSLQPEDFATYY YWGQGTLVTVSS CQQSYGSPTFGGGTKVEIK SEQ ID NO 7 8 AVE-01-B08 EVQLLESGGGLVQPGGSLRLSCAASGFTF DIQMTQSPSSLSASVGDRVTIT GASAMTWVRQAPGKGLEWVSGISGLGR CRASQNIGHYLNWYQQKPGK TTDYADSVKGRFTISRDNSKNTLYLQMN APKLLIYDASRLQVGVPSRFSG SLRAEDTAVYYCARVAPGAYAYAMDY SGSGTDFTLTISSLQPEDFATY WGQGTLVTVSS YCQQSYSTPPTFGGGTKVEIK SEQ ID NO 17 18 AVE-02-A03 EVQLLESGGGLVQPGGSLRLSCAASGFNF DIQMTQSPSSLSASVGDRVTIT RSYVMNWVRQAPGKGLEWVSAISDVGR CRASESIGNYLSWYQQKPGKA RTYYADSVKGRFTISRDNSKNTLYLQMN PKLLIYAASRLQRGVPSRFSGS SLRAEDTAVYYCAKAEILGDYAYMDYW GSGTDFTLTISSLQPEDFATYY GQGTLVTVSS CQQSYSTPTFGGGTKVEIK SEQ ID NO 27 28 AVE-02-B04 EVQLLESGGGLVQPGGSLRLSCAASGFAF DIQMTQSPSSLSASVGDRVTIT SAYAMNWVRQAPGKGLEWVSSITESGA CRASQSISSYLNWYQQKPGKA ATYYADSVKGRFTISRDNSKNTLYLQMN PKLLIYATSTLQSGVPSRFSGS SLRAEDTAVYYCARGLLASYTGDVWGQ GSGTDFTLTISSLQPEDFATYY GTLVTVSS CQQRDNAPWTFGGGTKVEIK SEQ ID NO 37 38 AVE-06-B07 EVQLLESGGGLVQPGGSLRLSCAASGFDF DIQMTQSPSSLSASVGDRVTIT SSFAMTWVRQAPGKGLEWVSHITGSGGT CRASQAIKNYLNWYQQKPGK IYYADSVKGRFTISRDNSKNTLYLQMNSL APKLLIYAGSTLQSGVPSRFSG RAEDTAVYYCASASSYYEPGDPWGQGTL SGSGTDFTLTISSLQPEDFATY VTVSS YCQQTYSTPLTFGGGTKVEIK SEQ ID NO 47 48 AVE-06-F07 EVQLLESGGGLVQPGGSLRLSCAASGFPF DIQMTQSPSSLSASVGDRVTIT SSHGMSWVRQAPGKGLEWVSTITGSGRS CRASQSISSYLNWYQQKPGKA TYYADSVKGRFTISRDNSKNTLYLQMNS PKLLIYDASHLQSGVPSRFSGS LRAEDTAVYYCASDYRDAPGTFDVWGQ GSGTDFTLTISSLQPEDFATYY GTLVTVSS CQQSYSTPVFGGGTKVEIK SEQ ID NO 57 58 AVE-06-A08 EVQLLESGGGLVQPGGSLRLSCAASGFPF DIQMTQSPSSLSASVGDRVTIT ASHAMTWVRQAPGKGLEWVSTITGSGRS CRASQSISSYLNWYQQKPGKA TYYADSVKGRFTISRDNSKNTLYLQMNS PKLLIYDASHLQSGVPSRFSGS LRAEDTAVYYCASDYRDAPGTFDVWGQ GSGTDFTLTISSLQPEDFATYY GTLVTVSS CQQSYSTPVFGGGTKVEIK SEQ ID NO 67 68 AVE-06-D08 EVQLLESGGGLVQPGGSLRLSCAASGFDF DIQMTQSPSSLSASVGDRVTIT SKFAMSWVRQAPGKGLEWVSHISGSGGT CRASQAIKNYLNWYQQKPGK IYYADSVKGRFTISRDNSKNTLYLQMNSL APKLLIYDASHPQSGVPSRFRG RAEDTAVYYCASASSYYEPGDPWGQGTL SGSGTDFPFTISSLQPEEFATYY VTVSS CQQSYSTPVFGGGTKVEIK SEQ ID NO 77 78 AVE-06-G08 EVQLLESGGGLVQPGGSLRLSCAASGFDF DIQMTQSPSSLSASVGDRVTIT SKFAMSWVRQAPGKGLEWVSHISGSGGT CRAGQAIKNYLNWYQQKPGK IYYADSVKGRFTISRDNSKNTLYLQMNSL APKLLIYAGSPLQSGVPSRFSG RAEDTAVYYCASDSSYYEPGDPWGQGTL SGSGTDFTLTISSLQPEDFATY VTVSS YCQQTYSTPLTFGGGTKVEIK SEQ ID NO 87 88 AVE-06-H08 EVQLLESGGGLVQPGGSLRLSCAASGFDF DIQMTQSPSSLSASVGDRVTIT SKFAMSWVRQAPGKGLEWVSSITRGSET CRASQPISSYVTWYQQKPGKA TYYADSVKGRFTISRDNSKNTLYLQMNS PKLLIYSASHLRSGVPSRFSGS LRAEDTAVYYCATLGLGYYYYFDVWGQ GSGTDFTLTISSLQPEDFATYYGTLVTVSS CQQSYNAPPTFGGGTKVEIKSEQ ID NO 97 98 AVE-06-A09 EVQLLESGGGLVQPGGSLRLSCAASGFPF DIQMTQSPSSLSASVGDRVTIT ASHAMTWVRQAPGKGLEWVSTITGSGRS CRASQTISSFVSWYQQKPGKA TYYADSVKGRFTISRDNSKNTLYLQMNS PKLLIYAATTLQKGVPSRFSGS LRAEDTAVYYCASASSYYEPGDPWGQGT GSGTDFTLTISSLQPEDFATYY LVTVSS CQQSYHTRSFGGGTKVEIK SEQ ID NO 107 108 AVE-06-B09 EVQLLESGGGLVQPGGSLRLSCAASGLTF DIQMTQSPSSLSASVGDRVTIT SNFAMTWVRQAPGKGLEWVSSIRGSGAT CRASQSISSYLNWYQQKPGKA TYYADSVKGRFTISRDNSKNTLYLQMNS PKLLIYAASSLQSGVPSRFSGS LRAEDTAVYYCARSREAYGFDYWGQGT GSGTDFTLTISSLQPEDFATYY LVTVSS CQQSYSTPYTFGGGTKVEIK SEQ ID NO 117 118 AVE-06-D09 EVHLLESGGGLVQPGGSLRLSCAASGFTF DIQMTQSPSSLSASVGDRVTIT SHYSMNWVRQAPGKGLEWVSGISGSGS CRASQSISTHLNWYQQKPGKA ATYYADSVKGRFTISRDNSKNTLYLQMN PKLLIYAASSLQSGVPSRFSGS SLRAEDTAVYYCASDRYLTFDVWGQGT GSGTDFTLTISSLQPEDFATYY LVTVSS CQQSHRTPLIFGGGTKVEIK SEQ ID NO 127 128 AVE-06-F09 EVQLLESGGGLVQPGGSLRLSCAASGFDF DIQMTQSPSSLSASVGDRVTIT SKFAMSWVRQAPGKGLEWVSHISGSGGT CRASQAIKNYLNWYQQKPGK IYYADSVKGRFTISRDNSKNTLYLQMNSL APKLLIYAGSTLQSGVPSRFSG RAEDTAVYYCASASSYYEPGDPWGQGTL SGSGTDFTLTISSLQPEDFATY VTVSS YCQQTYSTPLTFGGGTKGEIK SEQ ID NO 137 138 AVE-06-G09 EVQFLESGGGLVQPGGSLRLSCAASGFSF DIQMTQSPSSLSASVGDRVTIT DNYGINWVRQAPGKGLEWVSSISSSGGS CRASQSINNYLNWYQQKPGK AYYADSVKGRFTISRDNSKNTLYLQMNS APKLLIYAASSLQSGVPSRFSG LRAEDTAVYYCARGVVPGGFDYWGQGT SGSGTDFTLTISSLQPEDFATY LVTVSS YCQQSRTTPWTFGGGTKVEIK SEQ ID NO 147 148 AVE-06-C10 EVQLLESGGGLVQPGGSLRLSCAASGFDF DIQMTQSPSSLSASVGDRVTIT SKFAMSWVRQAPGKGLEWVSSITGTSGA CRASQTIGIYLNWYQQKPGKG TYYADSVKGRFTISRDNSKNTLYLQMNS PKPAIYSASPLQRGVPSRFSGC LRAEDTAV Y YCARDIRVRRS S WAMDPW GSGTDFTLTISSLQPEDFATYY GQGTLVTVSS CQQSYSTPHITFGGGTKVEIK SEQ ID NO 157 158 AVE-06-G10 EVQLLESGGGLVQPGGSLRLSCAASGFDF DIQMTQSPSSLSASVGDRVTIT SKFAMSWVRQAPGKGLEWVSHISGSGGT CRASQAIKNYLNWYQQKPGK IYYADSVKGRFTISRDNSKNTLYLQMNSL APKLLIYAGSTLQSGVPSRFSG RAEDTAVYYCASASSYYEPGDPWGQGTL SGSGTDFTLTISSLQPEEFATY VTVSS YCQQTYSTPLTFGGGTKGENQ SEQ ID NO 167 168 AVE-06-H10 EVQLLESGGGLVQPGGSLRLSCAASGFTF DIQMTQSPSSLSASVGDRVTIT TNYALAWVRQAPGKGLEWVSHISGSGG CRASQAIKNYLNWYQQKPGK TIYYADSVKGRFTISRDNSKNTLYLQMNS APKLLIYAGSTLQSGVPSRFSG LRAEDTAVYYCASASSYYEPGDPWGQGT SGSGTDFTLTISSLQPEDFATY LVTVSS YCQQTYSTPLTFGGGTKVEIK SEQ ID NO 177 178 AVE-06-B11 EVQLLESGGGLVQPGGSLRLSCAASGFDF DIQMTQSPSSLSASVGDRVTIT SKFAMSWVRQAPGKGLEWVSHISGSGGT CRASQAIKNYLNWYQQKPGK IYYADSVKGRFTISRDNSKNTLYLQMNSL APKLLIYAGSTLQSGVPSRFSG RAEDTAVYYCASASSYYEPGDPWGQGTL SGSGTDFTLTISSLQPEDFATY VTVSS YCQQTYSTPLTFGGGTKVEIKSEQ ID NO 187 188AVE-06-E11 EVQLLESGGGLVQPGGSLRLSCAASGIRF DIQMTQSPSSLSASVGDRVTIT SSYAMSWVRQAPGKGLEWVSHISGSGGT CRASQAIKNYLNWYQQKPGK IYYADSVKGRFTISRDNSKNTLYLQMNSL APKLLIYAGSTLQSGVPSRFSG RAEDTAVYYCASASSYYEPGDPWGQGTL SGSGTDFTLTISSLQPEDFATY VTVSS YCQQTYSTPLTFGGGTKVEIK SEQ ID NO 197 198 AVE-06-H11 EVQLLESGGGLVQPGGSLRLSCAVSGFDF DIQMTQSPSSLSASVGDRVTIT SKFVMSGVRQAPGKGLEWVSHISGSGGT CRASQAIKNYLNWYQQKPGK IYYADSVKGRFTISRDNSKNTLYLQMNSL APKLLIYAGSTLQSGVPSRFSG RAEDTAVYYCASASSYYEPGDPWGQGTL SGSGTDFTLTISSLQPEDFATY VTVSS YCQQTYSTPLTFGGGTKVEIK SEQ ID NO 207 208 AVE-06-A12 EVQLLESGGGLVQPGGSLRLSCAASGFDF DIQMTQSPSSLSASVGDRVTIT SKFAMSWVRQAPGKGLEWVSHISGSGGT CRASQAIKNYLNWYQQKPGK IYYADSVKGRFTISRDNSKNTLYLQMNSL APKLLIYAGSTLQSGVPSRFSG RAEDTAVYYCASASSYYEPGDPWGQGTL SGSGTDFTLTISSLQPEDFPTY VTVSS YFQQN YS TPF AFGGGTK VEIK SEQ ID NO 217 218 AVE-06-B12 EVQLLESGGGLVQPGGSLRLSCAASGFDF DIQMTQSPSSLSASVGDRVTIT SKFAMSWVRPAPCKGLEWVSHISGSGGT CRASQAIKNYLNWYQQKPGK IYYADSVKGRFTISRDNSKNTLYLQMNSL APKLLIYAGSTLQSGVPSRFSG RAEDTAVYYCASASSYYEPGDPWGQGTL SGSGTDFTLTISSLQPEDFATY VTVSS YCQQTYSTPLTFGGGTKVEIK SEQ ID NO 227 228 AVE-06-C12 EVQLLESGGGLVQPGGSLRLSCAASGFDF DIQMTQSPSSLSASVGDRVTIT SKFAMSWVRQAPGKGLEWVSHISGSGGT CRASQAIKNYLNWYQQKPGK IYYADSVKGRFTISRDNSKNTLYLQMNSL APKLLIYAGSTLQSGVPSRFSG RAEDTAVYYCASASSYYEPGDPWGQGTL SGSGTDFTLTISSLQPEDFATY VTVSS YCQQN YS TPLTFGGGTKVEIK SEQ ID NO 237 238 AVE-06-E12 EVQFLKSGGGLVNPAGILELSCAASGFPF DIQMTQSPSSLSASVGDRVTIT SSHGMSWVRQAPGKGLEWVSVISGSGAT CRASHSIASYLHWYQQKPGK TYYADSVKGRFTISRDNSKNTLYLQMNS APKLLIYRASTLHTGVPSRFSG LRAEDTAVYYCARGQPYYGFDYWGQGT SGSGTDFTLTISSLQPEDFATY LVTVSS YCQQTYSIPWTFGGGTKVEIK SEQ ID NO 247 248 AVE-06-G12 EVQFLESGGGLVQPGGSLRLSCAASGFDF DIQMTQSPSSLSASVGDRVTIT SKFAMSWVRQAPGKGLEWVSHISGSGGT CRASQAIKNYLNWYQQKPGK IYYADSVKGRFTISRDNSKNTLYLQMNSL APKLLIYGASNLQSGVPSRFSG RAEDTAVYYCASASSYYEPGDPWGQGTL SGSGTDFTLTISSLQPEDFATY VTVSS YCQQSESTPLTFGGGTKVEIK SEQ ID NO 257 258 AVE-07-A01 EVQLLESGGGLVQPGGSLRLSCAASGFAL DIQMTQSPSSLSASVGDRVTIT TDFAMSWVRQAPGKGLEWVSQISVSGG CRASAPVGRYLNWYQQKPGK VGYYADSVKGRFTISRDNSKNTLYLQMN APKLLIYAASSLQSGVPSRFSG SLRAEDTAVYYCARSRSYYAGAFDVWG SGSGTDFTLTISSLQPEDFATY QGTLVTVSS YCQQSYSAVTFGGGTKVEIK SEQ ID NO 267 268 AVE-07-B01 EVQLLESGGGLVQPGGSLRLSCAASGFTF DIQMTQSPSSLSASVGDRVTIT GSYAMTWVRQAPGKGLEWVSAIGTTDR CRASQTLRNYLNWYQQKPGK YTYYADSVKGRFTISRDNSKNTLYLQMN APKLLIYAASNLQTGVPSRFSG SLRAEDTAVYYCARSRSYYAGAFDVWG SGSGTDFTLTISSLQPEDFATY QGTLVTVSS YCQQRFSPPWTFGGGTKVEIK SEQ ID NO 277 278 AVE-07-C01 EVQLLESGGGLVQPGGSLRLSCAASGYTF DIQMTQSPSSLSASVGDRVTITSNFAISWVRQAPGKGLEWVSSITGSGVRT CRASQSIGSSVNWYQQKPGKAFYADSVKGRFTISRDNSKNTLYLQMNSL PKLLIYAASSLQSGVPSRFSGS RAEDTAVYYCARSRSYYAGAFDVWGQG GSGTDFTLTISSLQPEDFATYY TLVTVSS CQQSDNNPWTFGGGTKVEIK SEQ ID NO 287 288 AVE-07-D01 EVQLLKSGSGLVQPGGSLRLSCAASGFTF DIQMTQSPSSLSASVGDRVTIT NN A WMH WVRQ APGKGLE W V S Al S S S GG CRASAPVGRYLNWYQQKPGK YTYYADSVKGRFTISRDNSKNTLYLQMN APKLLIYAASSLQSGVPSRFSG SLRAEDTAVYYCARSRSYYAGAFDVWG SGSGTDFTLTISSLQPEDFATY QGTLVTVSS YCQQAYSIPITFGGGTKVEIK SEQ ID NO 297 298 AVE-07-E01 EVQLLESGGGLVQPGGSLRLSCAASGFSV DIQMTQSPSSLSASVGDRVTIT RDFAMNWVRQAPGKGLEWVSTITGTDR CRAPQNIFSYINWYQQKPGKA TPYYADSVKGRFTISRDNSKNTLYLQMN PKLLIYAASSLQSGVPSRFSGS SLRAEDTAVYYCARSRSYYAGAFDVWG GSGTDFTLTISSLQPEDFATYY QGTLVTVSS CQQTHSIPQTFGGGTKGEIK SEQ ID NO 307 308 AVE-07-F01 EVQLLESGGGLVQPGGSLRLSCAASGFTF DIQMTQSPSSLSASVGDRVTIT SSHNMAWVRQAPGKGLEWVSSIGGGGR CRASQRISTYINWYQQKPGKA TTNYADSVKGRFTISRDNSKNTLYLQMN PKLLIYGASYLHSGVPSRFSGS SLRAEDTAVYYCARAAPGAYAYALDYW GSGTDFTLTISSLQPEDFATYY GQGTLVTVSS CQQTYSTPPTFGGGTKVEIK SEQ ID NO 317 318 AVE-07-C02 EVQLLESGGGLVQPGGSLRLSCAASGFSV DIQMTQSPSSLSASVGDRVTIT RDFAMTWVRQAPGKGLEWVSAIRISGGG CRASQRISTYINWYQQKPGKA TFYADSVKGRFTISRDNSKNTLYLQMNSL PKLLIYSASVLENGVPSRFSGS RAEDTAVYYCARAAPGAYAYALDYWG GFGTDFTLTISSLQPEDFATYY QGTLVTVSS CQQNYRTPPTFGSGTKGENK SEQ ID NO 327 328 AVE-07-F02 EVQLLESGGGLVQPGGSLRLSCAASGFTF DIQMTQSPSSLSASVGDRVTIT SNYAMTWVRQAPGKGLEWVSTITSSASK CRASQSISSYLNWYQQKPGKA TNYADSVKGRFTISRDNSKNTLYLQMNS PKLLIYAASSLQSGVPSRFSGS LRAEDTAVYYCARTRYLERFAGGLDIWG GSGTDFTLTISSLQPEDFATYY QGTLVTVSS CQQSFTAPLTFGGGTKVEIK SEQ ID NO 337 338 AVE-07-G02 EVQLLESGGGLVQPGGSLRLSCAASGLTF DIQMTQSPSSLSASVGDRVTIT SNYTMTWVRQAPGKGLEWVSGISGTGG CRASVSISTFLNWYQQKPGKA STWYADSVKGRFTISRDNSKNTLYLQMN PKLLIYAASTLQSGVPSRFSGS SLRAEDTAVYYCARSRSYYAGAFDVWG GSGTDFTLTISSLQPEDFATYY QGTLVTVSS CQQSLRTPITFGGGTKVEIK SEQ ID NO 347 348 AVE-07-H03 EVQLLESGGGLVQPGGSLRLSCAASGFPF DIQMTQSPSSLSASVGDRVTIT SSFVMSWVRQAPGKGLEWVSSLSGSGDI CRTSQSVSTYFNWYQQKPGK TYYADSVKGRFTISRDNSKNTLYLQMNS APKLLIYAASSLQSGVPSRFSG LRAEDTAVYYCARAAPGAYAYALDYWG SGSGTDFTLTISSLQPEDFATY QGTLVTVSS YCQQSYRTPPTFGGGTKVEIK SEQ ID NO 357 358 AVE-07-D04 EVQLLESGGGLVQPGGSLRLSCAASGLTF DIQMTQSPSSLSASVGDRVTIT NAYAMSWVRQAPGKGLEWVSSLTGSGA CRASRTVTSYLNWYQQKPGK STFYADSVKGRFTISRDNSKNTLYLQMNS APKLLIYGASYLHSGVPSRFSG LRAEDTAVYYCARSRSYYAGAFDVWGQ SGSGTDFTLTISSLQPEDFATY GTLVTVSS YCQQSYRTPPTFGGGTKVEIK SEQ ID NO 367 368 AVE-07-E06 EVQLLESGGGLVQPGGSLRLSCAASGFSV DIQMTQSPSSLSASVGDRVTIT RDFAMNWVRQAPGKGLEWVSSIHRTGG CRANQNIGNYLNWYQQKPGKGTYYADSVKGRFTISRDNSKNTLYLQMN APKLLIYAASSLQSGVPSRFSGSLRAEDTAVYYCARSRSYYAGAFDVWG SGSGTDFTLTISSLQPEDFATY QGTLVTVSS YCQQSYSTSTFGGGTKVEIK SEQ ID NO 377 378 AVE-07-F06 EVQLLESGGGLVQPGGSLRLSCAASGFDF DIQMTQSPSSLSASVGDRVTIT RSYPMAWVRQAPGKGLEWVSVISGGGG CRASQKIARYVNWYQQKPGK STNYADSVKGRFTISRDNSKNTLYLQMN APKLLIYAASDLQSGVPSRFSG SLRAEDTAVYYCARSRSYYAGAFDVWG SGSGTDFTLTISSLQPEDFATY QGTLVTVSS YCQQAYSIPITFGGGTKVEIK SEQ ID NO 387 388 AVE-07-A07 EVQLLESGGGLVQPGGSLRLSCAASGFRF DIQMTQSPSSLSASVGDRVTIT SNYAMTWVRQAPGKGLEWVSGISGGGG CRASQPISRYLNWYQQKPGKA RTFYADSVKGRFTISRDNSKNTLYLQMN PKLLIYDASRLQVGVPSRFSGS SLRAEDTAVYYCARGYGAEYFDPWGQG GSGTDFTLTISSLQPEDFATYY TLVTVSS CQQSHSIPWTFGGGTKVEIK SEQ ID NO 397 398 AVE-07-E07 EVQLLESGGGLVQPGGSLRLSCAASGFRF DIQMTQSPSSLSASVGDRVTIT SNYAMTWVRQAPGKGLEWVSGISGGGG CRASQPISRHLNWYQQKPGKA RTFYADSVKGRFTISRDNSKNTLYLQMN PKLLIYSASSLQSGVPSRFSGS SLRAEDTAVYYCARGYGAEYFDPWGQG GSGTDFTLTISSLQPEDFATYY TLVTVSS CQQSYDRTWTFGGGTKGESK SEQ ID NO 407 408 AVE-07-D08 EVQLLESGGGLVQPGGSLRLSCAASGFRF DIQMTQSPSSLSASVGDRVTIT SNYAMTWVRQAPGKGLEWVSGISGGGG CRASQRIATYLNWYQQKPGK RTFYADSVKGRFTISRDNSKNTLYLQMN APKLLIYAASHLHGGVPSRFS SLRAEDTAVYYCARGYGAEYFDPWGQG GSGSGTDFTLTISSLQPEDFAT TLVTVSS YYCQQSYSIPLTFGGGTKVEIK SEQ ID NO 417 418 AVE-07-E08 GGAALKSGGGLVQPGGSLRLSCAASGFT DIQMTQSPSSLSASVGDRVTIT VSRDYMSWVRQAPGKGLEWVSVISTGG CRTSQTISIYLNWYQQKPGKA GSTYYADSVKGRFTISRDNSKNTLYLQM PKLLIYAASILHGGVPSRFSGS NSLRAEDTAVYYCAKPRPYSIAWFADPF GSGTDFTLTISSLQPEDFATYY DYWGQGTLVTVSS CQQNYSVPPTFGGGTKVEIK SEQ ID NO 427 428 AVE-07-H08 ELQLLESGGGLVQPGGSLRLSCAASGFPF DIQMTQSPSSLSASVGDRVTIT SNNAMSWVRQAPGKGLEWVSVISGSYG CRASQPISRYLNWYQQKPGKA TTYYADSVKGRFTISRDNSKNTLYLQMN PKLLIYDASRLQVGVPSRFSGS SLRAEDTAVYYCARVADGAAAYAMDY GSGTDFTLTISSLQPEDFATYY WGQGTLVTVSS CQQSHSIPWTFGGGTKVEIK SEQ ID NO 437 438 AVE-07-C10 EVQLLESGGGLVQPGGSLRLSCAASGFRF DIQMTQSPSSLSASVGDRVTIT SNYAMTWVRQAPGKGLEWVSGISGGGG CRASQPISRYLNWYQQKPGKA RTFYADSVKGRFTISRDNSKNTLYLQMN PKLLIYAASNLKKGVPSRFSGS SLRAEDTAVYYCARGYGAEYFDPWGQG GFGTDFTLTISSLQPEDFATYY TLVTVSS CQQSYNPPLTFGGGTKVEIK SEQ ID NO 447 448 AVE-07-D11 EVQLLESGGGLVQPGGSLRLSCAASGFTF DIQMTQSPSSLSASVGDRVTIT PHSAMSWVRQAPGKGLEWVSSIAGRGGS CRSSQNIITYLNWYQQKPGKA PNYADSVKGRFTISRDNSKNTLYLQMNS PKLAIYGASRVQSGVPSRFSGS LRAEDTAVYYCARVADGGAAYAFDYW GSGADFTLTISSLQPEDFSTYY GQGTLVTVSS CQQSFSTPLTFGGGTKVEIK SEQ ID NO 457 458 AVE-07-F11 EVQLLESGGGLVQPGGSLRLSCAASGFRF DIQMTQSPSSLSASVGDRVTIT SNYAMTWVRQAPGKGLEWVSGISGGGG CRASQPISRYLNWYQQKPGKA RTFYADSVKGRFTISRDNSKNTLYLQMN PKLLIYDASRLQVGVPSRFSGS SLRAEDTAVYYCARGYGAEYFDPWGQG GSGTDFTLTISSPQPEDFATYYTLVTVSS CQQSHSIPWTFGGGTKGEIKSEQ ID NO 467 468 AVE-07-G11 EVQLLESGGGLVQPGGSLRLSCAASGFTF DIQMTQSPSSLSASVGDRVTIT PHSAMSWVRQAPGKGLEWVSTVTGSGS CRASQSISSYLNWYQQKPGKA PTYYADSVKGRFTISRDNSKNTLYLQMN PKLLIYDASNLQSGVPSRFSGS SLRAEDTAVYYCARVAGGAYGYAMDY GSGTDFTLTISSLQPEDFATYY WGQGTLVTVSS CQQSFSNLYTFGGGTKVEIK SEQ ID NO 477 478 AVE-07-F12 EVQLLESGGGLVQPGGSLRLSCAASGFPF DIQMTQSPSSLSASVGDRVTIT SVYAMTWVRQAPGKGLEWVSSFGGSGH CRSSQNIITYLNWYQQKPGKA SPYYADSVKGRFTISRDNSKNTLYLQMN PKLLIYGASRLQSGVPSRFSGS SLRAEDTAVYYCARVAAGSYAYAMDY GSGTDFTLTISSLQPEDFATYY WGQGTLVTVSS CQQSFSTPLTFGGGTKEVDK SEQ ID NO 487 488 AVE-07-G12 EVQLLESGGGLVQPGGSLRLSCAASGFRF DIQMTQSPSSLSASVGDRVTIT SNYAMTWVRQAPGKGLEWVSGISGGGG CRASQPISRYLNWYQQKPGKA RTFYADSVKGRFTISRDNSKNTLYLQMN PKLLIYDASRLQVGVPSRFSGS SLRAEDTAVYYCARGYGAEYFDPWGQG GSGTDFTLTISSLQPEDFATYY TLVTVSS CQQSFSTPLTFGGGTKVEIKSEQ ID NO 497 498

[0119] In some embodiments, an anti-Activin E antibody of the disclosure comprises the combination of VH / VL variable chain nucleic acid sequences of any one of the combinations listed in Table 3.

[0120] Table 3: Exemplary Variable Heavy Chain and Variable Light Chain Nucleic Acid Sequences of Anti-Activin E antibodies (variable heavy nucleotides (VH NT) and variable light nucleotides (VL NT).ClonelD VH NT VL NTAVE-01-D07 GAAGTGCAGCTCCTAGAATCCGGCG GACATCCAGATGACACAGTCTCCT GTGGGCTGGTTCAGCCTGGAGGGTC TCTTCTCTGTCCGCTAGTGTGGGC CCTTAGACTGTCTTGTGCCGCGAGT GACAGAGTGACGATCACCTGTAG GGCTTCGCCTTTAACAATTATGCAA GGCGAGTCAAAGCATTTCATCCTA TGACCTGGGTGAGGCAGGCACCCGG CTTGCACTGGTACCAGCAGAAGCC CAAGGGACTGGAGTGGGTAAGCGT CGGAAAAGCACCTAAACTGTTAAT CATCAGCGGGAGCGGCACTTCTAAG TTACGCCGCCAGTTCCCTCCAAAG TACTACGCCGATTCTGTTAAAGGTC CGGTGTCCCATCTCGGTTTTCGGG GATTCACCATATCACGGGACAACTC GTCAGGGAGCGGCACTGATTTCAC CAAGAACACTTTGTATCTGCAAATG CCTTACCATCTCATCCCTGCAGCC AATAGTCTCCGCGCCGAGGATACGG CGAAGATTTTGCTACATATTATTG CTGTCTACTACTGCGCTAAACCGCG CCAGCAGAGCTATGGGAGCCCAA TCCAGGTTCAATTTTTTGGGGAGCT CATTCGGTGGAGGCACTAAGGTTG GGACCCTTCGACTATTGGGGGCAGG AGATAAAG GCACATTAGTGACAGTGTCGAGC SEQ ID NO 9 10 AVE-01-B08 GAAGTGCAATTGCTTGAGAGTGGCG GACATACAGATGACACAGTCTCCT GCGGCCTGGTTCAGCCTGGGGGCTC TCCTCACTTAGCGCGTCGGTTGGC CCTGAGACTTAGCTGTGCTGCCTCT GACCGCGTGACCATCACATGTAGA GGCTTCACCTTCGGAGCTTCAGCAA GCATCACAGAACATTGGTCACTAC TGACCTGGGTGCGTCAGGCTCCAGG CTGAATTGGTACCAGCAGAAACCC TAAGGGCCTGGAGTGGGTGTCAGGT GGAAAGGCCCCAAAATTATTGATC ATCAGCGGACTAGGGCGGACAACC TATGACGCCTCCAGGCTGCAAGTG GATTACGCTGATAGCGTCAAAGGGC GGCGTACCATCTCGGTTCTCCGGT GCTTTACGATTTCGAGGGACAACTC AGCGGGAGCGGCACCGATTTTAC TAAGAACACTCTGTATCTCCAGATG ACTGACTATCAGTTCTCTCCAGCC AATAGTTTAAGGGCAGAAGACACA CGAAGATTTTGCTACGTATTATTGGCCGTGTACTACTGCGCCCGAGTAG CCAACAGAGTTACAGCACCCCGCCCCCCCGGAGCGTATGCCTATGCAAT TACCTTCGGGGGAGGGACTAAGG GGACTACTGGGGGCAGGGAACTCTC TCGAGATTAAG GTCACAGTTTCCTCC SEQ ID NO 19 20 AVE-02-A03 GAGGTCCAGCTGCTGGAGTCAGGCG GACATCCAGATGACCCAGAGTCCC GTGGCCTTGTTCAGCCCGGCGGGTC TCATCTCTGAGTGCATCAGTGGGG TTTGCGGCTGTCCTGCGCCGCCAGC GACCGCGTGACTATTACCTGCAGA GGATTCAACTTCAGAAGCTACGTTA GCTTCTGAGTCCATAGGTAACTAT TGAACTGGGTGCGCCAGGCCCCTGG CTGTCCTGGTACCAGCAAAAACCT CAAGGGCTTAGAATGGGTGTCCGCT GGCAAGGCGCCCAAGTTGCTGATT ATCTCCGATGTCGGACGTAGGACTT TACGCCGCTTCGCGATTACAGAGG ACTATGCAGACTCTGTGAAAGGGAG GGCGTCCCATCCCGGTTTAGCGGG ATTTACCATTAGTCGAGATAACTCA TCAGGGTCCGGTACTGATTTCACA AAAAATACACTGTATCTCCAGATGA CTTACAATCAGCAGCCTCCAACCA ATAGTTTGAGGGCCGAGGACACCGC GAAGATTTTGCCACCTATTACTGT AGTATATTACTGTGCTAAGGCTGAA CAGCAGAGCTATTCTACACCTACC ATACTCGGTGACTATGCGTACATGG TTCGGAGGAGGCACGAAGGTTGA ATTACTGGGGGCAAGGAACACTAGT GATCAAA GACGGTGAGCTCG SEQ ID NO 29 30 AVE-02-B04 GAAGTGCAGCTCCTAGAGTCGGGCG GACATTCAGATGACACAAAGCCC GCGGGCTGGTGCAGCCCGGTGGCTC CTCCAGCCTGAGCGCATCGGTGGG CCTCCGGCTGAGCTGCGCCGCGAGC GGACCGCGTCACCATAACTTGTCG GGTTTCGCTTTCAGTGCCTACGCCAT GGCCAGTCAGTCTATCAGCTCATA GAACTGGGTTCGTCAAGCCCCTGGA TCTGAACTGGTACCAGCAGAAGCC AAAGGCCTGGAGTGGGTATCAAGC TGGCAAAGCTCCAAAGCTGCTTAT ATCACGGAGTCTGGGGCTGCTACAT CTACGCTACTTCCACTTTACAGTC ATTATGCAGATTCTGTGAAGGGAAG CGGTGTTCCATCCAGGTTCTCAGG ATTTACTATTTCCCGCGACAATAGC ATCTGGCTCTGGTACAGATTTCAC AAGAATACCCTGTATCTGCAGATGA CTTGACCATTTCAAGTCTCCAGCC ACAGTTTGCGAGCAGAAGACACCGC TGAAGATTTTGCCACGTACTATTG CGTCTACTACTGTGCAAGGGGGCTT CCAACAGAGAGACAATGCGCCCT CTTGCTTCATACACAGGGGATGTGT GGACATTTGGGGGCGGAACCAAA GGGGCCAGGGAACCTTAGTCACTGT GTGGAGATCAAG TTCCTCT SEQ ID NO 39 40 AVE-06-B07 GAAGTGCAGCTCCTAGAGTCGGGTG GACATCCAGATGACTCAGAGTCCC GCGGGCTGGTGCAGCCGGGCGGCTC AGCTCACTCTCCGCTTCAGTCGGT CCTGCGCCTGTCTTGCGCGGCTAGT GATCGGGTTACTATAACATGTAGA GGATTTGACTTTTCTAGCTTCGCAAT GCCAGCCAAGCTATTAAGAATTAC GACCTGGGTCAGACAGGCCCCAGG CTGAACTGGTATCAGCAAAAACCC GAAGGGATTGGAGTGGGTGTCCCAC GGGAAGGCACCTAAACTGTTGATT ATAACAGGTTCAGGAGGGACAATCT TATGCGGGGTCCACACTCCAGAGC ATTACGCCGATAGCGTTAAGGGACG GGGGTGCCTAGTAGGTTCTCTGGC GTTCACTATTAGCAGGGATAATTCA TCCGGATCTGGCACTGACTTTACC AAAAACACGCTTTACTTACAAATGA TTAACCATCTCTTCGCTTCAGCCA ACAGTCTGCGAGCCGAGGACACCGC GAAGATTTTGCCACATACTATTGC AGTATACTATTGTGCTTCCGCCAGC CAGCAGACATACAGCACGCCACT TCCTATTACGAACCCGGGGACCCTT GACCTTCGGTGGCGGAACCAAGG GGGGCCAGGGCACTCTCGTCACCGT TGGAGATCAAA GTCATCT SEQ ID NO 49 50 AVE-06-F07 GAAGTTCAGCTGTTAGAAAGCGGGG GACATCCAAATGACCCAGTCTCCC GGGGCCTGGTGCAGCCTGGCGGCTC TCCTCGCTGAGCGCAAGCGTAGGG ACTGAGATTGTCCTGCGCTGCATCC GACCGGGTCACCATAACGTGTAGGGATTCCCGTTTTCCTCACACGGAA AGCTTCTCAGTCAATCTCCTCATATGAGCTGGGTTAGGCAGGCTCCCGG CTTGAACTGGTATCAGCAGAAGCC GAAGGGCCTAGAGTGGGTCAGTACC CGGCAAAGCCCCTAAGCTCCTGAT ATTACAGGAAGCGGTAGGAGCACG TTACGATGCCAGCCACCTACAAAG TACTACGCCGATTCAGTAAAGGGCC CGGAGTTCCATCCAGGTTTAGTGG GATTCACAATCTCCCGTGACAACTC CTCTGGGTCAGGAACAGATTTCAC TAAAAATACTCTTTATCTCCAGATG ACTGACAATCAGTTCTCTTCAGCC AACAGTCTGCGGGCAGAGGATACA TGAAGACTTCGCGACTTACTATTG GCCGTGTATTATTGTGCGTCGGACT CCAGCAGTCCTATAGTACCCCAGT ACCGCGATGCCCCAGGAACCTTTGA GTTTGGTGGGGGCACTAAAGTGG CGTGTGGGGTCAAGGGACTCTCGTC AGATTAAG ACCGTGTCTTCT SEQ ID NO 59 60 AVE-06-A08 GAGGTCCAGCTGTTGGAATCCGGGG GATATACAGATGACTCAATCTCCC GAGGCTTAGTGCAACCGGGCGGCTC AGCAGTCTGTCCGCATCCGTCGGA CCTGCGACTGAGCTGTGCAGCCTCG GATAGGGTAACAATTACCTGCAG GGATTCCCCTTTGCTTCTCACGCAAT AGCGTCCCAATCGATCAGTTCATA GACCTGGGTTCGTCAGGCCCCAGGG TCTTAACTGGTACCAGCAGAAGCC AAAGGCCTGGAGTGGGTTTCTACTA TGGCAAAGCTCCAAAGCTGTTAAT TCACCGGTTCAGGTCGGAGCACATA TTACGACGCCTCTCACCTCCAGAG TTACGCTGACAGCGTGAAGGGGAG TGGCGTTCCTTCTCGGTTTTCTGGC ATTTACCATTTCACGCGACAATAGC AGCGGTTCCGGGACCGACTTCACG AAGAACACTCTCTATCTTCAGATGA TTGACAATCTCAAGCCTGCAGCCA ACAGTCTCAGGGCCGAAGATACAGC GAAGACTTTGCCACCTACTATTGT CGTCTATTACTGCGCTAGTGACTAC CAGCAGTCATATAGCACTCCCGTG AGGGATGCGCCTGGAACGTTCGATG TTCGGGGGTGGAACAAAAGTGGA TGTGGGGCCAGGGGACACTAGTGAC GATCAAG CGTATCCTCT SEQ ID NO 69 70 AVE-06-D08 GAAGTGCAACTGCTGGAATCGGGCG GATATACAGATGACTCAATCCCCT GTGGACTGGTCCAGCCTGGAGGCTC TCTTCTCTGTCCGCGTCTGTTGGG TTTGAGGCTTTCCTGTGCCGCCTCAG GACAGGGTGACAATCACCTGTCG GGTTTGATTTCAGTAAATTCGCTAT GGCTTCGCAGGCTATTAAAAATTA GTCCTGGGTTCGCCAGGCTCCCGGG TCTTAACTGGTATCAGCAGAAGCC AAAGGACTTGAGTGGGTGTCCCACA CGGTAAGGCCCCAAAGTTGCTCAT TCAGCGGTAGCGGCGGAACGATTTA CTATGATGCCAGCCACCCACAGTC TTACGCAGACTCAGTAAAGGGCAGA AGGAGTACCCAGTCGCTTCAGAG TTTACTATATCTCGGGACAATTCAA GCTCCGGAAGCGGCACCGACTTCC AGAACACACTCTACCTGCAGATGAA CTTTCACCATCTCAAGCCTGCAGC CAGTTTACGAGCAGAGGATACCGCG CGGAGGAATTTGCAACATACTACT GTCTATTACTGCGCCAGTGCCAGCT GCCAGCAAAGCTACAGTACGCCC CCTACTATGAGCCAGGCGACCCGTG GTCTTTGGCGGTGGGACTAAAGTG GGGGCAGGGGACACTCGTGACCGT GAGATTAAA GAGCTCT SEQ ID NO 79 80 AVE-06-G08 GAGGTACAACTCCTAGAGAGTGGCG GACATCCAGATGACACAGAGCCC GAGGCCTTGTGCAGCCCGGAGGATC GTCTTCACTCAGTGCAAGTGTTGG GCTGCGACTGTCATGCGCTGCATCC GGACAGAGTGACCATTACATGCA GGCTTTGATTTCTCTAAATTTGCCAT GGGCCGGACAGGCTATCAAAAAC GAGCTGGGTGAGACAGGCCCCGGG TATCTGAATTGGTACCAACAAAAA TAAGGGCCTGGAATGGGTGTCTCAC CCTGGCAAGGCGCCCAAATTGCTC ATATCAGGGAGCGGGGGAACAATTT ATCTATGCCGGTTCACCACTGCAG ACTATGCCGACTCAGTTAAGGGGCG AGCGGTGTGCCATCGCGGTTTAGC CTTCACCATCAGCAGGGACAATTCC GGATCTGGCTCCGGCACTGATTTC AAAAACACCCTGTATTTACAGATGA ACCCTTACCATTTCCTCTTTACAGC ACAGTTTGCGGGCGGAGGATACGGC CCGAGGATTTCGCTACCTACTATTAGTCTACTATTGTGCTTCCGACAGC GTCAGCAGACTTACTCCACGCCTCAGTTACTACGAACCAGGTGATCCTT TGACATTTGGAGGGGGGACTAAG GGGGCCAGGGGACTCTCGTGACAGT GTCGAAATAAAG CTCCTCT SEQ ID NO 89 90 AVE-06-H08 GAGGTGCAGCTGCTGGAGAGCGGC GACATCCAGATGACTCAGTCGCCC GGAGGGCTGGTGCAACCTGGGGGCT TCCTCACTGTCTGCTTCAGTTGGA CACTGCGACTTTCCTGCGCTGCCTC GATCGGGTGACCATTACCTGCCGC AGGTTTCGATTTCTCTAAGTTCGCTA GCTAGTCAACCGATCAGCTCCTAT TGAGCTGGGTCAGACAGGCACCCGG GTGACGTGGTATCAGCAGAAGCC GAAAGGCTTAGAGTGGGTGTCTTCT AGGCAAGGCCCCTAAATTGTTAAT ATTACGCGTGGCAGTGAAACTACCT CTATTCAGCGTCCCACCTCAGGAG ACTACGCCGACAGCGTTAAAGGACG CGGCGTCCCCAGCAGATTTTCTGG GTTTACAATCTCCAGGGACAATTCC AAGCGGGAGTGGTACCGATTTCAC AAGAACACCCTCTATCTGCAGATGA TCTGACAATATCCTCTCTTCAGCC ACAGTCTCCGCGCGGAAGACACAGC CGAGGACTTTGCAACATACTACTG CGTCTATTACTGTGCAACCCTAGGG TCAACAGAGTTACAACGCCCCACC TTGGGTTACTATTATTACTTTGATGT TACATTCGGTGGCGGGACCAAAGT ATGGGGCCAGGGAACATTGGTGACT AGAAATTAAG GTTAGCTCG SEQ ID NO 99 100 AVE-06-A09 GAGGTGCAGCTCCTCGAAAGCGGCG GACATTCAAATGACACAGAGCCC GCGGATTAGTCCAGCCTGGGGGATC ATCTAGTTTGAGCGCATCCGTAGG GCTGAGGTTGTCATGCGCCGCCTCA CGATAGAGTGACGATCACTTGTCG GGCTTTCCCTTCGCATCCCACGCAA GGCTTCACAGACCATATCTTCCTT TGACTTGGGTGAGACAGGCGCCAGG CGTGTCTTGGTATCAGCAGAAACC GAAGGGGCTTGAGTGGGTGTCTACG GGGTAAGGCGCCCAAATTACTCAT ATTACCGGCAGCGGGCGGTCCACAT CTACGCCGCCACAACCCTGCAAAA ATTATGCCGATAGTGTTAAGGGCCG GGGCGTTCCTTCACGCTTTTCAGG ATTCACTATCTCACGTGATAACTCC GAGCGGGTCCGGAACAGACTTCA AAAAACACCCTGTACCTGCAGATGA CACTTACCATTAGTTCGCTGCAGC ATAGTCTACGCGCTGAGGACACCGC CCGAGGATTTCGCTACTTATTACT TGTATACTATTGTGCTTCTGCCTCTA GCCAGCAGTCCTACCACACTAGGA GCTACTACGAACCCGGTGACCCGTG GCTTTGGCGGAGGGACCAAAGTC GGGACAAGGTACACTGGTGACAGTC GAAATCAAG TCCAGC SEQ ID NO 109 110 AVE-06-B09 GAAGTGCAGCTCCTAGAGAGCGGG GATATACAGATGACACAATCACCC GGCGGGCTGGTGCAGCCCGGAGGG TCCAGCCTTTCGGCCTCAGTGGGT TCACTGAGGCTGTCTTGCGCTGCCT GACAGAGTTACCATTACCTGCCGG CTGGCTTAACATTCTCCAATTTCGCA GCTTCACAGAGCATCAGCTCCTAC ATGACATGGGTGCGCCAGGCCCCTG TTGAACTGGTACCAGCAAAAGCCC GGAAAGGTCTTGAGTGGGTGTCCTC GGAAAAGCTCCAAAGCTCTTAATC GATTAGGGGATCTGGTGCCACCACT TACGCCGCATCTTCTCTGCAGTCT TACTACGCTGACTCCGTCAAGGGCA GGGGTGCCTTCTAGGTTTAGCGGA GATTTACGATCAGCAGAGATAACAG AGTGGCAGCGGCACCGACTTTACA TAAGAATACCCTGTACTTGCAGATG CTGACTATTAGTTCCCTGCAGCCT AACAGTCTTCGGGCCGAAGATACAG GAAGATTTCGCGACATATTACTGT CTGTCTATTATTGTGCACGAAGCCG CAGCAGTCCTATAGTACTCCATAT TGAGGCGTATGGATTTGACTACTGG ACCTTCGGTGGCGGGACGAAGGT GGCCAAGGCACCCTCGTAACTGTTA CGAGATCAAA GCTCA SEQ ID NO 119 120 AVE-06-D09 GAAGTCCACCTGTTGGAGAGCGGCG GACATCCAGATGACGCAATCCCCT GTGGCCTGGTTCAACCTGGGGGTTC TCTAGCCTGTCAGCGTCAGTGGGC TCTACGTTTGTCGTGTGCAGCCTCTG GATCGGGTCACAATCACTTGTAGAGGTTTACATTTAGCCATTA TAGCAT GCTTCTCAGAGTATTAGTACCCATGAATTGGGTGAGACAGGCACCCGG CTGAACTGGTACCAGCAGAAACC AAAGGGACTTGAGTGGGTTAGCGG AGGCAAGGCACCCAAACTCCTCAT GATCTCCGGGTCAGGCTCCGCGACT ATATGCCGCTTCCAGCTTACAGAG TACTATGCCGATTCAGTGAAAGGCC TGGTGTGCCATCGAGGTTCAGCGG GCTTCACCATTTCTCGGGACAACAG TTCCGGCAGCGGAACTGACTTTAC TAAGAATACTCTGTACCTCCAGATG CTTGACCATCTCCTCTCTGCAGCC AACAGTCTCCGAGCTGAAGACACCG TGAAGATTTTGCCACATATTACTG CCGTGTACTACTGCGCTTCCGACAG CCAACAGTCACACCGCACCCCCCT GTATCTGACCTTCGATGTCTGGGGA TATTTTCGGAGGGGGGACAAAGG CAGGGCACGTTAGTGACAGTATCCT TTGAGATTAAG CA SEQ ID NO 129 130 AVE-06-F09 GAGGTGCAGCTGCTGGAGTCTGGCG GATATTCAGATGACACAGAGCCCC GCGGTCTTGTCCAGCCCGGGGGGTC TCGTCACTGTCTGCGTCCGTCGGT ACTCCGACTAAGCTGCGCTGCGAGT GATCGGGTTACAATCACCTGTAGG GGATTTGACTTCTCCAAGTTTGCCAT GCTTCTCAAGCTATCAAGAACTAC GTCCTGGGTGAGACAGGCACCAGG CTCAATTGGTACCAGCAAAAACCT AAAGGGACTTGAGTGGGTGTCACAC GGCAAGGCCCCAAAACTGTTAATT ATATCTGGGAGCGGCGGAACTATTT TATGCAGGGTCTACATTGCAGAGT ACTACGCTGATAGCGTTAAAGGCCG GGCGTGCCTTCAAGATTCAGCGGC CTTCACAATCTCACGGGACAACAGT TCCGGGTCCGGAACTGACTTCACC AAAAACACCCTCTATTTGCAAATGA CTTACAATCAGCAGTCTGCAGCCC ATAGTCTGAGGGCCGAAGATACAGC GAGGACTTTGCCACCTATTATTGC AGTCTATTACTGTGCCTCCGCCTCTA CAGCAGACGTACAGCACCCCACTC GCTACTATGAACCTGGCGACCCGTG ACTTTTGGGGGTGGAACTAAAGG GGGGCAGGGTACGCTGGTGACCGTA AGAAATAAAG TCGTCC SEQ ID NO 139 140 AVE-06-G09 GAGGTGCAGTTCCTCGAATCCGGTG GACATCCAAATGACACAGTCCCCA GGGGTTTAGTGCAGCCCGGGGGCAG AGTTCTCTTTCCGCCTCTGTGGGT CCTTCGGCTGTCCTGCGCCGCCTCTG GACAGAGTGACAATCACCTGTCGC GGTTTAGCTTCGACAATTACGGTAT GCATCCCAGTCAATTAATAACTAT CAACTGGGTTCGACAAGCACCAGGG CTCAACTGGTACCAGCAGAAGCCT AAGGGACTGGAATGGGTGTCATCAA GGGAAGGCGCCCAAACTGCTGAT TTTCCTCGTCTGGAGGCTCCGCGTAT TTATGCCGCTTCCAGCTTACAAAG TACGCAGATTCAGTGAAAGGCCGTT TGGTGTCCCATCAAGGTTTTCAGG TTACCATAAGTAGGGACAATAGCAA CAGCGGAAGCGGGACCGATTTCA GAACACACTGTACCTCCAGATGAAC CTCTGACGATAAGCTCGTTGCAGC AGTCTGCGCGCTGAGGACACCGCCG CTGAAGATTTCGCTACCTACTACT TCTATTACTGTGCTAGAGGCGTAGT GCCAGCAGTCTCGGACTACCCCCT CCCTGGAGGATTCGATTATTGGGGC GGACTTTTGGCGGCGGAACAAAG CAGGGCACGTTGGTTACTGTGTCTA GTTGAGATCAAA GC SEQ ID NO 149 150 AVE-06-C10 GAAGTGCAGCTTCTTGAGTCCGGCG GACATCCAGATGACGCAAAGTCCT GGGGACTAGTTCAGCCCGGCGGCTC AGCAGCCTGTCCGCCTCAGTGGGC ACTGCGACTGAGTTGTGCGGCTTCA GACCGGGTGACTATCACATGTAGG GGGTTTGATTTCAGCAAATTCGCAA GCTTCTCAGACCATTGGCATATAT TGTCTTGGGTGAGACAGGCCCCAGG CTGAACTGGTACCAGCAGAAGCC AAAAGGTTTGGAGTGGGTGAGCTCT CGGGAAAGGTCCCAAACCGGCGA ATTACCGGGACCTCGGGCGCCACCT TCTACTCCGCATCCCCACTTCAGC ACTATGCTGATTCCGTTAAGGGTAG GCGGCGTCCCTTCCAGATTCTCGG ATTTACTATCTCTAGGGACAATAGC GGTGCGGCTCAGGTACAGATTTTA AAGAACACACTCTACCTCCAAATGA CTTTGACAATTTCTAGTCTCCAGC ACAGTCTGCGGGCCGAAGACACTGC CCGAAGATTTCGCCACTTACTATTCGTATACTATTGCGCTAGGGATATA GCCAACAGAGCTATTCTACCCCACCGCGTGCGGCGTAGCTCCTGGGCAA ACATTACCTTTGGAGGGGGAACCA TGGACCCTTGGGGACAGGGCACGCT AGGTTGAGATCAAG GGTCACAGTCTCCTCA SEQ ID NO 159 160 AVE-06-G10 GAGGTACAACTCCTGGAGTCAGGCG GACATTCAAATGACACAGAGTCCC GAGGGCTCGTCCAGCCAGGAGGTTC AGTAGCCTCAGCGCTTCCGTTGGC CCTAAGACTTTCTTGTGCCGCCTCA GATAGAGTGACAATTACCTGTAGG GGCTTTGACTTCAGCAAGTTCGCAA GCCTCCCAGGCAATAAAGAACTAT TGAGCTGGGTGAGGCAGGCGCCTGG CTTAACTGGTACCAGCAGAAACCA GAAGGGGTTAGAATGGGTGTCTCAC GGTAAGGCCCCTAAACTCTTAATC ATTAGTGGCTCTGGAGGAACTATCT TATGCTGGCTCAACCCTGCAATCT ACTATGCCGATTCGGTGAAAGGGCG GGGGTCCCCTCGCGGTTCTCAGGG ATTTACAATATCCCGCGACAATTCA TCTGGAAGCGGCACAGACTTCACT AAAAACACACTGTACCTGCAGATGA TTGACCATCTCTAGCCTGCAGCCA ACAGTTTGCGGGCTGAAGATACCGC GAGGAGTTTGCGACTTACTATTGC AGTCTACTATTGCGCTTCCGCCTCCA CAACAGACATACTCCACCCCTCTG GCTATTACGAGCCCGGTGACCCGTG ACGTTTGGAGGGGGTACTAAGGG GGGCCAGGGCACCCTGGTTACGGTG AGAAAATCAG AGTAGC SEQ ID NO 169 170 AVE-06-H10 GAAGTGCAGCTGCTAGAATCCGGAG GATATCCAAATGACACAGTCTCCC GGGGCTTAGTCCAGCCTGGCGGCTC AGTTCATTGTCCGCTTCCGTTGGA CCTTCGGCTCTCTTGTGCCGCTTCCG GATAGAGTCACCATTACCTGCAGG GATTTACGTTCACTAACTATGCACT GCCAGTCAGGCGATAAAAAACTA GGCCTGGGTGCGACAGGCGCCAGG CCTTAATTGGTATCAGCAGAAGCC GAAGGGGCTGGAGTGGGTAAGCCA TGGGAAAGCTCCCAAGCTGCTGAT CATCTCTGGATCAGGAGGTACAATT CTACGCCGGCTCAACTCTGCAGTC TACTATGCTGACAGCGTGAAGGGGC TGGGGTGCCTTCTCGGTTTTCCGG GCTTCACCATAAGCAGAGATAACTC TTCGGGCAGCGGGACGGACTTTAC TAAAAATACCCTTTATCTGCAAATG ACTCACAATTAGCAGCTTACAACC AATAGTCTCAGGGCCGAGGATACTG AGAGGACTTCGCAACTTATTACTG CAGTGTATTACTGCGCTTCGGCCTC TCAGCAGACCTATAGCACACCACT AAGCTACTACGAGCCCGGCGACCCG CACTTTCGGCGGAGGTACCAAGGT TGGGGTCAGGGCACATTGGTCACCG GGAAATCAAA TTAGTTCC SEQ ID NO 179 180 AVE-06-B11 GAGGTGCAGCTGCTGGAGTCTGGGG GATATCCAGATGACCCAGTCGCCA GCGGGCTAGTCCAACCCGGAGGATC AGCTCTCTCTCCGCTTCTGTTGGA GCTGAGGCTTTCCTGCGCCGCGTCA GACAGGGTCACAATTACTTGCCGG GGGTTTGACTTCAGCAAGTTTGCCA GCATCCCAAGCGATCAAGAACTAT TGTCTTGGGTGCGACAGGCACCTGG TTAAATTGGTACCAGCAGAAGCCT AAAAGGATTGGAATGGGTGTCACAC GGGAAAGCTCCTAAACTTCTGATA ATAAGCGGTTCTGGCGGCACTATCT TATGCCGGCTCTACCCTGCAGTCA ATTACGCCGACTCCGTCAAAGGCCG GGGGTGCCCAGTAGATTCTCAGGG CTTCACAATTAGCCGGGATAACAGC AGCGGCAGTGGTACCGATTTCACA AAGAATACGCTCTACTTACAGATGA CTGACCATTAGCAGCTTGCAACCA ACAGTCTCAGAGCCGAGGATACCGC GAGGACTTTGCCACATACTATTGT TGTTTACTATTGTGCATCAGCTAGTA CAGCAGACGTACTCCACTCCCCTC GTTACTATGAACCAGGTGACCCGTG ACATTTGGTGGCGGAACTAAAGTG GGGGCAGGGCACCCTGGTGACAGT GAAATCAAG ATCCTCCSEQ ID NO 189 190AVE-06-E11 GAGGTCCAGCTGCTAGAGTCTGGAG GATATTCAGATGACTCAGAGCCCA GCGGGCTGGTGCAGCCGGGAGGTA TCTAGCCTCAGCGCTTCTGTGGGG GTTTACGCCTGTCCTGTGCAGCTTCG GACAGGGTTACGATTACATGTAGA GGCATTAGGTTTTCAAGCTACGCAA GCAAGTCAGGCCATCAAGAACTA TGTCTTGGGTGCGACAAGCGCCTGG CCTTAATTGGTACCAGCAAAAGCC TAAGGGACTGGAATGGGTGAGCCA TGGCAAAGCTCCTAAACTGCTCAT CATCAGCGGCAGCGGCGGAACTATA CTACGCGGGGTCCACATTGCAATC TATTATGCCGACTCCGTAAAGGGGC TGGAGTCCCCTCGCGGTTTAGTGG GGTTCACGATCTCACGTGATAACTC AAGCGGCTCCGGTACAGACTTCAC AAAAAACACATTGTATCTCCAGATG TCTGACCATCTCATCATTACAGCC AATAGTCTTAGAGCCGAGGATACCG AGAGGATTTCGCCACATATTATTG CCGTTTACTACTGCGCTTCCGCCTCC CCAGCAGACCTATTCCACTCCCCT AGTTACTATGAACCAGGGGACCCCT GACCTTTGGCGGCGGGACCAAAG GGGGCCAGGGGACACTCGTCACCGT TGGAAATAAAG GTCTTCT SEQ ID NO 199 200 AVE-06-H11 GAAGTGCAGCTCTTAGAGAGCGGG GACATCCAGATGACCCAGTCTCCT GGCGGACTGGTCCAGCCAGGCGGTA TCCTCCCTTAGTGCTTCGGTGGGT GCCTGCGCCTAAGTTGCGCCGTTTC GATAGGGTCACCATTACATGCAGA TGGGTTCGATTTTTCTAAGTTCGTGA GCCAGTCAGGCAATAAAGAACTA TGAGTGGCGTGCGGCAGGCTCCTGG CTTGAATTGGTACCAGCAAAAACC CAAAGGTCTGGAGTGGGTTTCACAC CGGCAAGGCCCCCAAACTGCTGAT ATATCCGGGTCTGGGGGAACGATTT CTATGCTGGTTCCACGTTACAGTC ACTACGCTGATTCAGTGAAAGGAAG TGGAGTGCCAAGCCGGTTTAGCGG ATTTACCATCTCCAGGGACAACAGC CTCAGGGTCTGGAACTGATTTCAC AAGAATACTCTCTATCTGCAAATGA ACTGACAATTAGCTCACTCCAGCC ACAGTCTTCGAGCGGAAGACACAGC AGAAGACTTCGCGACTTATTATTG CGTCTACTATTGTGCATCCGCCTCGT TCAGCAAACCTACAGCACCCCTCT CATATTACGAGCCGGGTGACCCCTG CACTTTTGGGGGCGGGACAAAGG GGGACAGGGCACATTGGTGACCGTA TTGAGATCAAA AGCTCC SEQ ID NO 209 210 AVE-06-A12 GAAGTGCAGCTCCTAGAGTCCGGAG GATATACAGATGACCCAGTCACCC GTGGCCTCGTGCAGCCGGGAGGCTC TCCAGCTTGTCAGCTAGTGTTGGG CCTGCGCCTGTCCTGCGCGGCCTCT GACCGGGTCACCATCACATGCAG GGCTTTGACTTTAGTAAGTTCGCTAT AGCCTCTCAGGCGATCAAGAATTA GAGCTGGGTGAGACAGGCTCCAGGT CCTTAACTGGTATCAGCAGAAACC AAGGGCCTGGAGTGGGTATCTCACA AGGAAAAGCTCCGAAGTTACTGA TCTCCGGGTCAGGAGGGACCATATA TTTACGCAGGTAGCACACTGCAGT TTACGCCGACTCTGTCAAAGGCCGG CGGGCGTGCCCTCTAGGTTCAGTG TTCACTATTTCAAGGGATAATTCAA GGAGCGGCTCCGGAACAGACTTT AAAACACATTATACCTTCAAATGAA ACTCTGACCATTTCTTCCCTCCAA CAGTCTGCGAGCCGAAGACACAGC CCAGAAGATTTCCCTACTTATTAT AGTGTACTATTGTGCCAGCGCAAGC TTTCAGCAAAACTACAGCACGCCT AGCTACTATGAGCCTGGAGATCCCT TTCGCCTTTGGCGGTGGGACCAAA GGGGGCAGGGGACCTTGGTCACGGT GTGGAGATCAAG TAGTTCGSEQ ID NO 219 220AVE-06-B12 GAGGTGCAGCTTCTGGAGAGCGGA GACATCCAGATGACACAGAGTCC GGGGGACTGGTCCAGCCTGGCGGCA ATCTAGCTTATCCGCGAGTGTTGG GTCTAAGATTGTCCTGCGCCGCGTC GGACAGGGTCACCATCACATGTA AGGGTTCGATTTTTCCAAATTTGCC GAGCCTCTCAGGCAATTAAAAACT ATGTCATGGGTGCGCCCAGCTCCCT ACCTGAATTGGTATCAACAAAAGC GTAAGGGATTAGAATGGGTGAGTCA CCGGAAAGGCCCCAAAGCTGCTC CATCTCAGGTTCTGGGGGCACAATT ATCTACGCCGGCTCCACCCTGCAG TATTACGCAGACTCCGTCAAGGGGC AGCGGAGTGCCTAGCCGGTTTAGC GATTCACGATATCCCGGGACAACTC GGCTCTGGCTCGGGGACTGATTTT TAAAAACACTCTGTACCTCCAAATG ACATTGACTATTTCATCACTTCAG AATAGTCTCAGGGCCGAGGACACCG CCCGAAGATTTCGCTACATATTAT CTGTGTACTATTGCGCCTCGGCAAG TGCCAGCAGACCTACTCCACTCCT CAGCTATTACGAACCCGGCGATCCG CTCACGTTCGGTGGTGGGACCAAA TGGGGCCAGGGTACCCTGGTAACAG GTGGAGATAAAA TTAGCTCT SEQ ID NO 229 230 AVE-06-C12 GAGGTGCAGCTGCTGGAAAGCGGA GATATACAAATGACACAGAGTCC GGAGGGTTAGTGCAACCAGGAGGA CTCATCCCTGTCAGCTTCTGTGGG TCTCTCCGGCTGAGCTGCGCTGCCT TGATAGGGTCACAATCACATGCAG CAGGCTTTGATTTCAGCAAGTTCGC AGCCAGCCAGGCGATTAAAAATT CATGTCCTGGGTCCGACAGGCACCG ACCTCAACTGGTATCAGCAGAAGC GGGAAAGGCCTTGAGTGGGTGAGC CTGGCAAGGCTCCAAAATTACTTA CACATATCCGGCTCAGGTGGGACCA TCTACGCAGGTAGCACCCTGCAGT TTTACTACGCTGATTCTGTAAAAGG CCGGAGTGCCTTCTCGGTTCAGCG GAGATTTACGATCTCACGCGACAAC GGTCCGGCTCTGGGACCGACTTTA AGTAAGAATACACTCTACCTGCAGA CCCTCACCATCAGTAGCCTGCAGC TGAACAGTTTGAGGGCCGAAGACAC CAGAAGACTTCGCCACTTATTACT AGCCGTGTATTATTGTGCGTCTGCA GTCAGCAAAACTATTCGACTCCCT TCCTCGTACTATGAGCCTGGCGACC TGACGTTTGGAGGCGGGACTAAA CCTGGGGCCAGGGTACCCTAGTCAC GTTGAGATTAAG TGTTTCCAGT SEQ ID NO 239 240 AVE-06-E12 GAGGTCCAATTTCTGAAAAGCGGTG GACATACAGATGACACAGTCTCCC GCGGGCTGGTTAATCCCGCGGGCAT AGCTCTTTATCCGCTTCCGTGGGC CCTTGAGCTCTCTTGTGCAGCCTCCG GATAGAGTGACTATTACATGCCGC GGTTCCCGTTTAGCAGTCACGGTAT GCAAGTCACTCCATCGCCAGCTAT GTCATGGGTGAGGCAGGCTCCAGGA CTCCACTGGTACCAACAAAAGCCA AAGGGACTAGAATGGGTATCTGTGA GGTAAGGCGCCCAAACTGCTGATC TTTCAGGCTCCGGAGCCACCACCTA TACAGGGCCAGCACGCTGCATAC TTACGCAGATTCCGTTAAGGGCCGC AGGAGTCCCTTCTCGGTTTTCCGG TTCACTATATCGAGAGACAACAGCA AAGTGGCTCAGGGACAGATTTCAC AAAATACTTTATATTTGCAGATGAA TCTTACCATTTCATCGTTGCAGCCT CAGTCTGCGAGCCGAAGACACAGCT GAGGACTTTGCTACCTATTATTGT GTCTATTACTGCGCCCGGGGGCAGC CAGCAGACCTACAGCATCCCGTGG CTTACTATGGCTTCGATTACTGGGG ACTTTCGGTGGCGGGACCAAAGTT ACAGGGGACGCTCGTGACAGTGAG GAAATTAAG CTCTSEQ ID NO 249 250AVE-06-G12 GAGGTGCAATTTCTGGAGTCAGGGG GACATTCAGATGACACAGTCACCA GGGGTTTGGTTCAGCCGGGAGGCAG AGTAGTCTGTCCGCGTCTGTTGGG CCTTAGGTTATCCTGTGCCGCCTCA GATCGGGTGACGATTACATGCAG GGGTTCGATTTCAGCAAATTTGCAA GGCTTCGCAGGCCATCAAAAACTA TGAGTTGGGTCCGGCAGGCACCCGG CTTAAACTGGTATCAACAGAAGCC CAAGGGACTGGAATGGGTAAGCCA CGGCAAGGCCCCTAAGCTGCTTAT CATTTCTGGCTCTGGAGGCACCATC ATACGGGGCTTCCAATCTGCAGTC TACTACGCCGACTCCGTGAAGGGAC AGGAGTCCCTTCCAGATTTTCTGG GATTCACGATATCGCGCGACAATTC ATCTGGTAGCGGTACTGATTTTAC AAAAAACACCCTGTATCTCCAGATG ACTCACCATCTCCAGCCTCCAACC AACAGTCTGAGAGCTGAGGATACTG CGAGGACTTCGCAACCTATTACTG CCGTCTATTACTGCGCTTCCGCGTCT TCAGCAGAGCGAAAGCACTCCATT AGTTACTATGAACCAGGTGACCCTT GACCTTCGGGGGCGGCACCAAAG GGGGCCAGGGGACACTCGTGACAG TGGAGATCAAA TGAGCTCC SEQ ID NO 259 260 AVE-07-A01 GAAGTGCAGCTTTTAGAATCAGGCG GATATCCAAATGACCCAGTCTCCT GTGGACTCGTACAGCCTGGGGGCTC TCCTCGCTCAGCGCAAGTGTGGGC CCTGAGACTGAGCTGCGCTGCCTCA GACAGGGTGACCATTACATGTCGC GGCTTCGCCCTCACAGACTTTGCCA GCCAGTGCTCCAGTCGGAAGATAT TGTCCTGGGTGCGGCAAGCTCCCGG CTGAACTGGTATCAGCAGAAACCT GAAGGGACTAGAGTGGGTGTCCCA GGGAAGGCCCCCAAGCTGCTTATC GATCTCGGTGTCTGGTGGCGTTGGG TATGCAGCCTCATCCTTACAGTCT TACTACGCCGACAGCGTCAAAGGGA GGGGTGCCCTCCCGGTTCTCAGGT GGTTCACGATTTCCAGGGATAACAG AGCGGTAGCGGGACTGACTTTACA TAAGAATACCCTGTACCTGCAAATG CTGACCATTTCATCTTTGCAGCCA AACAGTTTGCGCGCGGAGGATACAG GAGGATTTTGCTACGTACTACTGC CAGTTTATTATTGTGCACGAAGCCG CAGCAAAGCTACTCCGCGGTTACA TTCTTATTACGCTGGAGCATTTGAC TTCGGAGGCGGCACTAAAGTAGA GTGTGGGGCCAGGGAACCCTTGTCA AATAAAG CTGTCAGCTCT SEQ ID NO 269 270 AVE-07-B01 GAGGTCCAGCTACTGGAAAGCGGG GATATTCAGATGACACAGAGCCCC GGCGGGTTAGTTCAGCCCGGGGGTA TCTAGTCTCAGCGCCTCCGTGGGT GCTTGCGCCTCTCATGCGCCGCCTC GACAGAGTTACCATTACCTGCAGG CGGATTCACCTTCGGCTCTTATGCC GCTTCGCAGACTCTGCGGAACTAC ATGACCTGGGTGAGACAGGCACCTG TTGAACTGGTACCAACAAAAACC GCAAGGGACTGGAATGGGTGTCTGC AGGGAAAGCGCCGAAGCTCCTTA TATTGGCACTACTGACAGATACACG TCTACGCAGCCTCCAATTTACAGA TACTACGCTGATAGCGTGAAAGGCC CTGGCGTCCCCTCTCGCTTTAGTG GTTTTACCATCTCCCGAGACAACAG GCTCAGGATCAGGCACGGACTTCA TAAGAACACACTGTATCTCCAGATG CTCTGACCATAAGCTCTCTGCAGC AATAGTCTGAGGGCTGAGGATACAG CAGAGGATTTCGCTACCTATTATT CCGTTTATTACTGTGCAAGGTCGCG GTCAGCAGCGATTTTCCCCTCCTT GTCCTACTATGCGGGTGCATTTGAC GGACATTCGGAGGTGGGACAAAG GTCTGGGGACAAGGGACCCTTGTAA GTGGAAATCAAG CAGTGTCTTCASEQ ID NO 279 280AVE-07-C01 GAGGTACAGCTCCTCGAAAGTGGAG GATATTCAGATGACTCAATCCCCT GAGGGCTGGTCCAGCCCGGCGGCTC AGCAGCCTGTCTGCGAGTGTGGGC ACTAAGACTTTCATGTGCGGCATCG GACAGAGTTACCATCACTTGCAGG GGGTATACTTTCAGCAATTTCGCTA GCTTCACAATCCATAGGGTCATCC TTTCCTGGGTGCGGCAAGCCCCTGG GTCAATTGGTATCAGCAGAAACCT CAAAGGGCTGGAATGGGTGAGCAG GGGAAAGCTCCCAAGTTGCTTATC CATAACTGGTTCTGGTGTGCGTACA TATGCCGCCTCTTCTCTGCAGTCC TTCTACGCCGATTCTGTTAAGGGAA GGCGTGCCATCTCGGTTCAGCGGC GATTTACCATCTCCAGGGACAATAG AGCGGAAGTGGGACAGACTTTAC CAAGAACACATTATATCTGCAGATG ACTCACCATCTCGTCATTACAGCC AACAGTTTGCGCGCCGAGGATACCG AGAAGATTTCGCAACGTACTACTG CTGTCTACTATTGCGCAAGGTCACG TCAGCAGAGTGACAACAACCCCT ATCCTACTACGCTGGCGCCTTTGAC GGACCTTTGGAGGTGGTACAAAG GTTTGGGGGCAGGGCACCCTGGTGA GTAGAGATTAAG CGGTGTCTTCC SEQ ID NO 289 290 AVE-07-D01 GAGGTACAACTCTTAAAGTCCGGAT GATATTCAGATGACACAGTCCCCA CTGGATTGGTCCAGCCTGGCGGCAG AGCTCGCTGTCTGCTTCCGTTGGC CCTCAGACTGTCATGCGCAGCCAGC GATAGAGTAACTATCACATGCCGC GGATTTACCTTCAACAATGCCTGGA GCCAGCGCTCCAGTGGGGAGGTA TGCACTGGGTGAGGCAGGCACCCGG CCTCAACTGGTACCAGCAGAAACC CAAAGGTCTTGAGTGGGTGTCGGCC CGGGAAGGCACCTAAATTGCTGAT ATCTCAAGCTCCGGGGGCTATACAT CTATGCCGCCTCTTCACTGCAGTC ATTATGCAGATTCAGTTAAGGGGCG AGGTGTCCCCTCTCGGTTTAGTGG GTTCACCATTTCTCGTGACAACTCC GAGCGGTAGTGGAACTGACTTTAC AAAAATACTCTGTACCTGCAGATGA ACTTACCATTTCCTCCTTACAGCCT ACAGTCTTCGAGCTGAAGATACAGC GAAGACTTCGCAACGTATTACTGT TGTGTATTACTGTGCTAGGTCCCGCT CAACAAGCGTATAGCATCCCCATA CTTACTACGCGGGCGCCTTTGACGT ACCTTCGGAGGCGGCACCAAGGT TTGGGGGCAGGGTACTCTGGTCACG GGAGATTAAG GTGAGCAGT SEQ ID NO 299 300 AVE-07-E01 GAGGTTCAGCTGTTAGAATCAGGAG GATATACAGATGACCCAGTCTCCC GGGGGTTGGTGCAGCCTGGAGGCTC AGCAGCCTTTCTGCCTCAGTCGGG TCTCCGGCTGTCCTGCGCCGCATCG GATAGAGTTACGATCACATGTCGG GGCTTCTCTGTCCGTGACTTCGCCAT GCTCCACAGAATATCTTCAGCTAC GAATTGGGTTCGGCAGGCCCCCGGT ATTAACTGGTACCAGCAGAAGCC AAGGGGCTGGAGTGGGTGAGCACC GGGCAAGGCACCTAAGTTGCTGAT ATCACAGGTACTGATAGAACACCAT CTATGCGGCTAGTTCCTTACAATC ACTACGCAGATTCAGTAAAGGGAA CGGAGTGCCATCGAGGTTTTCCGG GATTTACTATTAGCAGGGACAATTC CTCTGGGTCCGGTACAGACTTTAC TAAAAACACGCTTTACCTCCAGATG CCTGACTATTAGCTCACTCCAGCC AACAGTCTAAGGGCTGAAGATACA TGAGGACTTCGCCACCTATTACTG GCCGTGTATTATTGTGCTCGCAGCC CCAGCAAACACACAGTATCCCCCA GATCCTACTATGCTGGCGCGTTTGA AACTTTCGGCGGTGGGACCAAAG CGTGTGGGGCCAAGGCACCCTGGTC GAGAAATTAAA ACCGTGAGTTCCSEQ ID NO 309 310AVE-07-F01 GAAGTGCAATTGCTCGAAAGCGGCG GATATTCAGATGACCCAATCACCA GAGGCCTTGTTCAGCCTGGAGGTAG AGCAGCCTTAGCGCATCCGTTGGT CCTGAGGCTGTCTTGTGCGGCTTCC GATCGGGTGACAATTACCTGCAGG GGGTTCACCTTCAGCTCACACAACA GCCTCTCAGAGAATATCCACGTAC TGGCTTGGGTGCGGCAGGCACCAGG ATCAACTGGTACCAGCAGAAGCCT AAAGGGGCTAGAGTGGGTGAGTTCC GGGAAAGCGCCTAAGCTCCTGATT ATCGGTGGCGGTGGAAGGACTACG TATGGCGCCAGTTATTTGCACTCT AACTATGCCGACTCAGTCAAAGGGC GGCGTGCCCTCGCGCTTTAGCGGT GTTTTACAATTTCCCGCGATAATTCT AGTGGATCAGGGACCGACTTTACT AAGAATACTCTTTACCTCCAGATGA CTGACTATCTCTTCCTTACAGCCC ACAGTCTGCGAGCCGAGGATACCGC GAAGACTTCGCTACATATTACTGT TGTCTATTACTGCGCCAGAGCTGCA CAACAGACATACTCCACACCCCCA CCCGGCGCCTACGCCTATGCATTAG ACTTTCGGGGGCGGAACCAAAGT ACTACTGGGGCCAGGGGACCCTGGT CGAGATCAAG GACAGTATCGTCT SEQ ID NO 319 320 AVE-07-C02 GAAGTACAGCTTCTGGAGTCTGGCG GACATTCAGATGACCCAGTCACCG GAGGACTAGTTCAGCCCGGCGGGTC TCTTCACTCTCCGCCAGTGTGGGT ACTCCGGCTGAGCTGTGCTGCATCA GACAGAGTGACTATCACCTGTCGA GGGTTTAGCGTCCGTGATTTCGCCA GCCAGCCAAAGGATATCTACTTAT TGACATGGGTCAGACAGGCTCCTGG ATCAACTGGTATCAGCAGAAACC TAAGGGCCTTGAATGGGTGTCCGCC AGGGAAGGCACCTAAGTTATTGAT ATCAGAATATCGGGGGGGGGAACC CTACTCGGCGTCCGTTCTGGAAAA TTTTATGCCGACAGCGTGAAAGGCC TGGAGTCCCCTCTCGGTTTAGTGG GATTCACTATTTCCCGCGACAATTCT GAGCGGATTCGGCACGGATTTTAC AAGAACACTCTGTATTTGCAAATGA ACTTACCATTAGCTCCCTGCAGCC ACAGTCTGAGGGCCGAGGATACAG AGAGGATTTCGCTACCTACTACTG CCGTCTACTACTGCGCAAGGGCGGC CCAACAGAATTATCGCACTCCTCC ACCAGGTGCTTACGCTTATGCCCTC CACATTCGGTAGCGGCACAAAAG GACTACTGGGGACAGGGCACGTTAG GCGAGAACAAG TGACCGTGAGTTCC SEQ ID NO 329 330 AVE-07-F02 GAGGTCCAGCTGCTGGAATCAGGCG GACATCCAGATGACCCAGTCTCCT GAGGGCTGGTTCAGCCCGGCGGCTC AGTAGCCTTTCTGCAAGCGTTGGA CCTCAGGTTAAGCTGCGCGGCAAGC GATCGGGTGACCATCACATGCAG GGGTTTACCTTCTCTAATTACGCCAT AGCCAGCCAAAGTATAAGCTCAT GACATGGGTGAGACAAGCCCCTGG ACTTGAACTGGTACCAGCAGAAG AAAAGGTTTGGAGTGGGTGTCGACC CCAGGTAAGGCTCCAAAACTGTTA ATCACGAGCTCTGCTTCCAAGACTA ATTTACGCTGCCTCTTCCCTGCAG ACTATGCAGATTCTGTGAAAGGCCG TCGGGCGTGCCTAGTAGGTTTTCA GTTCACAATTTCCAGAGATAACTCA GGGTCAGGGTCCGGAACTGACTTC AAGAATACTCTTTACCTACAGATGA ACCCTCACAATCTCCTCCCTGCAG ACAGTCTGCGAGCCGAAGACACTGC CCCGAGGATTTCGCCACCTATTAT TGTCTATTACTGTGCCCGTACCAGG TGTCAACAGTCTTTTACGGCGCCC TATCTTGAGCGCTTTGCTGGCGGTCT CTCACTTTCGGCGGTGGCACAAAG GGACATATGGGGACAGGGGACACT GTCGAAATTAAA CGTGACCGTAAGCAGTSEQ ID NO 339 340AVE-07-G02 GAGGTGCAACTGCTGGAATCTGGTG GATATTCAGATGACTCAATCACCC GAGGTCTGGTCCAGCCCGGAGGCAG TCATCGCTGTCTGCGAGTGTAGGG TCTTAGGCTCAGCTGTGCCGCATCC GACCGCGTCACAATCACCTGTAGA GGCCTAACTTTTAGCAATTACACCA GCCTCCGTGAGCATCAGTACGTTT TGACATGGGTTCGTCAGGCCCCTGG TTAAACTGGTATCAACAGAAACCC GAAAGGGTTGGAATGGGTTTCTGGC GGGAAGGCTCCTAAGCTGCTCATA ATCTCAGGAACCGGGGGTTCGACAT TACGCAGCTTCAACACTTCAGAGC GGTACGCTGATTCAGTGAAGGGCAG GGTGTTCCAAGCAGGTTTTCTGGG ATTCACCATTTCCCGAGACAACAGC TCCGGATCTGGAACTGACTTCACA AAGAATACGCTGTATCTTCAGATGA TTGACTATCAGCTCCCTCCAGCCA ACAGTTTAAGGGCGGAGGACACTGC GAAGATTTCGCCACCTATTACTGC AGTCTATTATTGCGCCCGCTCCCGG CAGCAGTCCCTGCGGACCCCTATT TCCTACTACGCTGGGGCCTTCGATG ACCTTCGGCGGCGGCACAAAGGT TGTGGGGCCAGGGAACCCTCGTAAC GGAGATTAAA AGTGTCTAGC SEQ ID NO 349 350 AVE-07-H03 GAAGTCCAGCTCTTGGAATCCGGAG GATATCCAAATGACACAGTCGCCT GCGGCCTGGTGCAGCCCGGGGGGTC TCTTCCCTTAGCGCATCAGTCGGG ATTGCGACTGAGTTGCGCCGCATCT GACCGCGTGACAATTACCTGTAGG GGTTTCCCTTTTTCTAGCTTCGTGAT ACCTCCCAGAGCGTGAGTACTTAC GTCCTGGGTTAGACAGGCCCCGGGG TTTAACTGGTACCAACAGAAGCCC AAGGGTTTAGAGTGGGTGAGCTCGC GGCAAAGCCCCCAAGCTGCTGATC TGTCCGGAAGCGGGGACATTACTTA TATGCCGCGTCTAGTTTGCAGAGT TTATGCAGATTCTGTTAAGGGCCGC GGTGTTCCTTCACGGTTCTCAGGG TTTACCATCAGCCGGGACAACTCCA TCCGGCTCTGGCACAGATTTCACC AAAATACACTCTACCTTCAAATGAA TTAACTATTTCCAGCCTCCAGCCA CAGTCTACGTGCCGAGGACACCGCC GAGGACTTTGCTACGTATTACTGC GTGTACTACTGTGCTAGGGCTGCCC CAGCAGAGCTATAGAACTCCGCC CAGGCGCGTATGCATATGCTCTGGA AACATTCGGAGGAGGTACCAAGG TTACTGGGGACAGGGCACGCTGGTC TAGAAATAAAA ACAGTATCATCA SEQ ID NO 359 360 AVE-07-D04 GAGGTGCAGCTACTGGAGTCAGGA GATATCCAGATGACACAGTCGCCC GGCGGGCTGGTTCAGCCTGGGGGGT AGCTCCCTGAGCGCTTCAGTGGGG CATTGCGACTGAGCTGTGCCGCATC GACCGCGTAACTATTACATGTAGA TGGCCTCACCTTTAACGCCTACGCC GCCAGTCGAACCGTCACCTCCTAT ATGAGCTGGGTCCGTCAGGCGCCCG CTCAACTGGTACCAACAGAAGCCT GCAAAGGCTTGGAATGGGTGTCCAG GGCAAGGCGCCAAAATTACTGAT CTTAACTGGGTCTGGAGCCTCCACC ATACGGAGCATCTTATTTGCACTC TTCTACGCTGACTCGGTCAAGGGTA TGGTGTGCCGTCTAGGTTCTCCGG GATTCACAATCTCTCGGGACAATTC CAGTGGGAGCGGAACCGACTTCA AAAGAATACACTTTATCTGCAGATG CTCTTACTATCTCCAGCCTGCAGC AACAGTCTGAGGGCTGAAGATACG CAGAAGATTTTGCCACATATTACT GCTGTGTACTATTGCGCACGCTCCA GCCAACAGTCATACCGGACCCCTC GGTCCTACTATGCCGGTGCATTTGA CCACGTTTGGGGGTGGCACAAAG TGTTTGGGGCCAAGGAACCCTCGTA GTTGAGATTAAA ACTGTGAGCAGTSEQ ID NO 369 370AVE-07-E06 GAGGTCCAGCTCCTGGAATCAGGTG GATATTCAGATGACGCAGTCCCCC GGGGCCTGGTGCAGCCCGGCGGGA AGTAGCTTGAGTGCCAGCGTGGGT GCTTGCGGCTTTCTTGTGCTGCAAG GACCGGGTTACTATCACATGTAGA CGGATTTTCAGTGAGAGACTTCGCC GCGAACCAGAATATCGGCAACTA ATGAATTGGGTCCGTCAAGCCCCTG CCTTAATTGGTACCAACAGAAGCC GAAAGGGGTTAGAATGGGTGTCTAG TGGGAAGGCTCCCAAACTCCTGAT CATTCACAGGACAGGCGGGGGCAC CTATGCAGCCTCATCCCTGCAGTC ATACTACGCAGATAGTGTTAAAGGC AGGTGTGCCGTCCAGGTTTTCGGG AGGTTCACGATCTCCAGAGACAATT GTCCGGGAGCGGAACCGATTTCAC CCAAGAACACCCTCTACCTACAGAT CCTGACAATTTCTTCTTTACAACC GAACAGTCTGCGAGCGGAGGACAC AGAAGACTTTGCTACCTACTATTG CGCCGTTTATTACTGCGCCCGGAGC CCAGCAGTCATATAGCACCTCTAC CGCTCCTATTATGCTGGAGCTTTTGA TTTCGGCGGCGGAACAAAGGTCG TGTGTGGGGTCAGGGAACTCTGGTG AGATAAAA ACTGTATCTTCG SEQ ID NO 379 380 AVE-07-F06 GAGGTCCAGCTGTTGGAAAGCGGG GACATACAGATGACACAGTCTCCA GGGGGCTTAGTACAGCCTGGAGGTT TCTAGCCTTAGTGCCTCCGTTGGA CCCTCCGTCTAAGCTGCGCCGCATC GATCGGGTGACCATCACATGCCGC GGGATTCGACTTTCGCTCCTACCCA GCCTCACAGAAGATTGCAAGATAT ATGGCTTGGGTGCGGCAGGCCCCCG GTCAACTGGTACCAGCAGAAACCT GCAAGGGCCTGGAATGGGTTAGTGT GGTAAGGCACCAAAGCTCTTAATC TATTTCTGGTGGAGGCGGTTCAACC TATGCTGCGAGCGACTTGCAAAGC AACTACGCGGACAGCGTCAAAGGG GGCGTGCCCTCTAGGTTTTCCGGC AGATTTACTATCTCTAGGGACAATT AGCGGTTCAGGCACCGATTTCACC CCAAGAACACGCTGTACCTGCAGAT CTGACGATCTCCTCGCTGCAGCCT GAATAGTCTCCGAGCAGAGGATACA GAGGACTTTGCTACTTATTACTGT GCCGTGTATTATTGTGCCAGGTCAA CAGCAAGCCTACAGTATTCCCATT GATCCTACTATGCTGGAGCTTTCGA ACATTCGGGGGAGGGACTAAAGT TGTGTGGGGCCAAGGGACACTTGTG AGAAATCAAA ACCGTGAGCTCT SEQ ID NO 389 390 AVE-07-A07 GAGGTGCAACTCCTTGAGTCAGGTG GACATCCAGATGACCCAGTCACCC GCGGACTCGTGCAGCCTGGCGGATC TCTTCCCTGTCCGCAAGTGTGGGC GCTGAGACTGTCATGTGCGGCTTCT GACCGGGTGACTATTACTTGTCGC GGGTTTCGTTTCTCCAACTACGCAA GCCAGCCAGCCCATCAGTAGATAC TGACATGGGTGAGGCAGGCCCCCGG TTAAACTGGTATCAGCAGAAGCCG GAAAGGCCTGGAGTGGGTATCCGG GGCAAAGCGCCAAAGCTGTTGAT AATCAGCGGCGGCGGGGGCAGGAC ATATGACGCTTCTCGACTTCAAGT CTTCTATGCAGATAGTGTCAAGGGT CGGCGTACCTAGCAGGTTCTCAGG AGATTTACCATTAGCCGGGACAATT GAGCGGTTCTGGAACGGATTTCAC CCAAGAATACATTATACCTACAGAT ACTGACCATCTCGTCCCTCCAACC GAACAGTCTGCGCGCCGAAGATACG AGAGGATTTTGCCACATACTACTG GCTGTCTATTACTGCGCCCGAGGTT CCAGCAGAGCCACTCCATTCCTTG ACGGGGCCGAATATTTCGACCCGTG GACATTTGGGGGTGGAACCAAGG GGGGCAGGGAACTTTGGTTACTGTG TTGAAATTAAA AGCTCTSEQ ID NO 399 400AVE-07-E07 GAGGTGCAGCTGCTCGAATCGGGCG GACATCCAAATGACCCAGAGCCC GGGGCCTGGTCCAGCCCGGGGGGTC ATCATCCCTGAGCGCATCAGTGGG TTTGAGGCTCTCCTGTGCTGCCTCAG AGATAGAGTCACTATCACCTGTCG GGTTTAGGTTCAGTAATTACGCGAT CGCTTCTCAACCAATATCCCGACA GACTTGGGTGCGACAGGCCCCAGGA CCTCAACTGGTACCAGCAGAAACC AAGGGCCTAGAGTGGGTGAGCGGC CGGAAAGGCCCCTAAGCTGTTGAT ATTTCAGGTGGAGGAGGCAGAACAT TTATAGTGCCAGTTCCCTGCAGTC TTTATGCAGATAGCGTTAAAGGTAG AGGTGTTCCTAGCAGGTTTTCTGG ATTCACGATCTCTCGGGACAACTCC CTCTGGGTCCGGCACAGACTTCAC AAGAATACCCTTTACTTACAAATGA GCTTACTATTTCTAGCTTACAGCC ACAGTCTGCGCGCAGAGGATACCGC CGAAGATTTTGCGACATACTACTG CGTATACTATTGCGCTCGTGGGTAT CCAGCAGAGTTATGACCGGACAT GGAGCCGAATACTTCGACCCTTGGG GGACCTTCGGTGGGGGCACCAAG GCCAGGGTACCCTGGTCACAGTGAG GGGGAGTCGAAA CTCC SEQ ID NO 409 410 AVE-07-D08 GAAGTCCAGCTCTTGGAATCCGGGG GACATTCAGATGACCCAGTCACCC GGGGGTTAGTGCAGCCTGGAGGCTC AGTAGCTTGTCTGCCTCTGTGGGA TCTCAGACTGAGTTGCGCCGCCAGC GATCGCGTCACAATAACTTGCAGG GGATTTAGGTTCTCCAATTATGCCA GCTTCCCAACGGATCGCCACCTAC TGACGTGGGTGAGACAGGCCCCCGG CTGAACTGGTACCAGCAAAAACCT GAAGGGGCTGGAGTGGGTGTCTGGC GGTAAGGCACCAAAGCTGTTAATT ATTTCCGGCGGAGGCGGACGGACTT TACGCGGCCTCTCACCTTCATGGA TCTATGCAGACTCAGTAAAGGGTAG GGCGTGCCATCCAGATTCTCCGGC GTTCACAATCAGCCGAGACAACTCG AGCGGGTCAGGCACAGATTTTACC AAAAATACCCTTTACCTGCAAATGA CTGACTATCTCCTCGCTCCAGCCC ACAGTCTGCGCGCGGAGGATACCGC GAAGACTTCGCTACGTATTATTGT TGTGTACTACTGTGCACGTGGTTAC CAGCAGAGTTATAGCATCCCTCTC GGCGCTGAGTATTTTGATCCGTGGG ACATTTGGTGGGGGGACCAAGGTT GCCAGGGTACACTAGTCACTGTTAG GAGATTAAA CTCA SEQ ID NO 419 420 AVE-07-E08 GGAGGCGCGGCCTTAAAGTCCGGA GATATCCAAATGACTCAGAGCCCT GGTGGCCTGGTCCAGCCCGGAGGGT TCCAGCTTGAGTGCGTCCGTGGGG CCCTCAGATTGAGCTGTGCTGCCTC GATAGGGTAACTATCACATGTAGA TGGCTTTACAGTGTCACGGGATTAT ACAAGCCAGACCATATCTATTTAC ATGTCGTGGGTCCGCCAAGCTCCGG CTCAACTGGTATCAGCAGAAGCCC GCAAGGGACTGGAATGGGTGAGTG GGAAAGGCCCCAAAATTACTGATT TGATTAGCACCGGGGGTGGGTCCAC TATGCAGCCTCAATCCTGCACGGA GTACTATGCCGACTCTGTTAAGGGG GGTGTTCCGTCACGGTTCTCCGGG AGGTTCACAATCTCCAGGGATAATT TCGGGCTCTGGTACCGACTTTACC CAAAAAACACCCTGTACCTTCAGAT CTTACGATTAGTAGCCTGCAGCCT GAACAGTCTCCGTGCTGAGGACACC GAGGACTTCGCTACCTACTACTGC GCAGTTTATTATTGCGCAAAACCCC CAACAGAATTATTCTGTCCCACCC GACCATACAGCATAGCATGGTTCGC ACTTTTGGGGGCGGCACAAAAGT CGACCCTTTTGATTACTGGGGCCAG GGAAATCAAG GGTACTCTGGTGACTGTAAGCTCTSEQ ID NO 429 430AVE-07-H08 GAGCTGCAACTCTTAGAATCTGGCG GACATTCAGATGACCCAGTCACCA GAGGCCTGGTTCAGCCCGGAGGCAG TCCAGTCTGTCAGCTTCGGTGGGC TCTGCGTCTATCCTGTGCCGCATCTG GATAGGGTAACAATCACTTGCAG GGTTCCCTTTCTCCAACAACGCCAT AGCGTCCCAGCCCATCTCTCGCTA GTCATGGGTCCGCCAGGCCCCAGGT TCTTAACTGGTACCAGCAAAAGCC AAAGGTCTTGAATGGGTTTCTGTGA GGGGAAAGCACCAAAGCTGTTAA TCAGCGGCAGCTACGGGACTACATA TTTACGACGCCTCTCGGCTGCAGG CTATGCCGATTCCGTGAAGGGCAGA TCGGCGTTCCTAGCCGATTCAGCG TTTACCATTAGCCGGGATAATTCGA GTTCTGGGTCCGGAACAGATTTTA AGAACACGCTTTATCTGCAGATGAA CCCTCACAATTAGCTCCTTGCAGC TAGTTTGAGGGCTGAGGACACCGCA CCGAAGACTTTGCCACCTATTACT GTGTATTACTGCGCCCGAGTGGCTG GTCAGCAAAGTCACAGCATCCCTT ACGGGGCAGCTGCTTACGCGATGGA GGACGTTCGGTGGAGGCACTAAG CTATTGGGGGCAGGGAACTCTCGTC GTGGAGATAAAA ACAGTAAGCTCA SEQ ID NO 439 440 AVE-07-C10 GAGGTGCAACTGCTTGAGAGTGGCG GACATCCAGATGACCCAAAGTCCC GAGGCCTGGTGCAGCCTGGGGGCA TCTTCTCTTAGCGCTTCGGTGGGC GCCTCAGATTATCTTGCGCGGCCTC GATCGGGTGACCATTACTTGTAGA AGGTTTTCGTTTCTCTAACTATGCTA GCGTCACAGCCAATAAGCAGGTA TGACATGGGTCCGACAGGCTCCAGG TCTCAATTGGTATCAGCAGAAGCC GAAAGGGCTAGAATGGGTATCGGG CGGAAAAGCACCCAAGTTGCTGA AATTTCCGGTGGCGGGGGCCGGACT TCTACGCCGCCTCCAACTTAAAGA TTCTACGCCGATAGCGTCAAGGGAA AGGGGGTTCCTAGCCGCTTTAGTG GGTTCACAATCAGCCGCGACAATTC GGTCCGGCTTCGGAACCGATTTCA AAAGAATACCCTCTACCTGCAGATG CACTCACAATCTCATCCCTGCAGC AACAGTTTGAGGGCCGAGGACACTG CGGAGGACTTTGCTACGTACTATT CAGTGTATTACTGTGCCAGAGGCTA GCCAACAGTCTTACAACCCTCCAC CGGAGCAGAATATTTTGATCCCTGG TGACTTTCGGTGGCGGGACAAAA GGGCAGGGTACCCTGGTGACGGTTT GTCGAAATTAAA CCTCC SEQ ID NO 449 450 AVE-07-D11 GAGGTGCAGCTGCTGGAGAGCGGA GACATTCAAATGACACAGAGTCCT GGCGGACTAGTGCAGCCAGGTGGGT TCTTCCTTGTCTGCATCCGTCGGTG CCCTGCGACTTAGCTGCGCCGCTTC ATCGCGTTACCATCACTTGCCGGT GGGGTTTACGTTTCCGCACTCTGCA CGAGCCAGAACATAATCACTTATC ATGTCTTGGGTGCGTCAGGCACCTG TCAATTGGTACCAGCAGAAACCCG GAAAGGGCTTAGAATGGGTCAGCA GAAAAGCCCCAAAGTTAGCGATTT GCATCGCTGGCAGAGGTGGCTCTCC ACGGTGCCTCCAGGGTGCAGAGC CAATTACGCCGACTCCGTGAAGGGT GGCGTGCCCAGCAGATTCAGCGG AGGTTCACTATTTCCCGCGATAACT GAGTGGGTCAGGGGCTGATTTCAC CAAAAAATACACTCTATCTGCAGAT ACTGACCATCAGTTCTCTTCAGCC GAACAGTTTGAGGGCCGAAGACAC TGAGGACTTTTCAACCTATTACTG CGCGGTATATTATTGTGCACGGGTT TCAACAGTCCTTCTCAACGCCACT GCCGATGGCGGGGCTGCCTACGCTT GACCTTTGGCGGAGGCACAAAGG TCGACTACTGGGGGCAAGGAACCCT TAGAAATTAAG CGTTACAGTCAGTTCASEQ ID NO 459 460AVE-07-F11 GAGGTGCAGCTCCTGGAAAGCGGA GACATCCAGATGACACAGTCACCC GGGGGCTTGGTGCAGCCCGGAGGGT TCCAGCCTGTCTGCCTCTGTGGGG CCCTCCGATTATCCTGTGCTGCCTCA GACAGGGTCACCATTACTTGTCGG GGGTTTCGTTTTTCAAATTACGCAAT GCATCGCAACCAATTAGCAGATAC GACATGGGTCCGGCAGGCCCCTGGC TTGAACTGGTATCAGCAGAAGCCA AAGGGGCTGGAGTGGGTGAGCGGG GGAAAGGCCCCCAAGTTACTCATT ATTTCCGGAGGTGGTGGCAGAACGT TACGACGCTAGTCGACTTCAAGTG TCTACGCAGATTCGGTGAAGGGTAG GGTGTTCCTTCTCGCTTCTCCGGGT ATTCACCATCAGTAGGGACAATTCT CCGGAAGCGGCACTGATTTTACCC AAAAACACTCTATATCTGCAGATGA TGACCATCTCAAGTCCCCAGCCTG ACAGTCTGAGGGCTGAAGACACTGC AAGATTTTGCGACATATTACTGCC CGTTTATTATTGCGCGCGCGGATAC AGCAGTCCCACAGCATACCGTGG GGCGCCGAGTACTTCGATCCGTGGG ACGTTCGGTGGGGGCACAAAAGG GCCAAGGCACCCTTGTCACAGTAAG CGAGATCAAA CTCT SEQ ID NO 469 470 AVE-07-G11 GAAGTGCAGCTCCTGGAGTCAGGCG GACATACAGATGACCCAGTCCCCG GGGGACTGGTCCAGCCCGGAGGTTC TCAAGTCTCAGCGCCTCGGTCGGG ACTGCGTCTAAGCTGCGCTGCATCT GACAGAGTTACAATCACGTGTCGG GGCTTCACATTCCCACACTCCGCCA GCATCTCAATCCATTTCCAGCTAT TGTCTTGGGTTCGCCAGGCCCCTGG CTGAATTGGTACCAGCAGAAACCT GAAGGGATTGGAATGGGTGTCCACC GGGAAGGCTCCAAAGCTGCTTATC GTTACAGGTTCCGGCAGCCCGACAT TACGATGCCAGCAACCTGCAGAG ATTATGCCGATAGCGTGAAAGGGCG CGGAGTGCCCTCAAGGTTCTCCGG ATTTACCATCAGCAGGGACAACAGT CAGTGGCTCTGGGACTGATTTTAC AAGAATACGCTGTATCTTCAGATGA CCTCACAATTTCTTCTTTACAGCCC ACAGTCTCCGGGCTGAGGATACTGC GAAGACTTTGCGACTTACTATTGC GGTCTACTACTGTGCAAGAGTGGCT CAGCAATCATTCAGTAACTTGTAT GGAGGGGCCTACGGTTATGCAATGG ACCTTCGGTGGAGGCACAAAGGT ACTACTGGGGCCAAGGCACTTTAGT GGAGATCAAA GACCGTATCGTCT SEQ ID NO 479 480 AVE-07-F12 GAGGTGCAGCTTCTGGAATCAGGGG GATATCCAGATGACTCAGAGCCCA GTGGACTGGTTCAGCCTGGGGGTTC TCATCGCTCAGCGCATCTGTCGGG CCTCCGCCTGTCGTGTGCCGCTTCTG GACAGGGTTACCATAACCTGCAG GCTTTCCATTCTCCGTATATGCAATG AAGTTCACAGAACATCATCACCTA ACATGGGTGAGGCAGGCCCCGGGC CCTTAATTGGTACCAGCAAAAGCC AAGGGATTGGAGTGGGTGAGTTCTT TGGCAAAGCCCCTAAACTGCTCAT TTGGCGGCAGCGGGCACTCCCCCTA TTATGGAGCCTCCCGGCTGCAGAG TTACGCAGATTCCGTGAAGGGGCGT CGGCGTGCCCAGTCGCTTCTCCGG TTCACAATCTCAAGAGATAATTCTA TTCTGGATCAGGTACCGATTTCAC AAAACACGCTGTATCTACAGATGAA GCTGACAATTAGCTCCTTACAACC CAGTCTCCGGGCTGAAGACACCGCC CGAAGACTTTGCTACTTACTATTG GTTTACTACTGCGCGCGAGTGGCCG TCAGCAGTCCTTCTCTACTCCATT CTGGCAGCTACGCCTATGCAATGGA GACATTTGGCGGGGGGACAAAGG CTACTGGGGACAAGGAACCTTAGTC AGGTGGACAAG ACTGTCAGCAGCSEQ ID NO 489 490AVE-07-G12 GAAGTCCAGCTTCTGGAGAGCGGAG GATATTCAGATGACACAGAGCCC GCGGACTGGTGCAGCCAGGCGGGA ATCTTCACTGTCCGCTTCGGTAGG GCTTGCGTCTGTCCTGTGCGGCAAG GGATAGAGTGACAATAACATGCC CGGGTTCCGCTTCTCTAACTATGCC GCGCAAGCCAGCCTATCTCACGGT ATGACCTGGGTAAGGCAAGCACCTG ACCTCAACTGGTACCAACAGAAA GCAAAGGTCTTGAGTGGGTGTCCGG CCCGGGAAAGCCCCGAAGCTGTT AATTTCCGGCGGGGGCGGACGGAC AATCTATGACGCGAGTAGGCTGCA GTTCTACGCCGATTCAGTGAAGGGT AGTGGGTGTCCCCAGCCGATTCAG CGATTTACCATCTCTAGGGATAATA CGGTTCCGGATCTGGCACCGACTT GTAAGAACACTCTCTACCTCCAGAT CACCCTCACTATCTCTTCCTTGCA GAATAGTTTGAGAGCTGAAGACACA GCCAGAAGACTTTGCCACGTATTA GCCGTGTACTATTGCGCTAGAGGGT CTGTCAGCAGTCCTTTAGTACCCC ACGGTGCCGAGTATTTTGACCCCTG TCTTACCTTCGGCGGAGGCACTAA GGGGCAGGGCACTCTGGTTACAGTC GGTTGAGATTAAG TCATCGSEQ ID NO 499 500

[0121] In some embodiments, provided herein is an anti-Activin E antibody, wherein the antibody comprises at least 90, 95, 96, 97, 98, 99, or 100% sequence identity to the VH and VL pair amino acid sequences selected from SEQ ID NOS: 17, 8; 17, 18; 27, 28; 37, 38; 47, 48; 57, 58; 67, 68; 77, 78; 87, 88; 97, 98; 107, 108; 117, 118; 127, 128; 137, 138; 147, 148; 157, 158; 167, 168; 177, 178; 187, 188; 197, 198; 207, 208; 217, 218; 227, 228; 237, 238; 247, 248; 257, 258; 267, 268; 277, 278; 287, 288; 297, 298; 307, 308; 317, 318; 327, 328; 337, 338; 347, 348; 357, 358; 367, 368; 377, 378; 387, 388; 397, 398; 407, 408; 417, 418; 427, 428; 437, 438; 447, 448; 457, 458; 467, 468; 477, 478; 487, 488; or 497, 498.

[0122] In some embodiments, provided herein is an anti-Activin E antibody, wherein the antibody encoded by the polynucleotide comprises at least 90, 95, 96, 97, 98, 99, or 100% sequence identity to the VH and VL pair nucleic acid sequences selected from SEQ ID NOS: 9, 10; 19, 20; 29, 30; 39, 40; 49, 50; 59, 60; 69, 70; 79, 80; 89, 90; 99, 100; 109, 110; 119, 120; 129, 130; 139, 140; 149, 150; 159, 160; 169, 170; 179, 180; 189, 190; 199, 200; 209, 210; 219, 220; 229, 230; 239, 240; 249, 250; 259, 260; 269, 270; 279, 280; 289, 290; 299, 300; 309, 310; 319, 320; 329, 330; 339, 340; 349, 350; 359, 360; 369, 370; 379, 380; 389, 390; 399, 400; 409, 410; 419, 420; 429, 430; 439, 440; 449, 450; 459, 460; 469, 470; 479, 480; 489, 490; or 499, 500.

[0123] Table 4: Anti-Activin E scFv amino acid and Nucleic Acid Sequences.ClonelD scFv AA scFv NTAVE-01-D07 EVQLLESGGGLV GAAGTGCAGCTCCTAGAATCCGGCGGTGGGCTGGT QPGGSLRLSCAAS TCAGCCTGGAGGGTCCCTTAGACTGTCTTGTGCCGC GFAFNNYAMTW GAGTGGCTTCGCCTTTAACAATTATGCAATGACCTG VRQAPGKGLEWV GGTGAGGCAGGCACCCGGCAAGGGACTGGAGTGG SVISGSGTSKYYA GTAAGCGTCATCAGCGGGAGCGGCACTTCTAAGTA DSVKGRFTISRDN CTACGCCGATTCTGTTAAAGGTCGATTCACCATATC SKNTLYLQMNSL ACGGGACAACTCCAAGAACACTTTGTATCTGCAAA RAEDTAVYYCAK TGAATAGTCTCCGCGCCGAGGATACGGCTGTCTACT PRPGSIFWGAGPF ACTGCGCTAAACCGCGTCCAGGTTCAATTTTTTGGG DYWGQGTLVTVS GAGCTGGACCCTTCGACTATTGGGGGCAGGGCACA SGGGGSGGGGSG TTAGTGACAGTGTCGAGCGGTGGCGGTGGATCGGG GGGSDIQMTQSPS CGGTGGTGGATCTGGAGGAGGTGGCTCGGACATCCSLSASVGDRVTIT AGATGACACAGTCTCCTTCTTCTCTGTCCGCTAGTGCRASQSISSYLHW TGGGCGACAGAGTGACGATCACCTGTAGGGCGAGT YQQKPGKAPKLLI CAAAGCATTTCATCCTACTTGCACTGGTACCAGCAG YAASSLQSGVPSR AAGCCCGGAAAAGCACCTAAACTGTTAATTTACGC FSGSGSGTDFTLTI CGCCAGTTCCCTCCAAAGCGGTGTCCCATCTCGGTT SSLQPEDFATYYC TTCGGGGTCAGGGAGCGGCACTGATTTCACCCTTAC QQSYGSPTFGGGT CATCTCATCCCTGCAGCCCGAAGATTTTGCTACATA KVEIK TTATTGCCAGCAGAGCTATGGGAGCCCAACATTCG GTGGAGGCACTAAGGTTGAGATAAAG SEQ ID NO 501 502AVE-01-B08 EVQLLESGGGLV GAAGTGCAATTGCTTGAGAGTGGCGGCGGCCTGGT QPGGSLRLSCAAS TCAGCCTGGGGGCTCCCTGAGACTTAGCTGTGCTGC GFTFGASAMTWV CTCTGGCTTCACCTTCGGAGCTTCAGCAATGACCTG RQAPGKGLEWVS GGTGCGTCAGGCTCCAGGTAAGGGCCTGGAGTGGG GISGLGRTTDYAD TGTCAGGTATCAGCGGACTAGGGCGGACAACCGAT SVKGRFTISRDNS TACGCTGATAGCGTCAAAGGGCGCTTTACGATTTCG KNTLYLQMNSLR AGGGACAACTCTAAGAACACTCTGTATCTCCAGAT AEDTAVYYCARV GAATAGTTTAAGGGCAGAAGACACAGCCGTGTACT APGAYAYAMDY ACTGCGCCCGAGTAGCCCCCGGAGCGTATGCCTAT WGQGTLVTVSSG GCAATGGACTACTGGGGGCAGGGAACTCTCGTCAC GGGSGGGGSGGG AGTTTCCTCCGGTGGCGGTGGATCGGGCGGTGGTG GSDIQMTQSPSSL GATCTGGAGGAGGTGGCTCGGACATACAGATGACA SASVGDRVTITCR CAGTCTCCTTCCTCACTTAGCGCGTCGGTTGGCGAC ASQNIGHYLNWY CGCGTGACCATCACATGTAGAGCATCACAGAACAT QQKPGKAPKLLIY TGGTCACTACCTGAATTGGTACCAGCAGAAACCCG DASRLQVGVPSRF GAAAGGCCCCAAAATTATTGATCTATGACGCCTCC SGSGSGTDFTLTIS AGGCTGCAAGTGGGCGTACCATCTCGGTTCTCCGGT SLQPEDFATYYCQ AGCGGGAGCGGCACCGATTTTACACTGACTATCAG QSYSTPPTFGGGT TTCTCTCCAGCCCGAAGATTTTGCTACGTATTATTG KVEIK CCAACAGAGTTACAGCACCCCGCCTACCTTCGGGG GAGGGACTAAGGTCGAGATTAAG SEQ ID NO 503 504AVE-02-A03 EVQLLESGGGLV GAGGTCCAGCTGCTGGAGTCAGGCGGTGGCCTTGT QPGGSLRLSCAAS TCAGCCCGGCGGGTCTTTGCGGCTGTCCTGCGCCGC GFNFRSYVMNWV CAGCGGATTCAACTTCAGAAGCTACGTTATGAACT RQAPGKGLEWVS GGGTGCGCCAGGCCCCTGGCAAGGGCTTAGAATGG AISDVGRRTYYA GTGTCCGCTATCTCCGATGTCGGACGTAGGACTTAC DSVKGRFTISRDN TATGCAGACTCTGTGAAAGGGAGATTTACCATTAGT SKNTLYLQMNSL CGAGATAACTCAAAAAATACACTGTATCTCCAGAT RAEDTAVYYCAK GAATAGTTTGAGGGCCGAGGACACCGCAGTATATT AEILGDYAYMDY ACTGTGCTAAGGCTGAAATACTCGGTGACTATGCGT WGQGTLVTVSSG ACATGGATTACTGGGGGCAAGGAACACTAGTGACG GGGSGGGGSGGG GTGAGCTCGGGTGGCGGTGGATCGGGCGGTGGTGG GSDIQMTQSPSSL ATCTGGAGGAGGTGGCTCGGACATCCAGATGACCC SASVGDRVTITCR AGAGTCCCTCATCTCTGAGTGCATCAGTGGGGGAC ASESIGNYLSWYQ CGCGTGACTATTACCTGCAGAGCTTCTGAGTCCATA QKPGKAPKLLIYA GGTAACTATCTGTCCTGGTACCAGCAAAAACCTGG ASRLQRGVPSRFS CAAGGCGCCCAAGTTGCTGATTTACGCCGCTTCGCG GSGSGTDFTLTISS ATTACAGAGGGGCGTCCCATCCCGGTTTAGCGGGT LQPEDFATYYCQ CAGGGTCCGGTACTGATTTCACACTTACAATCAGCA QSYSTPTFGGGTK GCCTCCAACCAGAAGATTTTGCCACCTATTACTGTC VEIK AGCAGAGCTATTCTACACCTACCTTCGGAGGAGGC ACGAAGGTTGAGATCAAA SEQ ID NO 505 506AVE-02-B04 EVQLLESGGGLV GAAGTGCAGCTCCTAGAGTCGGGCGGCGGGCTGGT QPGGSLRLSCAAS GCAGCCCGGTGGCTCCCTCCGGCTGAGCTGCGCCGGFAFSAYAMNW CGAGCGGTTTCGCTTTCAGTGCCTACGCCATGAACTVRQAPGKGLEWV GGGTTCGTCAAGCCCCTGGAAAAGGCCTGGAGTGG SSITESGAATYYA GTATCAAGCATCACGGAGTCTGGGGCTGCTACATA DSVKGRFTISRDN TTATGCAGATTCTGTGAAGGGAAGATTTACTATTTC SKNTLYLQMNSL CCGCGACAATAGCAAGAATACCCTGTATCTGCAGA RAEDTAVYYCAR TGAACAGTTTGCGAGCAGAAGACACCGCCGTCTAC GLLASYTGDVWG TACTGTGCAAGGGGGCTTCTTGCTTCATACACAGGG QGTLVTVSSGGG GATGTGTGGGGCCAGGGAACCTTAGTCACTGTTTCC GSGGGGSGGGGS TCTGGTGGCGGTGGATCGGGCGGTGGTGGATCTGG DIQMTQSPSSLSA AGGAGGTGGCTCGGACATTCAGATGACACAAAGCC SVGDRVTITCRAS CCTCCAGCCTGAGCGCATCGGTGGGGGACCGCGTC QSISSYLNWYQQ ACCATAACTTGTCGGGCCAGTCAGTCTATCAGCTCA KPGKAPKLLIYAT TATCTGAACTGGTACCAGCAGAAGCCTGGCAAAGC STLQSGVPSRFSG TCCAAAGCTGCTTATCTACGCTACTTCCACTTTACA SGSGTDFTLTISSL GTCCGGTGTTCCATCCAGGTTCTCAGGATCTGGCTC QPEDFATYYCQQ TGGTACAGATTTCACCTTGACCATTTCAAGTCTCCA RDNAPWTFGGGT GCCTGAAGATTTTGCCACGTACTATTGCCAACAGAG KVEIK AGACAATGCGCCCTGGACATTTGGGGGCGGAACCA AAGTGGAGATCAAG SEQ ID NO 507 508AVE-06-B07 EVQLLESGGGLV GAAGTGCAGCTCCTAGAGTCGGGTGGCGGGCTGGT QPGGSLRLSCAAS GCAGCCGGGCGGCTCCCTGCGCCTGTCTTGCGCGGC GFDFSSFAMTWV TAGTGGATTTGACTTTTCTAGCTTCGCAATGACCTG RQAPGKGLEWVS GGTCAGACAGGCCCCAGGGAAGGGATTGGAGTGGG HITGSGGTIYYAD TGTCCCACATAACAGGTTCAGGAGGGACAATCTAT SVKGRFTISRDNS TACGCCGATAGCGTTAAGGGACGGTTCACTATTAG KNTLYLQMNSLR CAGGGATAATTCAAAAAACACGCTTTACTTACAAA AEDTAVYYCASA TGAACAGTCTGCGAGCCGAGGACACCGCAGTATAC SSYYEPGDPWGQ TATTGTGCTTCCGCCAGCTCCTATTACGAACCCGGG GTLVTVSSGGGG GACCCTTGGGGCCAGGGCACTCTCGTCACCGTGTCA SGGGGSGGGGSDI TCTGGTGGCGGTGGATCGGGCGGTGGTGGATCTGG QMTQSPSSLSASV AGGAGGTGGCTCGGACATCCAGATGACTCAGAGTC GDRVTITCRASQA CCAGCTCACTCTCCGCTTCAGTCGGTGATCGGGTTA IKNYLNWYQQKP CTATAACATGTAGAGCCAGCCAAGCTATTAAGAAT GKAPKLLIYAGST TACCTGAACTGGTATCAGCAAAAACCCGGGAAGGC LQSGVPSRFSGSG ACCTAAACTGTTGATTTATGCGGGGTCCACACTCCA SGTDFTLTISSLQP GAGCGGGGTGCCTAGTAGGTTCTCTGGCTCCGGATC EDFATYYCQQTY TGGCACTGACTTTACCTTAACCATCTCTTCGCTTCA STPLTFGGGTKVE GCCAGAAGATTTTGCCACATACTATTGCCAGCAGA IK CATACAGCACGCCACTGACCTTCGGTGGCGGAACC AAGGTGGAGATCAAA SEQ ID NO 509 510AVE-06-F07 EVQLLESGGGLV GAAGTTCAGCTGTTAGAAAGCGGGGGGGGCCTGGT QPGGSLRLSCAAS GCAGCCTGGCGGCTCACTGAGATTGTCCTGCGCTGC GFPFSSHGMSWV ATCCGGATTCCCGTTTTCCTCACACGGAATGAGCTG RQAPGKGLEWVS GGTTAGGCAGGCTCCCGGGAAGGGCCTAGAGTGGG TITGSGRSTYYAD TCAGTACCATTACAGGAAGCGGTAGGAGCACGTAC SVKGRFTISRDNS TACGCCGATTCAGTAAAGGGCCGATTCACAATCTCC KNTLYLQMNSLR CGTGACAACTCTAAAAATACTCTTTATCTCCAGATG AEDTAVYYCASD AACAGTCTGCGGGCAGAGGATACAGCCGTGTATTA YRDAPGTFDVWG TTGTGCGTCGGACTACCGCGATGCCCCAGGAACCTT QGTLVTVSSGGG TGACGTGTGGGGTCAAGGGACTCTCGTCACCGTGTC GSGGGGSGGGGS TTCTGGTGGCGGTGGATCGGGCGGTGGTGGATCTG DIQMTQSPSSLSA GAGGAGGTGGCTCGGACATCCAAATGACCCAGTCT SVGDRVTITCRAS CCCTCCTCGCTGAGCGCAAGCGTAGGGGACCGGGT QSISSYLNWYQQ CACCATAACGTGTAGAGCTTCTCAGTCAATCTCCTCKPGKAPKLLIYDA ATACTTGAACTGGTATCAGCAGAAGCCCGGCAAAGSHLQSGVPSRFSG CCCCTAAGCTCCTGATTTACGATGCCAGCCACCTAC SGSGTDFTLTISSL AAAGCGGAGTTCCATCCAGGTTTAGTGGCTCTGGGT QPEDFATYYCQQ CAGGAACAGATTTCACACTGACAATCAGTTCTCTTC SYSTPVFGGGTKV AGCCTGAAGACTTCGCGACTTACTATTGCCAGCAGT EIK CCTATAGTACCCCAGTGTTTGGTGGGGGCACTAAA GTGGAGATTAAG SEQ ID NO 511 512AVE-06-A08 EVQLLESGGGLV GAGGTCCAGCTGTTGGAATCCGGGGGAGGCTTAGT QPGGSLRLSCAAS GCAACCGGGCGGCTCCCTGCGACTGAGCTGTGCAG GFPFASHAMTWV CCTCGGGATTCCCCTTTGCTTCTCACGCAATGACCT RQAPGKGLEWVS GGGTTCGTCAGGCCCCAGGGAAAGGCCTGGAGTGG TITGSGRSTYYAD GTTTCTACTATCACCGGTTCAGGTCGGAGCACATAT SVKGRFTISRDNS TACGCTGACAGCGTGAAGGGGAGATTTACCATTTC KNTLYLQMNSLR ACGCGACAATAGCAAGAACACTCTCTATCTTCAGA AEDTAVYYCASD TGAACAGTCTCAGGGCCGAAGATACAGCCGTCTAT YRDAPGTFDVWG TACTGCGCTAGTGACTACAGGGATGCGCCTGGAAC QGTLVTVSSGGG GTTCGATGTGTGGGGCCAGGGGACACTAGTGACCG GSGGGGSGGGGS TATCCTCTGGTGGCGGTGGATCGGGCGGTGGTGGA DIQMTQSPSSLSA TCTGGAGGAGGTGGCTCGGATATACAGATGACTCA SVGDRVTITCRAS ATCTCCCAGCAGTCTGTCCGCATCCGTCGGAGATAG QSISSYLNWYQQ GGTAACAATTACCTGCAGAGCGTCCCAATCGATCA KPGKAPKLLIYDA GTTCATATCTTAACTGGTACCAGCAGAAGCCTGGCA SHLQSGVPSRFSG AAGCTCCAAAGCTGTTAATTTACGACGCCTCTCACC SGSGTDFTLTISSL TCCAGAGTGGCGTTCCTTCTCGGTTTTCTGGCAGCG QPEDFATYYCQQ GTTCCGGGACCGACTTCACGTTGACAATCTCAAGCC SYSTPVFGGGTKV TGCAGCCAGAAGACTTTGCCACCTACTATTGTCAGC EIK AGTCATATAGCACTCCCGTGTTCGGGGGTGGAACA AAAGTGGAGATCAAG SEQ ID NO 513 514AVE-06-D08 EVQLLESGGGLV GAAGTGCAACTGCTGGAATCGGGCGGTGGACTGGT QPGGSLRLSCAAS CCAGCCTGGAGGCTCTTTGAGGCTTTCCTGTGCCGC GFDFSKFAMSWV CTCAGGGTTTGATTTCAGTAAATTCGCTATGTCCTG RQAPGKGLEWVS GGTTCGCCAGGCTCCCGGGAAAGGACTTGAGTGGG HISGSGGTIYYAD TGTCCCACATCAGCGGTAGCGGCGGAACGATTTATT SVKGRFTISRDNS ACGCAGACTCAGTAAAGGGCAGATTTACTATATCT KNTLYLQMNSLR CGGGACAATTCAAAGAACACACTCTACCTGCAGAT AEDTAVYYCASA GAACAGTTTACGAGCAGAGGATACCGCGGTCTATT SSYYEPGDPWGQ ACTGCGCCAGTGCCAGCTCCTACTATGAGCCAGGC GTLVTVSSGGGG GACCCGTGGGGGCAGGGGACACTCGTGACCGTGAG SGGGGSGGGGSDI CTCTGGTGGCGGTGGATCGGGCGGTGGTGGATCTG QMTQSPSSLSASV GAGGAGGTGGCTCGGATATACAGATGACTCAATCC GDRVTITCRASQA CCTTCTTCTCTGTCCGCGTCTGTTGGGGACAGGGTG IKNYLNWYQQKP ACAATCACCTGTCGGGCTTCGCAGGCTATTAAAAAT GKAPKLLIYDASH TATCTTAACTGGTATCAGCAGAAGCCCGGTAAGGC PQSGVPSRFRGSG CCCAAAGTTGCTCATCTATGATGCCAGCCACCCACA SGTDFPFTISSLQP GTCAGGAGTACCCAGTCGCTTCAGAGGCTCCGGAA EEFATYYCQQSYS GCGGCACCGACTTCCCTTTCACCATCTCAAGCCTGC TPVFGGGTKVEIK AGCCGGAGGAATTTGCAACATACTACTGCCAGCAA AGCTACAGTACGCCCGTCTTTGGCGGTGGGACTAA AGTGGAGATTAAA SEQ ID NO 515 516AVE-06-G08 EVQLLESGGGLV GAGGTACAACTCCTAGAGAGTGGCGGAGGCCTTGT QPGGSLRLSCAAS GCAGCCCGGAGGATCGCTGCGACTGTCATGCGCTG GFDFSKFAMSWV CATCCGGCTTTGATTTCTCTAAATTTGCCATGAGCT RQAPGKGLEWVS GGGTGAGACAGGCCCCGGGTAAGGGCCTGGAATGGHISGSGGTIYYAD GTGTCTCACATATCAGGGAGCGGGGGAACAATTTASVKGRFTISRDNS CTATGCCGACTCAGTTAAGGGGCGCTTCACCATCAG KNTLYLQMNSLR CAGGGACAATTCCAAAAACACCCTGTATTTACAGA AEDTAVYYCASD TGAACAGTTTGCGGGCGGAGGATACGGCAGTCTAC SSYYEPGDPWGQ TATTGTGCTTCCGACAGCAGTTACTACGAACCAGGT GTLVTVSSGGGG GATCCTTGGGGCCAGGGGACTCTCGTGACAGTCTCC SGGGGSGGGGSDI TCTGGTGGCGGTGGATCGGGCGGTGGTGGATCTGG QMTQSPSSLSASV AGGAGGTGGCTCGGACATCCAGATGACACAGAGCC GDRVTITCRAGQ CGTCTTCACTCAGTGCAAGTGTTGGGGACAGAGTG AIKNYLNWYQQK ACCATTACATGCAGGGCCGGACAGGCTATCAAAAA PGKAPKLLIYAGS CTATCTGAATTGGTACCAACAAAAACCTGGCAAGG PLQSGVPSRFSGS CGCCCAAATTGCTCATCTATGCCGGTTCACCACTGC GSGTDFTLTISSLQ AGAGCGGTGTGCCATCGCGGTTTAGCGGATCTGGC PEDFATYYCQQT TCCGGCACTGATTTCACCCTTACCATTTCCTCTTTAC YSTPLTFGGGTKV AGCCCGAGGATTTCGCTACCTACTATTGTCAGCAGA EIK CTTACTCCACGCCTCTGACATTTGGAGGGGGGACTA AGGTCGAAATAAAG SEQ ID NO 517 518AVE-06-H08 EVQLLESGGGLV GAGGTGCAGCTGCTGGAGAGCGGCGGAGGGCTGGT QPGGSLRLSCAAS GCAACCTGGGGGCTCACTGCGACTTTCCTGCGCTGC GFDFSKFAMSWV CTCAGGTTTCGATTTCTCTAAGTTCGCTATGAGCTG RQAPGKGLEWVS GGTCAGACAGGCACCCGGGAAAGGCTTAGAGTGGG SITRGSETTYYAD TGTCTTCTATTACGCGTGGCAGTGAAACTACCTACT SVKGRFTISRDNS ACGCCGACAGCGTTAAAGGACGGTTTACAATCTCC KNTLYLQMNSLR AGGGACAATTCCAAGAACACCCTCTATCTGCAGAT AEDTAVYYCATL GAACAGTCTCCGCGCGGAAGACACAGCCGTCTATT GLGYYYYFDVW ACTGTGCAACCCTAGGGTTGGGTTACTATTATTACT GQGTLVTVSSGG TTGATGTATGGGGCCAGGGAACATTGGTGACTGTT GGSGGGGSGGGG AGCTCGGGTGGCGGTGGATCGGGCGGTGGTGGATC SDIQMTQSPSSLS TGGAGGAGGTGGCTCGGACATCCAGATGACTCAGT ASVGDRVTITCRA CGCCCTCCTCACTGTCTGCTTCAGTTGGAGATCGGG SQPISSYVTWYQQ TGACCATTACCTGCCGCGCTAGTCAACCGATCAGCT KPGKAPKLLIYSA CCTATGTGACGTGGTATCAGCAGAAGCCAGGCAAG SHLRSGVPSRFSG GCCCCTAAATTGTTAATCTATTCAGCGTCCCACCTC SGSGTDFTLTISSL AGGAGCGGCGTCCCCAGCAGATTTTCTGGAAGCGG QPEDFATYYCQQ GAGTGGTACCGATTTCACTCTGACAATATCCTCTCT SYNAPPTFGGGTK TCAGCCCGAGGACTTTGCAACATACTACTGTCAACA VEIK GAGTTACAACGCCCCACCTACATTCGGTGGCGGGA CCAAAGTAGAAATTAAG SEQ ID NO 519 520AVE-06-A09 EVQLLESGGGLV GAGGTGCAGCTCCTCGAAAGCGGCGGCGGATTAGT QPGGSLRLSCAAS CCAGCCTGGGGGATCGCTGAGGTTGTCATGCGCCG GFPFASHAMTWV CCTCAGGCTTTCCCTTCGCATCCCACGCAATGACTT RQAPGKGLEWVS GGGTGAGACAGGCGCCAGGGAAGGGGCTTGAGTG TITGSGRSTYYAD GGTGTCTACGATTACCGGCAGCGGGCGGTCCACAT SVKGRFTISRDNS ATTATGCCGATAGTGTTAAGGGCCGATTCACTATCT KNTLYLQMNSLR CACGTGATAACTCCAAAAACACCCTGTACCTGCAG AEDTAVYYCASA ATGAATAGTCTACGCGCTGAGGACACCGCTGTATA SSYYEPGDPWGQ CTATTGTGCTTCTGCCTCTAGCTACTACGAACCCGG GTLVTVSSGGGG TGACCCGTGGGGACAAGGTACACTGGTGACAGTCT SGGGGSGGGGSDI CCAGCGGTGGCGGTGGATCGGGCGGTGGTGGATCT QMTQSPSSLSASV GGAGGAGGTGGCTCGGACATTCAAATGACACAGAG GDRVTITCRASQT CCCATCTAGTTTGAGCGCATCCGTAGGCGATAGAGT ISSFVSWYQQKPG GACGATCACTTGTCGGGCTTCACAGACCATATCTTC KAPKLLIYAATTL CTTCGTGTCTTGGTATCAGCAGAAACCGGGTAAGG QKGVPSRFSGSGS CGCCCAAATTACTCATCTACGCCGCCACAACCCTGCGTDFTLTISSLQPE AAAAGGGCGTTCCTTCACGCTTTTCAGGGAGCGGGDFATYYCQQSYH TCCGGAACAGACTTCACACTTACCATTAGTTCGCTG TRSFGGGTKVEIK CAGCCCGAGGATTTCGCTACTTATTACTGCCAGCAG TCCTACCACACTAGGAGCTTTGGCGGAGGGACCAA AGTCGAAATCAAG SEQ ID NO 521 522AVE-06-B09 EVQLLESGGGLV GAAGTGCAGCTCCTAGAGAGCGGGGGCGGGCTGGT QPGGSLRLSCAAS GCAGCCCGGAGGGTCACTGAGGCTGTCTTGCGCTG GLTFSNFAMTWV CCTCTGGCTTAACATTCTCCAATTTCGCAATGACAT RQAPGKGLEWVS GGGTGCGCCAGGCCCCTGGGAAAGGTCTTGAGTGG SIRGSGATTYYAD GTGTCCTCGATTAGGGGATCTGGTGCCACCACTTAC SVKGRFTISRDNS TACGCTGACTCCGTCAAGGGCAGATTTACGATCAG KNTLYLQMNSLR CAGAGATAACAGTAAGAATACCCTGTACTTGCAGA AEDTAVYYCARS TGAACAGTCTTCGGGCCGAAGATACAGCTGTCTATT REAYGFDYWGQ ATTGTGCACGAAGCCGTGAGGCGTATGGATTTGAC GTLVTVSSGGGG TACTGGGGCCAAGGCACCCTCGTAACTGTTAGCTCA SGGGGSGGGGSDI GGTGGCGGTGGATCGGGCGGTGGTGGATCTGGAGG QMTQSPSSLSASV AGGTGGCTCGGATATACAGATGACACAATCACCCT GDRVTITCRASQS CCAGCCTTTCGGCCTCAGTGGGTGACAGAGTTACCA ISSYLNWYQQKP TTACCTGCCGGGCTTCACAGAGCATCAGCTCCTACT GKAPKLLIYAASS TGAACTGGTACCAGCAAAAGCCCGGAAAAGCTCCA LQSGVPSRFSGSG AAGCTCTTAATCTACGCCGCATCTTCTCTGCAGTCT SGTDFTLTISSLQP GGGGTGCCTTCTAGGTTTAGCGGAAGTGGCAGCGG EDFATYYCQQSY CACCGACTTTACACTGACTATTAGTTCCCTGCAGCC STPYTFGGGTKVE TGAAGATTTCGCGACATATTACTGTCAGCAGTCCTA IK TAGTACTCCATATACCTTCGGTGGCGGGACGAAGG TCGAGATCAAA SEQ ID NO 523 524AVE-06-D09 EVHLLESGGGLV GAAGTCCACCTGTTGGAGAGCGGCGGTGGCCTGGT QPGGSLRLSCAAS TCAACCTGGGGGTTCTCTACGTTTGTCGTGTGCAGC GFTFSHYSMNWV CTCTGGGTTTACATTTAGCCATTATAGCATGAATTG RQAPGKGLEWVS GGTGAGACAGGCACCCGGAAAGGGACTTGAGTGGG GISGSGSATYYAD TTAGCGGGATCTCCGGGTCAGGCTCCGCGACTTACT SVKGRFTISRDNS ATGCCGATTCAGTGAAAGGCCGCTTCACCATTTCTC KNTLYLQMNSLR GGGACAACAGTAAGAATACTCTGTACCTCCAGATG AEDTAVYYCASD AACAGTCTCCGAGCTGAAGACACCGCCGTGTACTA RYLTFDVWGQGT CTGCGCTTCCGACAGGTATCTGACCTTCGATGTCTG LVTVSSGGGGSG GGGACAGGGCACGTTAGTGACAGTATCCTCAGGTG GGGSGGGGSDIQ GCGGTGGATCGGGCGGTGGTGGATCTGGAGGAGGT MTQSPSSLSASVG GGCTCGGACATCCAGATGACGCAATCCCCTTCTAGC DRVTITCRASQSIS CTGTCAGCGTCAGTGGGCGATCGGGTCACAATCAC THLNWYQQKPGK TTGTAGAGCTTCTCAGAGTATTAGTACCCATCTGAA APKLLIYAASSLQ CTGGTACCAGCAGAAACCAGGCAAGGCACCCAAAC SGVPSRFSGSGSG TCCTCATATATGCCGCTTCCAGCTTACAGAGTGGTG TDFTLTISSLQPED TGCCATCGAGGTTCAGCGGTTCCGGCAGCGGAACT FATYYCQQSHRT GACTTTACCTTGACCATCTCCTCTCTGCAGCCTGAA PLIFGGGTKVEIK GATTTTGCCACATATTACTGCCAACAGTCACACCGC ACCCCCCTTATTTTCGGAGGGGGGACAAAGGTTGA GATTAAG SEQ ID NO 525 526AVE-06-F09 EVQLLESGGGLV GAGGTGCAGCTGCTGGAGTCTGGCGGCGGTCTTGT QPGGSLRLSCAAS CCAGCCCGGGGGGTCACTCCGACTAAGCTGCGCTG GFDFSKFAMSWV CGAGTGGATTTGACTTCTCCAAGTTTGCCATGTCCT RQAPGKGLEWVS GGGTGAGACAGGCACCAGGAAAGGGACTTGAGTG HISGSGGTIYYAD GGTGTCACACATATCTGGGAGCGGCGGAACTATTT SVKGRFTISRDNS ACTACGCTGATAGCGTTAAAGGCCGCTTCACAATCTKNTLYLQMNSLR CACGGGACAACAGTAAAAACACCCTCTATTTGCAAAEDTAVYYCASA ATGAATAGTCTGAGGGCCGAAGATACAGCAGTCTA SSYYEPGDPWGQ TTACTGTGCCTCCGCCTCTAGCTACTATGAACCTGG GTLVTVSSGGGG CGACCCGTGGGGGCAGGGTACGCTGGTGACCGTAT SGGGGSGGGGSDI CGTCCGGTGGCGGTGGATCGGGCGGTGGTGGATCT QMTQSPSSLSASV GGAGGAGGTGGCTCGGATATTCAGATGACACAGAG GDRVTITCRASQA CCCCTCGTCACTGTCTGCGTCCGTCGGTGATCGGGT IKNYLNWYQQKP TACAATCACCTGTAGGGCTTCTCAAGCTATCAAGAA GKAPKLLIYAGST CTACCTCAATTGGTACCAGCAAAAACCTGGCAAGG LQSGVPSRFSGSG CCCCAAAACTGTTAATTTATGCAGGGTCTACATTGC SGTDFTLTISSLQP AGAGTGGCGTGCCTTCAAGATTCAGCGGCTCCGGG EDFATYYCQQTY TCCGGAACTGACTTCACCCTTACAATCAGCAGTCTG STPLTFGGGTKGE CAGCCCGAGGACTTTGCCACCTATTATTGCCAGCAG IK ACGTACAGCACCCCACTCACTTTTGGGGGTGGAACT AAAGGAGAAATAAAG SEQ ID NO 527 528AVE-06-G09 EVQFLESGGGLV GAGGTGCAGTTCCTCGAATCCGGTGGGGGTTTAGT QPGGSLRLSCAAS GCAGCCCGGGGGCAGCCTTCGGCTGTCCTGCGCCG GFSFDNYGINWV CCTCTGGGTTTAGCTTCGACAATTACGGTATCAACT RQAPGKGLEWVS GGGTTCGACAAGCACCAGGGAAGGGACTGGAATGG SISSSGGSAYYAD GTGTCATCAATTTCCTCGTCTGGAGGCTCCGCGTAT SVKGRFTISRDNS TACGCAGATTCAGTGAAAGGCCGTTTTACCATAAGT KNTLYLQMNSLR AGGGACAATAGCAAGAACACACTGTACCTCCAGAT AEDTAVYYCARG GAACAGTCTGCGCGCTGAGGACACCGCCGTCTATT VVPGGFDYWGQ ACTGTGCTAGAGGCGTAGTCCCTGGAGGATTCGATT GTLVTVSSGGGG ATTGGGGCCAGGGCACGTTGGTTACTGTGTCTAGCG SGGGGSGGGGSDI GTGGCGGTGGATCGGGCGGTGGTGGATCTGGAGGA QMTQSPSSLSASV GGTGGCTCGGACATCCAAATGACACAGTCCCCAAG GDRVTITCRASQS TTCTCTTTCCGCCTCTGTGGGTGACAGAGTGACAAT INNYLNWYQQKP CACCTGTCGCGCATCCCAGTCAATTAATAACTATCT GKAPKLLIYAASS CAACTGGTACCAGCAGAAGCCTGGGAAGGCGCCCA LQSGVPSRFSGSG AACTGCTGATTTATGCCGCTTCCAGCTTACAAAGTG SGTDFTLTISSLQP GTGTCCCATCAAGGTTTTCAGGCAGCGGAAGCGGG EDFATYYCQQSR ACCGATTTCACTCTGACGATAAGCTCGTTGCAGCCT TTPWTFGGGTKV GAAGATTTCGCTACCTACTACTGCCAGCAGTCTCGG EIK ACTACCCCCTGGACTTTTGGCGGCGGAACAAAGGT TGAGATCAAA SEQ ID NO 529 530AVE-06-C10 EVQLLESGGGLV GAAGTGCAGCTTCTTGAGTCCGGCGGGGGACTAGT QPGGSLRLSCAAS TCAGCCCGGCGGCTCACTGCGACTGAGTTGTGCGG GFDFSKFAMSWV CTTCAGGGTTTGATTTCAGCAAATTCGCAATGTCTT RQAPGKGLEWVS GGGTGAGACAGGCCCCAGGAAAAGGTTTGGAGTGG SITGTSGATYYAD GTGAGCTCTATTACCGGGACCTCGGGCGCCACCTAC SVKGRFTISRDNS TATGCTGATTCCGTTAAGGGTAGATTTACTATCTCT KNTLYLQMNSLR AGGGACAATAGCAAGAACACACTCTACCTCCAAAT AEDTAVYYCARD GAACAGTCTGCGGGCCGAAGACACTGCCGTATACT IRVRRSSWAMDP ATTGCGCTAGGGATATACGCGTGCGGCGTAGCTCCT WGQGTLVTVSSG GGGCAATGGACCCTTGGGGACAGGGCACGCTGGTC GGGSGGGGSGGG ACAGTCTCCTCAGGTGGCGGTGGATCGGGCGGTGG GSDIQMTQSPSSL TGGATCTGGAGGAGGTGGCTCGGACATCCAGATGA SASVGDRVTITCR CGCAAAGTCCTAGCAGCCTGTCCGCCTCAGTGGGC ASQTIGIYLNWYQ GACCGGGTGACTATCACATGTAGGGCTTCTCAGAC QKPGKGPKPAIYS CATTGGCATATATCTGAACTGGTACCAGCAGAAGC ASPLQRGVPSRFS CCGGGAAAGGTCCCAAACCGGCGATCTACTCCGCA GCGSGTDFTLTIS TCCCCACTTCAGCGCGGCGTCCCTTCCAGATTCTCG SLQPEDFATYYCQ GGGTGCGGCTCAGGTACAGATTTTACTTTGACAATTTCTAGTCTCCAGCCCGAAGATTTCGCCACTTACTATQSYSTPHITFGGG TGCCAACAGAGCTATTCTACCCCACACATTACCTTT TKVEIK GGAGGGGGAACCAAGGTTGAGATCAAG SEQ ID NO 531 532AVE-06-G10 EVQLLESGGGLV GAGGTACAACTCCTGGAGTCAGGCGGAGGGCTCGT QPGGSLRLSCAAS CCAGCCAGGAGGTTCCCTAAGACTTTCTTGTGCCGC GFDFSKFAMSWV CTCAGGCTTTGACTTCAGCAAGTTCGCAATGAGCTG RQAPGKGLEWVS GGTGAGGCAGGCGCCTGGGAAGGGGTTAGAATGGG HISGSGGTIYYAD TGTCTCACATTAGTGGCTCTGGAGGAACTATCTACT SVKGRFTISRDNS ATGCCGATTCGGTGAAAGGGCGATTTACAATATCC KNTLYLQMNSLR CGCGACAATTCAAAAAACACACTGTACCTGCAGAT AEDTAVYYCASA GAACAGTTTGCGGGCTGAAGATACCGCAGTCTACT SSYYEPGDPWGQ ATTGCGCTTCCGCCTCCAGCTATTACGAGCCCGGTG GTLVTVSSGGGG ACCCGTGGGGCCAGGGCACCCTGGTTACGGTGAGT SGGGGSGGGGSDI AGCGGTGGCGGTGGATCGGGCGGTGGTGGATCTGG QMTQSPSSLSASV AGGAGGTGGCTCGGACATTCAAATGACACAGAGTC GDRVTITCRASQA CCAGTAGCCTCAGCGCTTCCGTTGGCGATAGAGTG IKNYLNWYQQKP ACAATTACCTGTAGGGCCTCCCAGGCAATAAAGAA GKAPKLLIYAGST CTATCTTAACTGGTACCAGCAGAAACCAGGTAAGG LQSGVPSRFSGSG CCCCTAAACTCTTAATCTATGCTGGCTCAACCCTGC SGTDFTLTISSLQP AATCTGGGGTCCCCTCGCGGTTCTCAGGGTCTGGAA EEFATYYCQQTY GCGGCACAGACTTCACTTTGACCATCTCTAGCCTGC STPLTFGGGTKGE AGCCAGAGGAGTTTGCGACTTACTATTGCCAACAG NQ ACATACTCCACCCCTCTGACGTTTGGAGGGGGTACT AAGGGAGAAAATCAG SEQ ID NO 533 534AVE-06-H10 EVQLLESGGGLV GAAGTGCAGCTGCTAGAATCCGGAGGGGGCTTAGT QPGGSLRLSCAAS CCAGCCTGGCGGCTCCCTTCGGCTCTCTTGTGCCGC GFTFTNYALAWV TTCCGGATTTACGTTCACTAACTATGCACTGGCCTG RQAPGKGLEWVS GGTGCGACAGGCGCCAGGGAAGGGGCTGGAGTGG HISGSGGTIYYAD GTAAGCCACATCTCTGGATCAGGAGGTACAATTTA SVKGRFTISRDNS CTATGCTGACAGCGTGAAGGGGCGCTTCACCATAA KNTLYLQMNSLR GCAGAGATAACTCTAAAAATACCCTTTATCTGCAA AEDTAVYYCASA ATGAATAGTCTCAGGGCCGAGGATACTGCAGTGTA SSYYEPGDPWGQ TTACTGCGCTTCGGCCTCAAGCTACTACGAGCCCGG GTLVTVSSGGGG CGACCCGTGGGGTCAGGGCACATTGGTCACCGTTA SGGGGSGGGGSDI GTTCCGGTGGCGGTGGATCGGGCGGTGGTGGATCT QMTQSPSSLSASV GGAGGAGGTGGCTCGGATATCCAAATGACACAGTC GDRVTITCRASQA TCCCAGTTCATTGTCCGCTTCCGTTGGAGATAGAGT IKNYLNWYQQKP CACCATTACCTGCAGGGCCAGTCAGGCGATAAAAA GKAPKLLIYAGST ACTACCTTAATTGGTATCAGCAGAAGCCTGGGAAA LQSGVPSRFSGSG GCTCCCAAGCTGCTGATCTACGCCGGCTCAACTCTG SGTDFTLTISSLQP CAGTCTGGGGTGCCTTCTCGGTTTTCCGGTTCGGGC EDFATYYCQQTY AGCGGGACGGACTTTACACTCACAATTAGCAGCTT STPLTFGGGTKVE ACAACCAGAGGACTTCGCAACTTATTACTGTCAGC IK AGACCTATAGCACACCACTCACTTTCGGCGGAGGT ACCAAGGTGGAAATCAAA SEQ ID NO 535 536AVE-06-B11 EVQLLESGGGLV GAGGTGCAGCTGCTGGAGTCTGGGGGCGGGCTAGT QPGGSLRLSCAAS CCAACCCGGAGGATCGCTGAGGCTTTCCTGCGCCG GFDFSKFAMSWV CGTCAGGGTTTGACTTCAGCAAGTTTGCCATGTCTT RQAPGKGLEWVS GGGTGCGACAGGCACCTGGAAAAGGATTGGAATGG HISGSGGTIYYAD GTGTCACACATAAGCGGTTCTGGCGGCACTATCTAT SVKGRFTISRDNS TACGCCGACTCCGTCAAAGGCCGCTTCACAATTAGC KNTLYLQMNSLR CGGGATAACAGCAAGAATACGCTCTACTTACAGAT AEDTAVYYCASA GAACAGTCTCAGAGCCGAGGATACCGCTGTTTACTSSYYEPGDPWGQ ATTGTGCATCAGCTAGTAGTTACTATGAACCAGGTGGTLVTVSSGGGG ACCCGTGGGGGCAGGGCACCCTGGTGACAGTATCC SGGGGSGGGGSDI TCCGGTGGCGGTGGATCGGGCGGTGGTGGATCTGG QMTQSPSSLSASV AGGAGGTGGCTCGGATATCCAGATGACCCAGTCGC GDRVTITCRASQA CAAGCTCTCTCTCCGCTTCTGTTGGAGACAGGGTCA IKNYLNWYQQKP CAATTACTTGCCGGGCATCCCAAGCGATCAAGAAC GKAPKLLIYAGST TATTTAAATTGGTACCAGCAGAAGCCTGGGAAAGC LQSGVPSRFSGSG TCCTAAACTTCTGATATATGCCGGCTCTACCCTGCA SGTDFTLTISSLQP GTCAGGGGTGCCCAGTAGATTCTCAGGGAGCGGCA EDFATYYCQQTY GTGGTACCGATTTCACACTGACCATTAGCAGCTTGC STPLTFGGGTKVE AACCAGAGGACTTTGCCACATACTATTGTCAGCAG IK ACGTACTCCACTCCCCTCACATTTGGTGGCGGAACT AAAGTGGAAATCAAG SEQ ID NO 537 538AVE-06-E11 EVQLLESGGGLV GAGGTCCAGCTGCTAGAGTCTGGAGGCGGGCTGGT QPGGSLRLSCAAS GCAGCCGGGAGGTAGTTTACGCCTGTCCTGTGCAG GIRFSSYAMSWV CTTCGGGCATTAGGTTTTCAAGCTACGCAATGTCTT RQAPGKGLEWVS GGGTGCGACAAGCGCCTGGTAAGGGACTGGAATGG HISGSGGTIYYAD GTGAGCCACATCAGCGGCAGCGGCGGAACTATATA SVKGRFTISRDNS TTATGCCGACTCCGTAAAGGGGCGGTTCACGATCTC KNTLYLQMNSLR ACGTGATAACTCAAAAAACACATTGTATCTCCAGA AEDTAVYYCASA TGAATAGTCTTAGAGCCGAGGATACCGCCGTTTACT SSYYEPGDPWGQ ACTGCGCTTCCGCCTCCAGTTACTATGAACCAGGGG GTLVTVSSGGGG ACCCCTGGGGCCAGGGGACACTCGTCACCGTGTCTT SGGGGSGGGGSDI CTGGTGGCGGTGGATCGGGCGGTGGTGGATCTGGA QMTQSPSSLSASV GGAGGTGGCTCGGATATTCAGATGACTCAGAGCCC GDRVTITCRASQA ATCTAGCCTCAGCGCTTCTGTGGGGGACAGGGTTAC IKNYLNWYQQKP GATTACATGTAGAGCAAGTCAGGCCATCAAGAACT GKAPKLLIYAGST ACCTTAATTGGTACCAGCAAAAGCCTGGCAAAGCT LQSGVPSRFSGSG CCTAAACTGCTCATCTACGCGGGGTCCACATTGCAA SGTDFTLTISSLQP TCTGGAGTCCCCTCGCGGTTTAGTGGAAGCGGCTCC EDFATYYCQQTY GGTACAGACTTCACTCTGACCATCTCATCATTACAG STPLTFGGGTKVE CCAGAGGATTTCGCCACATATTATTGCCAGCAGACC IK TATTCCACTCCCCTGACCTTTGGCGGCGGGACCAAA GTGGAAATAAAG SEQ ID NO 539 540AVE-06-H11 EVQLLESGGGLV GAAGTGCAGCTCTTAGAGAGCGGGGGCGGACTGGT QPGGSLRLSCAVS CCAGCCAGGCGGTAGCCTGCGCCTAAGTTGCGCCG GFDFSKFVMSGV TTTCTGGGTTCGATTTTTCTAAGTTCGTGATGAGTG RQAPGKGLEWVS GCGTGCGGCAGGCTCCTGGCAAAGGTCTGGAGTGG HISGSGGTIYYAD GTTTCACACATATCCGGGTCTGGGGGAACGATTTAC SVKGRFTISRDNS TACGCTGATTCAGTGAAAGGAAGATTTACCATCTCC KNTLYLQMNSLR AGGGACAACAGCAAGAATACTCTCTATCTGCAAAT AEDTAVYYCASA GAACAGTCTTCGAGCGGAAGACACAGCCGTCTACT SSYYEPGDPWGQ ATTGTGCATCCGCCTCGTCATATTACGAGCCGGGTG GTLVTVSSGGGG ACCCCTGGGGACAGGGCACATTGGTGACCGTAAGC SGGGGSGGGGSDI TCCGGTGGCGGTGGATCGGGCGGTGGTGGATCTGG QMTQSPSSLSASV AGGAGGTGGCTCGGACATCCAGATGACCCAGTCTC GDRVTITCRASQA CTTCCTCCCTTAGTGCTTCGGTGGGTGATAGGGTCA IKNYLNWYQQKP CCATTACATGCAGAGCCAGTCAGGCAATAAAGAAC GKAPKLLIYAGST TACTTGAATTGGTACCAGCAAAAACCCGGCAAGGC LQSGVPSRFSGSG CCCCAAACTGCTGATCTATGCTGGTTCCACGTTACA SGTDFTLTISSLQP GTCTGGAGTGCCAAGCCGGTTTAGCGGCTCAGGGT EDFATYYCQQTY CTGGAACTGATTTCACACTGACAATTAGCTCACTCC STPLTFGGGTKVE AGCCAGAAGACTTCGCGACTTATTATTGTCAGCAA IK ACCTACAGCACCCCTCTCACTTTTGGGGGCGGGACAAAGGTTGAGATCAAASEQ ID NO 541 542AVE-06-A12 EVQLLESGGGLV GAAGTGCAGCTCCTAGAGTCCGGAGGTGGCCTCGT QPGGSLRLSCAAS GCAGCCGGGAGGCTCCCTGCGCCTGTCCTGCGCGG GFDFSKFAMSWV CCTCTGGCTTTGACTTTAGTAAGTTCGCTATGAGCT RQAPGKGLEWVS GGGTGAGACAGGCTCCAGGTAAGGGCCTGGAGTGG HISGSGGTIYYAD GTATCTCACATCTCCGGGTCAGGAGGGACCATATAT SVKGRFTISRDNS TACGCCGACTCTGTCAAAGGCCGGTTCACTATTTCA KNTLYLQMNSLR AGGGATAATTCAAAAAACACATTATACCTTCAAAT AEDTAVYYCASA GAACAGTCTGCGAGCCGAAGACACAGCAGTGTACT SSYYEPGDPWGQ ATTGTGCCAGCGCAAGCAGCTACTATGAGCCTGGA GTLVTVSSGGGG GATCCCTGGGGGCAGGGGACCTTGGTCACGGTTAG SGGGGSGGGGSDI TTCGGGTGGCGGTGGATCGGGCGGTGGTGGATCTG QMTQSPSSLSASV GAGGAGGTGGCTCGGATATACAGATGACCCAGTCA GDRVTITCRASQA CCCTCCAGCTTGTCAGCTAGTGTTGGGGACCGGGTC IKNYLNWYQQKP ACCATCACATGCAGAGCCTCTCAGGCGATCAAGAA GKAPKLLIYAGST TTACCTTAACTGGTATCAGCAGAAACCAGGAAAAG LQSGVPSRFSGSG CTCCGAAGTTACTGATTTACGCAGGTAGCACACTGC SGTDFTLTISSLQP AGTCGGGCGTGCCCTCTAGGTTCAGTGGGAGCGGC EDFPTYYFQQNYS TCCGGAACAGACTTTACTCTGACCATTTCTTCCCTC TPFAFGGGTKVEI CAACCAGAAGATTTCCCTACTTATTATTTTCAGCAA K AACTACAGCACGCCTTTCGCCTTTGGCGGTGGGACC AAAGTGGAGATCAAG SEQ ID NO 543 544AVE-06-B12 EVQLLESGGGLV GAGGTGCAGCTTCTGGAGAGCGGAGGGGGACTGGT QPGGSLRLSCAAS CCAGCCTGGCGGCAGTCTAAGATTGTCCTGCGCCGC GFDFSKFAMSWV GTCAGGGTTCGATTTTTCCAAATTTGCCATGTCATG RPAPCKGLEWVS GGTGCGCCCAGCTCCCTGTAAGGGATTAGAATGGG HISGSGGTIYYAD TGAGTCACATCTCAGGTTCTGGGGGCACAATTTATT SVKGRFTISRDNS ACGCAGACTCCGTCAAGGGGCGATTCACGATATCC KNTLYLQMNSLR CGGGACAACTCTAAAAACACTCTGTACCTCCAAAT AEDTAVYYCASA GAATAGTCTCAGGGCCGAGGACACCGCTGTGTACT SSYYEPGDPWGQ ATTGCGCCTCGGCAAGCAGCTATTACGAACCCGGC GTLVTVSSGGGG GATCCGTGGGGCCAGGGTACCCTGGTAACAGTTAG SGGGGSGGGGSDI CTCTGGTGGCGGTGGATCGGGCGGTGGTGGATCTG QMTQSPSSLSASV GAGGAGGTGGCTCGGACATCCAGATGACACAGAGT GDRVTITCRASQA CCATCTAGCTTATCCGCGAGTGTTGGGGACAGGGTC IKNYLNWYQQKP ACCATCACATGTAGAGCCTCTCAGGCAATTAAAAA GKAPKLLIYAGST CTACCTGAATTGGTATCAACAAAAGCCCGGAAAGG LQSGVPSRFSGSG CCCCAAAGCTGCTCATCTACGCCGGCTCCACCCTGC SGTDFTLTISSLQP AGAGCGGAGTGCCTAGCCGGTTTAGCGGCTCTGGC EDFATYYCQQTY TCGGGGACTGATTTTACATTGACTATTTCATCACTT STPLTFGGGTKVE CAGCCCGAAGATTTCGCTACATATTATTGCCAGCAG IK ACCTACTCCACTCCTCTCACGTTCGGTGGTGGGACC AAAGTGGAGATAAAA SEQ ID NO 545 546AVE-06-C12 EVQLLESGGGLV GAGGTGCAGCTGCTGGAAAGCGGAGGAGGGTTAGT QPGGSLRLSCAAS GCAACCAGGAGGATCTCTCCGGCTGAGCTGCGCTG GFDFSKFAMSWV CCTCAGGCTTTGATTTCAGCAAGTTCGCCATGTCCT RQAPGKGLEWVS GGGTCCGACAGGCACCGGGGAAAGGCCTTGAGTGG HISGSGGTIYYAD GTGAGCCACATATCCGGCTCAGGTGGGACCATTTA SVKGRFTISRDNS CTACGCTGATTCTGTAAAAGGGAGATTTACGATCTC KNTLYLQMNSLR ACGCGACAACAGTAAGAATACACTCTACCTGCAGA AEDTAVYYCASA TGAACAGTTTGAGGGCCGAAGACACAGCCGTGTAT SSYYEPGDPWGQ TATTGTGCGTCTGCATCCTCGTACTATGAGCCTGGC GTLVTVSSGGGG GACCCCTGGGGCCAGGGTACCCTAGTCACTGTTTCCSGGGGSGGGGSDI AGTGGTGGCGGTGGATCGGGCGGTGGTGGATCTGGQMTQSPSSLSASV AGGAGGTGGCTCGGATATACAAATGACACAGAGTC GDRVTITCRASQA CCTCATCCCTGTCAGCTTCTGTGGGTGATAGGGTCA IKNYLNWYQQKP CAATCACATGCAGAGCCAGCCAGGCGATTAAAAAT GKAPKLLIYAGST TACCTCAACTGGTATCAGCAGAAGCCTGGCAAGGC LQSGVPSRFSGSG TCCAAAATTACTTATCTACGCAGGTAGCACCCTGCA SGTDFTLTISSLQP GTCCGGAGTGCCTTCTCGGTTCAGCGGGTCCGGCTC EDFATYYCQQNY TGGGACCGACTTTACCCTCACCATCAGTAGCCTGCA STPLTFGGGTKVE GCCAGAAGACTTCGCCACTTATTACTGTCAGCAAA IK ACTATTCGACTCCCTTGACGTTTGGAGGCGGGACTA AAGTTGAGATTAAG SEQ ID NO 547 548AVE-06-E12 EVQFLKSGGGLV GAGGTCCAATTTCTGAAAAGCGGTGGCGGGCTGGT NPAGILELSCAAS TAATCCCGCGGGCATCCTTGAGCTCTCTTGTGCAGC GFPFSSHGMSWV CTCCGGGTTCCCGTTTAGCAGTCACGGTATGTCATG RQAPGKGLEWVS GGTGAGGCAGGCTCCAGGAAAGGGACTAGAATGG VISGSGATTYYAD GTATCTGTGATTTCAGGCTCCGGAGCCACCACCTAT SVKGRFTISRDNS TACGCAGATTCCGTTAAGGGCCGCTTCACTATATCG KNTLYLQMNSLR AGAGACAACAGCAAAAATACTTTATATTTGCAGAT AEDTAVYYCARG GAACAGTCTGCGAGCCGAAGACACAGCTGTCTATT QPYYGFDYWGQ ACTGCGCCCGGGGGCAGCCTTACTATGGCTTCGATT GTLVTVSSGGGG ACTGGGGACAGGGGACGCTCGTGACAGTGAGCTCT SGGGGSGGGGSDI GGTGGCGGTGGATCGGGCGGTGGTGGATCTGGAGG QMTQSPSSLSASV AGGTGGCTCGGACATACAGATGACACAGTCTCCCA GDRVTITCRASHS GCTCTTTATCCGCTTCCGTGGGCGATAGAGTGACTA IASYLHWYQQKP TTACATGCCGCGCAAGTCACTCCATCGCCAGCTATC GKAPKLLIYRAST TCCACTGGTACCAACAAAAGCCAGGTAAGGCGCCC LHTGVPSRFSGSG AAACTGCTGATCTACAGGGCCAGCACGCTGCATAC SGTDFTLTISSLQP AGGAGTCCCTTCTCGGTTTTCCGGAAGTGGCTCAGG EDFATYYCQQTY GACAGATTTCACTCTTACCATTTCATCGTTGCAGCC SIPWTFGGGTKVE TGAGGACTTTGCTACCTATTATTGTCAGCAGACCTA IK CAGCATCCCGTGGACTTTCGGTGGCGGGACCAAAG TTGAAATTAAG SEQ ID NO 549 550AVE-06-G12 EVQFLESGGGLV GAGGTGCAATTTCTGGAGTCAGGGGGGGGTTTGGT QPGGSLRLSCAAS TCAGCCGGGAGGCAGCCTTAGGTTATCCTGTGCCGC GFDFSKFAMSWV CTCAGGGTTCGATTTCAGCAAATTTGCAATGAGTTG RQAPGKGLEWVS GGTCCGGCAGGCACCCGGCAAGGGACTGGAATGGG HISGSGGTIYYAD TAAGCCACATTTCTGGCTCTGGAGGCACCATCTACT SVKGRFTISRDNS ACGCCGACTCCGTGAAGGGACGATTCACGATATCG KNTLYLQMNSLR CGCGACAATTCAAAAAACACCCTGTATCTCCAGAT AEDTAVYYCASA GAACAGTCTGAGAGCTGAGGATACTGCCGTCTATT SSYYEPGDPWGQ ACTGCGCTTCCGCGTCTAGTTACTATGAACCAGGTG GTLVTVSSGGGG ACCCTTGGGGCCAGGGGACACTCGTGACAGTGAGC SGGGGSGGGGSDI TCCGGTGGCGGTGGATCGGGCGGTGGTGGATCTGG QMTQSPSSLSASV AGGAGGTGGCTCGGACATTCAGATGACACAGTCAC GDRVTITCRASQA CAAGTAGTCTGTCCGCGTCTGTTGGGGATCGGGTGA IKNYLNWYQQKP CGATTACATGCAGGGCTTCGCAGGCCATCAAAAAC GKAPKLLIYGASN TACTTAAACTGGTATCAACAGAAGCCCGGCAAGGC LQSGVPSRFSGSG CCCTAAGCTGCTTATATACGGGGCTTCCAATCTGCA SGTDFTLTISSLQP GTCAGGAGTCCCTTCCAGATTTTCTGGATCTGGTAG EDFATYYCQQSES CGGTACTGATTTTACACTCACCATCTCCAGCCTCCA TPLTFGGGTKVEI ACCCGAGGACTTCGCAACCTATTACTGTCAGCAGA K GCGAAAGCACTCCATTGACCTTCGGGGGCGGCACC AAAGTGGAGATCAAASEQ ID NO 551 552AVE-07-A01 EVQLLESGGGLV GAAGTGCAGCTTTTAGAATCAGGCGGTGGACTCGT QPGGSLRLSCAAS ACAGCCTGGGGGCTCCCTGAGACTGAGCTGCGCTG GFALTDFAMSWV CCTCAGGCTTCGCCCTCACAGACTTTGCCATGTCCT RQAPGKGLEWVS GGGTGCGGCAAGCTCCCGGGAAGGGACTAGAGTGG QISVSGGVGYYA GTGTCCCAGATCTCGGTGTCTGGTGGCGTTGGGTAC DSVKGRFTISRDN TACGCCGACAGCGTCAAAGGGAGGTTCACGATTTC SKNTLYLQMNSL CAGGGATAACAGTAAGAATACCCTGTACCTGCAAA RAEDTAVYYCAR TGAACAGTTTGCGCGCGGAGGATACAGCAGTTTAT SRSYYAGAFDVW TATTGTGCACGAAGCCGTTCTTATTACGCTGGAGCA GQGTLVTVSSGG TTTGACGTGTGGGGCCAGGGAACCCTTGTCACTGTC GGSGGGGSGGGG AGCTCTGGTGGCGGTGGATCGGGCGGTGGTGGATC SDIQMTQSPSSLS TGGAGGAGGTGGCTCGGATATCCAAATGACCCAGT ASVGDRVTITCRA CTCCTTCCTCGCTCAGCGCAAGTGTGGGCGACAGG SAPVGRYLNWYQ GTGACCATTACATGTCGCGCCAGTGCTCCAGTCGGA QKPGKAPKLLIYA AGATATCTGAACTGGTATCAGCAGAAACCTGGGAA ASSLQSGVPSRFS GGCCCCCAAGCTGCTTATCTATGCAGCCTCATCCTT GSGSGTDFTLTISS ACAGTCTGGGGTGCCCTCCCGGTTCTCAGGTAGCGG LQPEDFATYYCQ TAGCGGGACTGACTTTACACTGACCATTTCATCTTT QSYSAVTFGGGT GCAGCCAGAGGATTTTGCTACGTACTACTGCCAGC KVEIK AAAGCTACTCCGCGGTTACATTCGGAGGCGGCACT AAAGTAGAAATAAAG SEQ ID NO 553 554AVE-07-B01 EVQLLESGGGLV GAGGTCCAGCTACTGGAAAGCGGGGGCGGGTTAGT QPGGSLRLSCAAS TCAGCCCGGGGGTAGCTTGCGCCTCTCATGCGCCGC GFTFGSYAMTWV CTCCGGATTCACCTTCGGCTCTTATGCCATGACCTG RQAPGKGLEWVS GGTGAGACAGGCACCTGGCAAGGGACTGGAATGGG AIGTTDRYTYYA TGTCTGCTATTGGCACTACTGACAGATACACGTACT DSVKGRFTISRDN ACGCTGATAGCGTGAAAGGCCGTTTTACCATCTCCC SKNTLYLQMNSL GAGACAACAGTAAGAACACACTGTATCTCCAGATG RAEDTAVYYCAR AATAGTCTGAGGGCTGAGGATACAGCCGTTTATTA SRSYYAGAFDVW CTGTGCAAGGTCGCGGTCCTACTATGCGGGTGCATT GQGTLVTVSSGG TGACGTCTGGGGACAAGGGACCCTTGTAACAGTGT GGSGGGGSGGGG CTTCAGGTGGCGGTGGATCGGGCGGTGGTGGATCT SDIQMTQSPSSLS GGAGGAGGTGGCTCGGATATTCAGATGACACAGAG ASVGDRVTITCRA CCCCTCTAGTCTCAGCGCCTCCGTGGGTGACAGAGT SQTLRNYLNWYQ TACCATTACCTGCAGGGCTTCGCAGACTCTGCGGAA QKPGKAPKLLIYA CTACTTGAACTGGTACCAACAAAAACCAGGGAAAG ASNLQTGVPSRFS CGCCGAAGCTCCTTATCTACGCAGCCTCCAATTTAC GSGSGTDFTLTISS AGACTGGCGTCCCCTCTCGCTTTAGTGGCTCAGGAT LQPEDFATYYCQ CAGGCACGGACTTCACTCTGACCATAAGCTCTCTGC QRFSPPWTFGGGT AGCCAGAGGATTTCGCTACCTATTATTGTCAGCAGC KVEIK GATTTTCCCCTCCTTGGACATTCGGAGGTGGGACAA AGGTGGAAATCAAG SEQ ID NO 555 556AVE-07-C01 EVQLLESGGGLV GAGGTACAGCTCCTCGAAAGTGGAGGAGGGCTGGT QPGGSLRLSCAAS CCAGCCCGGCGGCTCACTAAGACTTTCATGTGCGGC GYTFSNFAISWVR ATCGGGGTATACTTTCAGCAATTTCGCTATTTCCTG QAPGKGLEWVSSI GGTGCGGCAAGCCCCTGGCAAAGGGCTGGAATGGG TGSGVRTFYADS TGAGCAGCATAACTGGTTCTGGTGTGCGTACATTCT VKGRFTISRDNSK ACGCCGATTCTGTTAAGGGAAGATTTACCATCTCCA NTLYLQMNSLRA GGGACAATAGCAAGAACACATTATATCTGCAGATG EDTAVYYCARSR AACAGTTTGCGCGCCGAGGATACCGCTGTCTACTAT SYYAGAFDVWG TGCGCAAGGTCACGATCCTACTACGCTGGCGCCTTT QGTLVTVSSGGG GACGTTTGGGGGCAGGGCACCCTGGTGACGGTGTC GSGGGGSGGGGS TTCCGGTGGCGGTGGATCGGGCGGTGGTGGATCTGDIQMTQSPSSLSA GAGGAGGTGGCTCGGATATTCAGATGACTCAATCCSVGDRVTITCRAS CCTAGCAGCCTGTCTGCGAGTGTGGGCGACAGAGT QSIGSSVNWYQQ TACCATCACTTGCAGGGCTTCACAATCCATAGGGTC KPGKAPKLLIYAA ATCCGTCAATTGGTATCAGCAGAAACCTGGGAAAG SSLQSGVPSRFSG CTCCCAAGTTGCTTATCTATGCCGCCTCTTCTCTGCA SGSGTDFTLTISSL GTCCGGCGTGCCATCTCGGTTCAGCGGCAGCGGAA QPEDFATYYCQQ GTGGGACAGACTTTACACTCACCATCTCGTCATTAC SDNNPWTFGGGT AGCCAGAAGATTTCGCAACGTACTACTGTCAGCAG KVEIK AGTGACAACAACCCCTGGACCTTTGGAGGTGGTAC AAAGGTAGAGATTAAG SEQ ID NO 557 558AVE-07-D01 EVQLLKSGSGLV GAGGTACAACTCTTAAAGTCCGGATCTGGATTGGTC QPGGSLRLSCAAS CAGCCTGGCGGCAGCCTCAGACTGTCATGCGCAGC GFTFNNAWMHW CAGCGGATTTACCTTCAACAATGCCTGGATGCACTG VRQAPGKGLEWV GGTGAGGCAGGCACCCGGCAAAGGTCTTGAGTGGG SAISSSGGYTYYA TGTCGGCCATCTCAAGCTCCGGGGGCTATACATATT DSVKGRFTISRDN ATGCAGATTCAGTTAAGGGGCGGTTCACCATTTCTC SKNTLYLQMNSL GTGACAACTCCAAAAATACTCTGTACCTGCAGATG RAEDTAVYYCAR AACAGTCTTCGAGCTGAAGATACAGCTGTGTATTAC SRSYYAGAFDVW TGTGCTAGGTCCCGCTCTTACTACGCGGGCGCCTTT GQGTLVTVSSGG GACGTTTGGGGGCAGGGTACTCTGGTCACGGTGAG GGSGGGGSGGGG CAGTGGTGGCGGTGGATCGGGCGGTGGTGGATCTG SDIQMTQSPSSLS GAGGAGGTGGCTCGGATATTCAGATGACACAGTCC ASVGDRVTITCRA CCAAGCTCGCTGTCTGCTTCCGTTGGCGATAGAGTA SAPVGRYLNWYQ ACTATCACATGCCGCGCCAGCGCTCCAGTGGGGAG QKPGKAPKLLIYA GTACCTCAACTGGTACCAGCAGAAACCCGGGAAGG ASSLQSGVPSRFS CACCTAAATTGCTGATCTATGCCGCCTCTTCACTGC GSGSGTDFTLTISS AGTCAGGTGTCCCCTCTCGGTTTAGTGGGAGCGGTA LQPEDFATYYCQ GTGGAACTGACTTTACACTTACCATTTCCTCCTTAC QAYSIPITFGGGT AGCCTGAAGACTTCGCAACGTATTACTGTCAACAA KVEIK GCGTATAGCATCCCCATAACCTTCGGAGGCGGCAC CAAGGTGGAGATTAAG SEQ ID NO 559 560AVE-07-E01 EVQLLESGGGLV GAGGTTCAGCTGTTAGAATCAGGAGGGGGGTTGGT QPGGSLRLSCAAS GCAGCCTGGAGGCTCTCTCCGGCTGTCCTGCGCCGC GFSVRDFAMNWV ATCGGGCTTCTCTGTCCGTGACTTCGCCATGAATTG RQAPGKGLEWVS GGTTCGGCAGGCCCCCGGTAAGGGGCTGGAGTGGG TITGTDRTPYYAD TGAGCACCATCACAGGTACTGATAGAACACCATAC SVKGRFTISRDNS TACGCAGATTCAGTAAAGGGAAGATTTACTATTAG KNTLYLQMNSLR CAGGGACAATTCTAAAAACACGCTTTACCTCCAGA AEDTAVYYCARS TGAACAGTCTAAGGGCTGAAGATACAGCCGTGTAT RSYYAGAFDVWG TATTGTGCTCGCAGCCGATCCTACTATGCTGGCGCG QGTLVTVSSGGG TTTGACGTGTGGGGCCAAGGCACCCTGGTCACCGT GSGGGGSGGGGS GAGTTCCGGTGGCGGTGGATCGGGCGGTGGTGGAT DIQMTQSPSSLSA CTGGAGGAGGTGGCTCGGATATACAGATGACCCAG SVGDRVTITCRAP TCTCCCAGCAGCCTTTCTGCCTCAGTCGGGGATAGA QNIFSYINWYQQK GTTACGATCACATGTCGGGCTCCACAGAATATCTTC PGKAPKLLIYAAS AGCTACATTAACTGGTACCAGCAGAAGCCGGGCAA SLQSGVPSRFSGS GGCACCTAAGTTGCTGATCTATGCGGCTAGTTCCTT GSGTDFTLTISSLQ ACAATCCGGAGTGCCATCGAGGTTTTCCGGCTCTGG PEDFATYYCQQT GTCCGGTACAGACTTTACCCTGACTATTAGCTCACT HSIPQTFGGGTKG CCAGCCTGAGGACTTCGCCACCTATTACTGCCAGCA EIK AACACACAGTATCCCCCAAACTTTCGGCGGTGGGA CCAAAGGAGAAATTAAA SEQ ID NO 561 562AVE-07-F01 EVQLLESGGGLV GAAGTGCAATTGCTCGAAAGCGGCGGAGGCCTTGTQPGGSLRLSCAAS TCAGCCTGGAGGTAGCCTGAGGCTGTCTTGTGCGGCGFTFSSHNMAWV TTCCGGGTTCACCTTCAGCTCACACAACATGGCTTG RQAPGKGLEWVS GGTGCGGCAGGCACCAGGAAAGGGGCTAGAGTGG SIGGGGRTTNYA GTGAGTTCCATCGGTGGCGGTGGAAGGACTACGAA DSVKGRFTISRDN CTATGCCGACTCAGTCAAAGGGCGTTTTACAATTTC SKNTLYLQMNSL CCGCGATAATTCTAAGAATACTCTTTACCTCCAGAT RAEDTAVYYCAR GAACAGTCTGCGAGCCGAGGATACCGCTGTCTATT AAPGAYAYALDY ACTGCGCCAGAGCTGCACCCGGCGCCTACGCCTAT WGQGTLVTVSSG GCATTAGACTACTGGGGCCAGGGGACCCTGGTGAC GGGSGGGGSGGG AGTATCGTCTGGTGGCGGTGGATCGGGCGGTGGTG GSDIQMTQSPSSL GATCTGGAGGAGGTGGCTCGGATATTCAGATGACC SASVGDRVTITCR CAATCACCAAGCAGCCTTAGCGCATCCGTTGGTGAT ASQRISTYINWYQ CGGGTGACAATTACCTGCAGGGCCTCTCAGAGAAT QKPGKAPKLLIYG ATCCACGTACATCAACTGGTACCAGCAGAAGCCTG ASYLHSGVPSRFS GGAAAGCGCCTAAGCTCCTGATTTATGGCGCCAGTT GSGSGTDFTLTISS ATTTGCACTCTGGCGTGCCCTCGCGCTTTAGCGGTA LQPEDFATYYCQ GTGGATCAGGGACCGACTTTACTCTGACTATCTCTT QTYSTPPTFGGGT CCTTACAGCCCGAAGACTTCGCTACATATTACTGTC KVEIK AACAGACATACTCCACACCCCCAACTTTCGGGGGC GGAACCAAAGTCGAGATCAAG SEQ ID NO 563 564AVE-07-C02 EVQLLESGGGLV GAAGTACAGCTTCTGGAGTCTGGCGGAGGACTAGT QPGGSLRLSCAAS TCAGCCCGGCGGGTCACTCCGGCTGAGCTGTGCTGC GFSVRDFAMTWV ATCAGGGTTTAGCGTCCGTGATTTCGCCATGACATG RQAPGKGLEWVS GGTCAGACAGGCTCCTGGTAAGGGCCTTGAATGGG AIRISGGGTFYAD TGTCCGCCATCAGAATATCGGGGGGGGGAACCTTT SVKGRFTISRDNS TATGCCGACAGCGTGAAAGGCCGATTCACTATTTCC KNTLYLQMNSLR CGCGACAATTCTAAGAACACTCTGTATTTGCAAATG AEDTAVYYCARA AACAGTCTGAGGGCCGAGGATACAGCCGTCTACTA APGAYAYALDY CTGCGCAAGGGCGGCACCAGGTGCTTACGCTTATG WGQGTLVTVSSG CCCTCGACTACTGGGGACAGGGCACGTTAGTGACC GGGSGGGGSGGG GTGAGTTCCGGTGGCGGTGGATCGGGCGGTGGTGG GSDIQMTQSPSSL ATCTGGAGGAGGTGGCTCGGACATTCAGATGACCC SASVGDRVTITCR AGTCACCGTCTTCACTCTCCGCCAGTGTGGGTGACA ASQRISTYINWYQ GAGTGACTATCACCTGTCGAGCCAGCCAAAGGATA QKPGKAPKLLIYS TCTACTTATATCAACTGGTATCAGCAGAAACCAGG ASVLENGVPSRFS GAAGGCACCTAAGTTATTGATCTACTCGGCGTCCGT GSGFGTDFTLTISS TCTGGAAAATGGAGTCCCCTCTCGGTTTAGTGGGAG LQPEDFATYYCQ CGGATTCGGCACGGATTTTACACTTACCATTAGCTC QNYRTPPTFGSGT CCTGCAGCCAGAGGATTTCGCTACCTACTACTGCCA KGENK ACAGAATTATCGCACTCCTCCCACATTCGGTAGCGG CACAAAAGGCGAGAACAAG SEQ ID NO 565 566AVE-07-F02 EVQLLESGGGLV GAGGTCCAGCTGCTGGAATCAGGCGGAGGGCTGGT QPGGSLRLSCAAS TCAGCCCGGCGGCTCCCTCAGGTTAAGCTGCGCGG GFTFSNYAMTWV CAAGCGGGTTTACCTTCTCTAATTACGCCATGACAT RQAPGKGLEWVS GGGTGAGACAAGCCCCTGGAAAAGGTTTGGAGTGG TITSSASKTNYAD GTGTCGACCATCACGAGCTCTGCTTCCAAGACTAAC SVKGRFTISRDNS TATGCAGATTCTGTGAAAGGCCGGTTCACAATTTCC KNTLYLQMNSLR AGAGATAACTCAAAGAATACTCTTTACCTACAGAT AEDTAVYYCART GAACAGTCTGCGAGCCGAAGACACTGCTGTCTATT RYLERFAGGLDI ACTGTGCCCGTACCAGGTATCTTGAGCGCTTTGCTG WGQGTLVTVSSG GCGGTCTGGACATATGGGGACAGGGGACACTCGTG GGGSGGGGSGGG ACCGTAAGCAGTGGTGGCGGTGGATCGGGCGGTGG GSDIQMTQSPSSL TGGATCTGGAGGAGGTGGCTCGGACATCCAGATGA SASVGDRVTITCR CCCAGTCTCCTAGTAGCCTTTCTGCAAGCGTTGGAGASQSISSYLNWYQ ATCGGGTGACCATCACATGCAGAGCCAGCCAAAGTQKPGKAPKLLIYA ATAAGCTCATACTTGAACTGGTACCAGCAGAAGCC ASSLQSGVPSRFS AGGTAAGGCTCCAAAACTGTTAATTTACGCTGCCTC GSGSGTDFTLTISS TTCCCTGCAGTCGGGCGTGCCTAGTAGGTTTTCAGG LQPEDFATYYCQ GTCAGGGTCCGGAACTGACTTCACCCTCACAATCTC QSFTAPLTFGGGT CTCCCTGCAGCCCGAGGATTTCGCCACCTATTATTG KVEIK TCAACAGTCTTTTACGGCGCCCCTCACTTTCGGCGG TGGCACAAAGGTCGAAATTAAA SEQ ID NO 567 568AVE-07-G02 EVQLLESGGGLV GAGGTGCAACTGCTGGAATCTGGTGGAGGTCTGGT QPGGSLRLSCAAS CCAGCCCGGAGGCAGTCTTAGGCTCAGCTGTGCCG GLTFSNYTMTWV CATCCGGCCTAACTTTTAGCAATTACACCATGACAT RQAPGKGLEWVS GGGTTCGTCAGGCCCCTGGGAAAGGGTTGGAATGG GISGTGGSTWYA GTTTCTGGCATCTCAGGAACCGGGGGTTCGACATG DSVKGRFTISRDN GTACGCTGATTCAGTGAAGGGCAGATTCACCATTTC SKNTLYLQMNSL CCGAGACAACAGCAAGAATACGCTGTATCTTCAGA RAEDTAVYYCAR TGAACAGTTTAAGGGCGGAGGACACTGCAGTCTAT SRSYYAGAFDVW TATTGCGCCCGCTCCCGGTCCTACTACGCTGGGGCC GQGTLVTVSSGG TTCGATGTGTGGGGCCAGGGAACCCTCGTAACAGT GGSGGGGSGGGG GTCTAGCGGTGGCGGTGGATCGGGCGGTGGTGGAT SDIQMTQSPSSLS CTGGAGGAGGTGGCTCGGATATTCAGATGACTCAA ASVGDRVTITCRA TCACCCTCATCGCTGTCTGCGAGTGTAGGGGACCGC SVSISTFLNWYQQ GTCACAATCACCTGTAGAGCCTCCGTGAGCATCAGT KPGKAPKLLIYAA ACGTTTTTAAACTGGTATCAACAGAAACCCGGGAA STLQSGVPSRFSG GGCTCCTAAGCTGCTCATATACGCAGCTTCAACACT SGSGTDFTLTISSL TCAGAGCGGTGTTCCAAGCAGGTTTTCTGGGTCCGG QPEDFATYYCQQ ATCTGGAACTGACTTCACATTGACTATCAGCTCCCT SLRTPITFGGGTK CCAGCCAGAAGATTTCGCCACCTATTACTGCCAGCA VEIK GTCCCTGCGGACCCCTATTACCTTCGGCGGCGGCAC AAAGGTGGAGATTAAA SEQ ID NO 569 570AVE-07-H03 EVQLLESGGGLV GAAGTCCAGCTCTTGGAATCCGGAGGCGGCCTGGT QPGGSLRLSCAAS GCAGCCCGGGGGGTCATTGCGACTGAGTTGCGCCG GFPFSSFVMSWV CATCTGGTTTCCCTTTTTCTAGCTTCGTGATGTCCTG RQAPGKGLEWVS GGTTAGACAGGCCCCGGGGAAGGGTTTAGAGTGGG SLSGSGDITYYAD TGAGCTCGCTGTCCGGAAGCGGGGACATTACTTATT SVKGRFTISRDNS ATGCAGATTCTGTTAAGGGCCGCTTTACCATCAGCC KNTLYLQMNSLR GGGACAACTCCAAAAATACACTCTACCTTCAAATG AEDTAVYYCARA AACAGTCTACGTGCCGAGGACACCGCCGTGTACTA APGAYAYALDY CTGTGCTAGGGCTGCCCCAGGCGCGTATGCATATGC WGQGTLVTVSSG TCTGGATTACTGGGGACAGGGCACGCTGGTCACAG GGGSGGGGSGGG TATCATCAGGTGGCGGTGGATCGGGCGGTGGTGGA GSDIQMTQSPSSL TCTGGAGGAGGTGGCTCGGATATCCAAATGACACA SASVGDRVTITCR GTCGCCTTCTTCCCTTAGCGCATCAGTCGGGGACCG TSQSVSTYFNWY CGTGACAATTACCTGTAGGACCTCCCAGAGCGTGA QQKPGKAPKLLIY GTACTTACTTTAACTGGTACCAACAGAAGCCCGGC AASSLQSGVPSRF AAAGCCCCCAAGCTGCTGATCTATGCCGCGTCTAGT SGSGSGTDFTLTIS TTGCAGAGTGGTGTTCCTTCACGGTTCTCAGGGTCC SLQPEDFATYYCQ GGCTCTGGCACAGATTTCACCTTAACTATTTCCAGC QSYRTPPTFGGGT CTCCAGCCAGAGGACTTTGCTACGTATTACTGCCAG KVEIK CAGAGCTATAGAACTCCGCCAACATTCGGAGGAGG TACCAAGGTAGAAATAAAA SEQ ID NO 571 572AVE-07-D04 EVQLLESGGGLV GAGGTGCAGCTACTGGAGTCAGGAGGCGGGCTGGT QPGGSLRLSCAAS TCAGCCTGGGGGGTCATTGCGACTGAGCTGTGCCG GLTFNAYAMSWV CATCTGGCCTCACCTTTAACGCCTACGCCATGAGCTRQAPGKGLEWVS GGGTCCGTCAGGCGCCCGGCAAAGGCTTGGAATGGSLTGSGASTFYAD GTGTCCAGCTTAACTGGGTCTGGAGCCTCCACCTTC SVKGRFTISRDNS TACGCTGACTCGGTCAAGGGTAGATTCACAATCTCT KNTLYLQMNSLR CGGGACAATTCAAAGAATACACTTTATCTGCAGAT AEDTAVYYCARS GAACAGTCTGAGGGCTGAAGATACGGCTGTGTACT RSYYAGAFDVWG ATTGCGCACGCTCCAGGTCCTACTATGCCGGTGCAT QGTLVTVSSGGG TTGATGTTTGGGGCCAAGGAACCCTCGTAACTGTGA GSGGGGSGGGGS GCAGTGGTGGCGGTGGATCGGGCGGTGGTGGATCT DIQMTQSPSSLSA GGAGGAGGTGGCTCGGATATCCAGATGACACAGTC SVGDRVTITCRAS GCCCAGCTCCCTGAGCGCTTCAGTGGGGGACCGCG RTVTSYLNWYQQ TAACTATTACATGTAGAGCCAGTCGAACCGTCACCT KPGKAPKLLIYGA CCTATCTCAACTGGTACCAACAGAAGCCTGGCAAG SYLHSGVPSRFSG GCGCCAAAATTACTGATATACGGAGCATCTTATTTG SGSGTDFTLTISSL CACTCTGGTGTGCCGTCTAGGTTCTCCGGCAGTGGG QPEDFATYYCQQ AGCGGAACCGACTTCACTCTTACTATCTCCAGCCTG SYRTPPTFGGGTK CAGCCAGAAGATTTTGCCACATATTACTGCCAACA VEIK GTCATACCGGACCCCTCCCACGTTTGGGGGTGGCAC AAAGGTTGAGATTAAA SEQ ID NO 573 574AVE-07-E06 EVQLLESGGGLV GAGGTCCAGCTCCTGGAATCAGGTGGGGGCCTGGT QPGGSLRLSCAAS GCAGCCCGGCGGGAGCTTGCGGCTTTCTTGTGCTGC GFSVRDFAMNWV AAGCGGATTTTCAGTGAGAGACTTCGCCATGAATT RQAPGKGLEWVS GGGTCCGTCAAGCCCCTGGAAAGGGGTTAGAATGG SIHRTGGGTYYA GTGTCTAGCATTCACAGGACAGGCGGGGGCACATA DSVKGRFTISRDN CTACGCAGATAGTGTTAAAGGCAGGTTCACGATCT SKNTLYLQMNSL CCAGAGACAATTCCAAGAACACCCTCTACCTACAG RAEDTAVYYCAR ATGAACAGTCTGCGAGCGGAGGACACCGCCGTTTA SRSYYAGAFDVW TTACTGCGCCCGGAGCCGCTCCTATTATGCTGGAGC GQGTLVTVSSGG TTTTGATGTGTGGGGTCAGGGAACTCTGGTGACTGT GGSGGGGSGGGG ATCTTCGGGTGGCGGTGGATCGGGCGGTGGTGGAT SDIQMTQSPSSLS CTGGAGGAGGTGGCTCGGATATTCAGATGACGCAG ASVGDRVTITCRA TCCCCCAGTAGCTTGAGTGCCAGCGTGGGTGACCG NQNIGNYLNWYQ GGTTACTATCACATGTAGAGCGAACCAGAATATCG QKPGKAPKLLIYA GCAACTACCTTAATTGGTACCAACAGAAGCCTGGG ASSLQSGVPSRFS AAGGCTCCCAAACTCCTGATCTATGCAGCCTCATCC GSGSGTDFTLTISS CTGCAGTCAGGTGTGCCGTCCAGGTTTTCGGGGTCC LQPEDFATYYCQ GGGAGCGGAACCGATTTCACCCTGACAATTTCTTCT QSYSTSTFGGGTK TTACAACCAGAAGACTTTGCTACCTACTATTGCCAG VEIK CAGTCATATAGCACCTCTACTTTCGGCGGCGGAACA AAGGTCGAGATAAAA SEQ ID NO 575 576AVE-07-F06 EVQLLESGGGLV GAGGTCCAGCTGTTGGAAAGCGGGGGGGGCTTAGT QPGGSLRLSCAAS ACAGCCTGGAGGTTCCCTCCGTCTAAGCTGCGCCGC GFDFRSYPMAWV ATCGGGATTCGACTTTCGCTCCTACCCAATGGCTTG RQAPGKGLEWVS GGTGCGGCAGGCCCCCGGCAAGGGCCTGGAATGGG VISGGGGSTNYA TTAGTGTTATTTCTGGTGGAGGCGGTTCAACCAACT DSVKGRFTISRDN ACGCGGACAGCGTCAAAGGGAGATTTACTATCTCT SKNTLYLQMNSL AGGGACAATTCCAAGAACACGCTGTACCTGCAGAT RAEDTAVYYCAR GAATAGTCTCCGAGCAGAGGATACAGCCGTGTATT SRSYYAGAFDVW ATTGTGCCAGGTCAAGATCCTACTATGCTGGAGCTT GQGTLVTVSSGG TCGATGTGTGGGGCCAAGGGACACTTGTGACCGTG GGSGGGGSGGGG AGCTCTGGTGGCGGTGGATCGGGCGGTGGTGGATC SDIQMTQSPSSLS TGGAGGAGGTGGCTCGGACATACAGATGACACAGT ASVGDRVTITCRA CTCCATCTAGCCTTAGTGCCTCCGTTGGAGATCGGG SQKIARYVNWYQ TGACCATCACATGCCGCGCCTCACAGAAGATTGCA QKPGKAPKLLIYA AGATATGTCAACTGGTACCAGCAGAAACCTGGTAAASDLQSGVPSRFS GGCACCAAAGCTCTTAATCTATGCTGCGAGCGACTTGSGSGTDFTLTISS GCAAAGCGGCGTGCCCTCTAGGTTTTCCGGCAGCG LQPEDFATYYCQ GTTCAGGCACCGATTTCACCCTGACGATCTCCTCGC QAYSIPITFGGGT TGCAGCCTGAGGACTTTGCTACTTATTACTGTCAGC KVEIK AAGCCTACAGTATTCCCATTACATTCGGGGGAGGG ACTAAAGTAGAAATCAAA SEQ ID NO 577 578AVE-07-A07 EVQLLESGGGLV GAGGTGCAACTCCTTGAGTCAGGTGGCGGACTCGT QPGGSLRLSCAAS GCAGCCTGGCGGATCGCTGAGACTGTCATGTGCGG GFRFSNYAMTWV CTTCTGGGTTTCGTTTCTCCAACTACGCAATGACAT RQAPGKGLEWVS GGGTGAGGCAGGCCCCCGGGAAAGGCCTGGAGTGG GISGGGGRTFYAD GTATCCGGAATCAGCGGCGGCGGGGGCAGGACCTT SVKGRFTISRDNS CTATGCAGATAGTGTCAAGGGTAGATTTACCATTAG KNTLYLQMNSLR CCGGGACAATTCCAAGAATACATTATACCTACAGA AEDTAVYYCARG TGAACAGTCTGCGCGCCGAAGATACGGCTGTCTATT YGAEYFDPWGQG ACTGCGCCCGAGGTTACGGGGCCGAATATTTCGAC TLVTVSSGGGGS CCGTGGGGGCAGGGAACTTTGGTTACTGTGAGCTCT GGGGSGGGGSDI GGTGGCGGTGGATCGGGCGGTGGTGGATCTGGAGG QMTQSPSSLSASV AGGTGGCTCGGACATCCAGATGACCCAGTCACCCT GDRVTITCRASQP CTTCCCTGTCCGCAAGTGTGGGCGACCGGGTGACTA ISRYLNWYQQKP TTACTTGTCGCGCCAGCCAGCCCATCAGTAGATACT GKAPKLLIYDASR TAAACTGGTATCAGCAGAAGCCGGGCAAAGCGCCA LQVGVPSRFSGSG AAGCTGTTGATATATGACGCTTCTCGACTTCAAGTC SGTDFTLTISSLQP GGCGTACCTAGCAGGTTCTCAGGGAGCGGTTCTGG EDFATYYCQQSH AACGGATTTCACACTGACCATCTCGTCCCTCCAACC SIPWTFGGGTKVE AGAGGATTTTGCCACATACTACTGCCAGCAGAGCC IK ACTCCATTCCTTGGACATTTGGGGGTGGAACCAAG GTTGAAATTAAA SEQ ID NO 579 580AVE-07-E07 EVQLLESGGGLV GAGGTGCAGCTGCTCGAATCGGGCGGGGGCCTGGT QPGGSLRLSCAAS CCAGCCCGGGGGGTCTTTGAGGCTCTCCTGTGCTGC GFRFSNYAMTWV CTCAGGGTTTAGGTTCAGTAATTACGCGATGACTTG RQAPGKGLEWVS GGTGCGACAGGCCCCAGGAAAGGGCCTAGAGTGGG GISGGGGRTFYAD TGAGCGGCATTTCAGGTGGAGGAGGCAGAACATTT SVKGRFTISRDNS TATGCAGATAGCGTTAAAGGTAGATTCACGATCTCT KNTLYLQMNSLR CGGGACAACTCCAAGAATACCCTTTACTTACAAAT AEDTAVYYCARG GAACAGTCTGCGCGCAGAGGATACCGCCGTATACT YGAEYFDPWGQG ATTGCGCTCGTGGGTATGGAGCCGAATACTTCGACC TLVTVSSGGGGS CTTGGGGCCAGGGTACCCTGGTCACAGTGAGCTCC GGGGSGGGGSDI GGTGGCGGTGGATCGGGCGGTGGTGGATCTGGAGG QMTQSPSSLSASV AGGTGGCTCGGACATCCAAATGACCCAGAGCCCAT GDRVTITCRASQP CATCCCTGAGCGCATCAGTGGGAGATAGAGTCACT ISRHLNWYQQKP ATCACCTGTCGCGCTTCTCAACCAATATCCCGACAC GKAPKLLIYSASS CTCAACTGGTACCAGCAGAAACCCGGAAAGGCCCC LQSGVPSRFSGSG TAAGCTGTTGATTTATAGTGCCAGTTCCCTGCAGTC SGTDFTLTISSLQP AGGTGTTCCTAGCAGGTTTTCTGGCTCTGGGTCCGG EDFATYYCQQSY CACAGACTTCACGCTTACTATTTCTAGCTTACAGCC DRTWTFGGGTKG CGAAGATTTTGCGACATACTACTGCCAGCAGAGTT ESK ATGACCGGACATGGACCTTCGGTGGGGGCACCAAG GGGGAGTCGAAA SEQ ID NO 581 582AVE-07-D08 EVQLLESGGGLV GAAGTCCAGCTCTTGGAATCCGGGGGGGGGTTAGT QPGGSLRLSCAAS GCAGCCTGGAGGCTCTCTCAGACTGAGTTGCGCCG GFRFSNYAMTWV CCAGCGGATTTAGGTTCTCCAATTATGCCATGACGT RQAPGKGLEWVS GGGTGAGACAGGCCCCCGGGAAGGGGCTGGAGTG GISGGGGRTFYAD GGTGTCTGGCATTTCCGGCGGAGGCGGACGGACTTSVKGRFTISRDNS TCTATGCAGACTCAGTAAAGGGTAGGTTCACAATCKNTLYLQMNSLR AGCCGAGACAACTCGAAAAATACCCTTTACCTGCA AEDTAVYYCARG AATGAACAGTCTGCGCGCGGAGGATACCGCTGTGT YGAEYFDPWGQG ACTACTGTGCACGTGGTTACGGCGCTGAGTATTTTG TLVTVSSGGGGS ATCCGTGGGGCCAGGGTACACTAGTCACTGTTAGCT GGGGSGGGGSDI CAGGTGGCGGTGGATCGGGCGGTGGTGGATCTGGA QMTQSPSSLSASV GGAGGTGGCTCGGACATTCAGATGACCCAGTCACC GDRVTITCRASQR CAGTAGCTTGTCTGCCTCTGTGGGAGATCGCGTCAC IATYLNWYQQKP AATAACTTGCAGGGCTTCCCAACGGATCGCCACCT GKAPKLLIYAASH ACCTGAACTGGTACCAGCAAAAACCTGGTAAGGCA LHGGVPSRFSGSG CCAAAGCTGTTAATTTACGCGGCCTCTCACCTTCAT SGTDFTLTISSLQP GGAGGCGTGCCATCCAGATTCTCCGGCAGCGGGTC EDFATYYCQQSY AGGCACAGATTTTACCCTGACTATCTCCTCGCTCCA SIPLTFGGGTKVEI GCCCGAAGACTTCGCTACGTATTATTGTCAGCAGAG K TTATAGCATCCCTCTCACATTTGGTGGGGGGACCAA GGTTGAGATTAAA SEQ ID NO 583 584AVE-07-E08 GGAALKSGGGLV GGAGGCGCGGCCTTAAAGTCCGGAGGTGGCCTGGT QPGGSLRLSCAAS CCAGCCCGGAGGGTCCCTCAGATTGAGCTGTGCTG GFTVSRDYMSWV CCTCTGGCTTTACAGTGTCACGGGATTATATGTCGT RQAPGKGLEWVS GGGTCCGCCAAGCTCCGGGCAAGGGACTGGAATGG VISTGGGSTYYAD GTGAGTGTGATTAGCACCGGGGGTGGGTCCACGTA SVKGRFTISRDNS CTATGCCGACTCTGTTAAGGGGAGGTTCACAATCTC KNTLYLQMNSLR CAGGGATAATTCAAAAAACACCCTGTACCTTCAGA AEDTAVYYCAKP TGAACAGTCTCCGTGCTGAGGACACCGCAGTTTATT RPYSIAWFADPFD ATTGCGCAAAACCCCGACCATACAGCATAGCATGG YWGQGTLVTVSS TTCGCCGACCCTTTTGATTACTGGGGCCAGGGTACT GGGGSGGGGSGG CTGGTGACTGTAAGCTCTGGTGGCGGTGGATCGGG GGSDIQMTQSPSS CGGTGGTGGATCTGGAGGAGGTGGCTCGGATATCC LSASVGDRVTITC AAATGACTCAGAGCCCTTCCAGCTTGAGTGCGTCCG RTSQTISIYLNWY TGGGGGATAGGGTAACTATCACATGTAGAACAAGC QQKPGKAPKLLIY CAGACCATATCTATTTACCTCAACTGGTATCAGCAG AASILHGGVPSRF AAGCCCGGAAAGGCCCCAAAATTACTGATTTATGC SGSGSGTDFTLTIS AGCCTCAATCCTGCACGGAGGTGTTCCGTCACGGTT SLQPEDFATYYCQ CTCCGGGTCGGGCTCTGGTACCGACTTTACCCTTAC QNYSVPPTFGGGT GATTAGTAGCCTGCAGCCTGAGGACTTCGCTACCTA KVEIK CTACTGCCAACAGAATTATTCTGTCCCACCCACTTT TGGGGGCGGCACAAAAGTGGAAATCAAG SEQ ID NO 585 586AVE-07-H08 ELQLLESGGGLV GAGCTGCAACTCTTAGAATCTGGCGGAGGCCTGGT QPGGSLRLSCAAS TCAGCCCGGAGGCAGTCTGCGTCTATCCTGTGCCGC GFPFSNNAMSWV ATCTGGGTTCCCTTTCTCCAACAACGCCATGTCATG RQAPGKGLEWVS GGTCCGCCAGGCCCCAGGTAAAGGTCTTGAATGGG VISGSYGTTYYAD TTTCTGTGATCAGCGGCAGCTACGGGACTACATACT SVKGRFTISRDNS ATGCCGATTCCGTGAAGGGCAGATTTACCATTAGCC KNTLYLQMNSLR GGGATAATTCGAAGAACACGCTTTATCTGCAGATG AEDTAVYYCARV AATAGTTTGAGGGCTGAGGACACCGCAGTGTATTA ADGAAAYAMDY CTGCGCCCGAGTGGCTGACGGGGCAGCTGCTTACG WGQGTLVTVSSG CGATGGACTATTGGGGGCAGGGAACTCTCGTCACA GGGSGGGGSGGG GTAAGCTCAGGTGGCGGTGGATCGGGCGGTGGTGG GSDIQMTQSPSSL ATCTGGAGGAGGTGGCTCGGACATTCAGATGACCC SASVGDRVTITCR AGTCACCATCCAGTCTGTCAGCTTCGGTGGGCGATA ASQPISRYLNWY GGGTAACAATCACTTGCAGAGCGTCCCAGCCCATC QQKPGKAPKLLIY TCTCGCTATCTTAACTGGTACCAGCAAAAGCCGGG DASRLQVGVPSRF GAAAGCACCAAAGCTGTTAATTTACGACGCCTCTC SGSGSGTDFTLTIS GGCTGCAGGTCGGCGTTCCTAGCCGATTCAGCGGTTSLQPEDFATYYCQ CTGGGTCCGGAACAGATTTTACCCTCACAATTAGCTQSHSIPWTFGGGT CCTTGCAGCCCGAAGACTTTGCCACCTATTACTGTC KVEIK AGCAAAGTCACAGCATCCCTTGGACGTTCGGTGGA GGCACTAAGGTGGAGATAAAA SEQ ID NO 587 588AVE-07-C10 EVQLLESGGGLV GAGGTGCAACTGCTTGAGAGTGGCGGAGGCCTGGT QPGGSLRLSCAAS GCAGCCTGGGGGCAGCCTCAGATTATCTTGCGCGG GFRFSNYAMTWV CCTCAGGTTTTCGTTTCTCTAACTATGCTATGACAT RQAPGKGLEWVS GGGTCCGACAGGCTCCAGGGAAAGGGCTAGAATGG GISGGGGRTFYAD GTATCGGGAATTTCCGGTGGCGGGGGCCGGACTTT SVKGRFTISRDNS CTACGCCGATAGCGTCAAGGGAAGGTTCACAATCA KNTLYLQMNSLR GCCGCGACAATTCAAAGAATACCCTCTACCTGCAG AEDTAVYYCARG ATGAACAGTTTGAGGGCCGAGGACACTGCAGTGTA YGAEYFDPWGQG TTACTGTGCCAGAGGCTACGGAGCAGAATATTTTG TLVTVSSGGGGS ATCCCTGGGGGCAGGGTACCCTGGTGACGGTTTCCT GGGGSGGGGSDI CCGGTGGCGGTGGATCGGGCGGTGGTGGATCTGGA QMTQSPSSLSASV GGAGGTGGCTCGGACATCCAGATGACCCAAAGTCC GDRVTITCRASQP CTCTTCTCTTAGCGCTTCGGTGGGCGATCGGGTGAC ISRYLNWYQQKP CATTACTTGTAGAGCGTCACAGCCAATAAGCAGGT GKAPKLLIYAASN ATCTCAATTGGTATCAGCAGAAGCCCGGAAAAGCA LKKGVPSRFSGSG CCCAAGTTGCTGATCTACGCCGCCTCCAACTTAAAG FGTDFTLTISSLQP AAGGGGGTTCCTAGCCGCTTTAGTGGGTCCGGCTTC EDFATYYCQQSY GGAACCGATTTCACACTCACAATCTCATCCCTGCAG NPPLTFGGGTKVE CCGGAGGACTTTGCTACGTACTATTGCCAACAGTCT IK TACAACCCTCCACTGACTTTCGGTGGCGGGACAAA AGTCGAAATTAAA SEQ ID NO 589 590AVE-07-D11 EVQLLESGGGLV GAGGTGCAGCTGCTGGAGAGCGGAGGCGGACTAGT QPGGSLRLSCAAS GCAGCCAGGTGGGTCCCTGCGACTTAGCTGCGCCG GFTFPHSAMSWV CTTCGGGGTTTACGTTTCCGCACTCTGCAATGTCTT RQAPGKGLEWVS GGGTGCGTCAGGCACCTGGAAAGGGCTTAGAATGG SIAGRGGSPNYAD GTCAGCAGCATCGCTGGCAGAGGTGGCTCTCCCAA SVKGRFTISRDNS TTACGCCGACTCCGTGAAGGGTAGGTTCACTATTTC KNTLYLQMNSLR CCGCGATAACTCAAAAAATACACTCTATCTGCAGA AEDTAVYYCARV TGAACAGTTTGAGGGCCGAAGACACCGCGGTATAT ADGGAAYAFDY TATTGTGCACGGGTTGCCGATGGCGGGGCTGCCTAC WGQGTLVTVSSG GCTTTCGACTACTGGGGGCAAGGAACCCTCGTTAC GGGSGGGGSGGG AGTCAGTTCAGGTGGCGGTGGATCGGGCGGTGGTG GSDIQMTQSPSSL GATCTGGAGGAGGTGGCTCGGACATTCAAATGACA SASVGDRVTITCR CAGAGTCCTTCTTCCTTGTCTGCATCCGTCGGTGAT SSQNIITYLNWYQ CGCGTTACCATCACTTGCCGGTCGAGCCAGAACAT QKPGKAPKLAIY AATCACTTATCTCAATTGGTACCAGCAGAAACCCG GASRVQSGVPSRF GAAAAGCCCCAAAGTTAGCGATTTACGGTGCCTCC SGSGSGADFTLTI AGGGTGCAGAGCGGCGTGCCCAGCAGATTCAGCGG SSLQPEDFSTYYC GAGTGGGTCAGGGGCTGATTTCACACTGACCATCA QQSFSTPLTFGGG GTTCTCTTCAGCCTGAGGACTTTTCAACCTATTACT TKVEIK GTCAACAGTCCTTCTCAACGCCACTGACCTTTGGCG GAGGCACAAAGGTAGAAATTAAG SEQ ID NO 591 592AVE-07-F11 EVQLLESGGGLV GAGGTGCAGCTCCTGGAAAGCGGAGGGGGCTTGGT QPGGSLRLSCAAS GCAGCCCGGAGGGTCCCTCCGATTATCCTGTGCTGC GFRFSNYAMTWV CTCAGGGTTTCGTTTTTCAAATTACGCAATGACATG RQAPGKGLEWVS GGTCCGGCAGGCCCCTGGCAAGGGGCTGGAGTGGG GISGGGGRTFYAD TGAGCGGGATTTCCGGAGGTGGTGGCAGAACGTTC SVKGRFTISRDNS TACGCAGATTCGGTGAAGGGTAGATTCACCATCAG KNTLYLQMNSLR TAGGGACAATTCTAAAAACACTCTATATCTGCAGATAEDTAVYYCARG GAACAGTCTGAGGGCTGAAGACACTGCCGTTTATTYGAEYFDPWGQG ATTGCGCGCGCGGATACGGCGCCGAGTACTTCGAT TLVTVSSGGGGS CCGTGGGGCCAAGGCACCCTTGTCACAGTAAGCTC GGGGSGGGGSDI TGGTGGCGGTGGATCGGGCGGTGGTGGATCTGGAG QMTQSPSSLSASV GAGGTGGCTCGGACATCCAGATGACACAGTCACCC GDRVTITCRASQP TCCAGCCTGTCTGCCTCTGTGGGGGACAGGGTCACC ISRYLNWYQQKP ATTACTTGTCGGGCATCGCAACCAATTAGCAGATAC GKAPKLLIYDASR TTGAACTGGTATCAGCAGAAGCCAGGAAAGGCCCC LQVGVPSRFSGSG CAAGTTACTCATTTACGACGCTAGTCGACTTCAAGT SGTDFTLTISSPQP GGGTGTTCCTTCTCGCTTCTCCGGGTCCGGAAGCGG EDFATYYCQQSH CACTGATTTTACCCTGACCATCTCAAGTCCCCAGCC SIPWTFGGGTKGE TGAAGATTTTGCGACATATTACTGCCAGCAGTCCCA IK CAGCATACCGTGGACGTTCGGTGGGGGCACAAAAG GCGAGATCAAA SEQ ID NO 593 594AVE-07-G11 EVQLLESGGGLV GAAGTGCAGCTCCTGGAGTCAGGCGGGGGACTGGT QPGGSLRLSCAAS CCAGCCCGGAGGTTCACTGCGTCTAAGCTGCGCTGC GFTFPHSAMSWV ATCTGGCTTCACATTCCCACACTCCGCCATGTCTTG RQAPGKGLEWVS GGTTCGCCAGGCCCCTGGGAAGGGATTGGAATGGG TVTGSGSPTYYA TGTCCACCGTTACAGGTTCCGGCAGCCCGACATATT DSVKGRFTISRDN ATGCCGATAGCGTGAAAGGGCGATTTACCATCAGC SKNTLYLQMNSL AGGGACAACAGTAAGAATACGCTGTATCTTCAGAT RAEDTAVYYCAR GAACAGTCTCCGGGCTGAGGATACTGCGGTCTACT VAGGAYGYAMD ACTGTGCAAGAGTGGCTGGAGGGGCCTACGGTTAT YWGQGTLVTVSS GCAATGGACTACTGGGGCCAAGGCACTTTAGTGAC GGGGSGGGGSGG CGTATCGTCTGGTGGCGGTGGATCGGGCGGTGGTG GGSDIQMTQSPSS GATCTGGAGGAGGTGGCTCGGACATACAGATGACC LSASVGDRVTITC CAGTCCCCGTCAAGTCTCAGCGCCTCGGTCGGGGA RASQSISSYLNWY CAGAGTTACAATCACGTGTCGGGCATCTCAATCCAT QQKPGKAPKLLIY TTCCAGCTATCTGAATTGGTACCAGCAGAAACCTGG DASNLQSGVPSRF GAAGGCTCCAAAGCTGCTTATCTACGATGCCAGCA SGSGSGTDFTLTIS ACCTGCAGAGCGGAGTGCCCTCAAGGTTCTCCGGC SLQPEDFATYYCQ AGTGGCTCTGGGACTGATTTTACCCTCACAATTTCT QSFSNLYTFGGGT TCTTTACAGCCCGAAGACTTTGCGACTTACTATTGC KVEIK CAGCAATCATTCAGTAACTTGTATACCTTCGGTGGA GGCACAAAGGTGGAGATCAAA SEQ ID NO 595 596AVE-07-F12 EVQLLESGGGLV GAGGTGCAGCTTCTGGAATCAGGGGGTGGACTGGT QPGGSLRLSCAAS TCAGCCTGGGGGTTCCCTCCGCCTGTCGTGTGCCGC GFPFSVYAMTWV TTCTGGCTTTCCATTCTCCGTATATGCAATGACATG RQAPGKGLEWVS GGTGAGGCAGGCCCCGGGCAAGGGATTGGAGTGGG SFGGSGHSPYYA TGAGTTCTTTTGGCGGCAGCGGGCACTCCCCCTATT DSVKGRFTISRDN ACGCAGATTCCGTGAAGGGGCGTTTCACAATCTCA SKNTLYLQMNSL AGAGATAATTCTAAAAACACGCTGTATCTACAGAT RAEDTAVYYCAR GAACAGTCTCCGGGCTGAAGACACCGCCGTTTACT VAAGSYAYAMD ACTGCGCGCGAGTGGCCGCTGGCAGCTACGCCTAT YWGQGTLVTVSS GCAATGGACTACTGGGGACAAGGAACCTTAGTCAC GGGGSGGGGSGG TGTCAGCAGCGGTGGCGGTGGATCGGGCGGTGGTG GGSDIQMTQSPSS GATCTGGAGGAGGTGGCTCGGATATCCAGATGACT LSASVGDRVTITC CAGAGCCCATCATCGCTCAGCGCATCTGTCGGGGA RSSQNIITYLNWY CAGGGTTACCATAACCTGCAGAAGTTCACAGAACA QQKPGKAPKLLIY TCATCACCTACCTTAATTGGTACCAGCAAAAGCCTG GASRLQSGVPSRF GCAAAGCCCCTAAACTGCTCATTTATGGAGCCTCCC SGSGSGTDFTLTIS GGCTGCAGAGCGGCGTGCCCAGTCGCTTCTCCGGTT SLQPEDFATYYCQ CTGGATCAGGTACCGATTTCACGCTGACAATTAGCT QSFSTPLTFGGGT CCTTACAACCCGAAGACTTTGCTACTTACTATTGTCKEVDKAGCAGTCCTTCTCTACTCCATTGACATTTGGCGGGG GGACAAAGGAGGTGGACAAG SEQ ID NO 597 598AVE-07-G12 EVQLLESGGGLV GAAGTCCAGCTTCTGGAGAGCGGAGGCGGACTGGT QPGGSLRLSCAAS GCAGCCAGGCGGGAGCTTGCGTCTGTCCTGTGCGG GFRFSNYAMTWV CAAGCGGGTTCCGCTTCTCTAACTATGCCATGACCT RQAPGKGLEWVS GGGTAAGGCAAGCACCTGGCAAAGGTCTTGAGTGG GISGGGGRTFYAD GTGTCCGGAATTTCCGGCGGGGGCGGACGGACGTT SVKGRFTISRDNS CTACGCCGATTCAGTGAAGGGTCGATTTACCATCTC KNTLYLQMNSLR TAGGGATAATAGTAAGAACACTCTCTACCTCCAGA AEDTAVYYCARG TGAATAGTTTGAGAGCTGAAGACACAGCCGTGTAC YGAEYFDPWGQG TATTGCGCTAGAGGGTACGGTGCCGAGTATTTTGAC TLVTVSSGGGGS CCCTGGGGGCAGGGCACTCTGGTTACAGTCTCATCG GGGGSGGGGSDI GGTGGCGGTGGATCGGGCGGTGGTGGATCTGGAGG QMTQSPSSLSASV AGGTGGCTCGGATATTCAGATGACACAGAGCCCAT GDRVTITCRASQP CTTCACTGTCCGCTTCGGTAGGGGATAGAGTGACA ISRYLNWYQQKP ATAACATGCCGCGCAAGCCAGCCTATCTCACGGTA GKAPKLLIYDASR CCTCAACTGGTACCAACAGAAACCCGGGAAAGCCC LQVGVPSRFSGSG CGAAGCTGTTAATCTATGACGCGAGTAGGCTGCAA SGTDFTLTISSLQP GTGGGTGTCCCCAGCCGATTCAGCGGTTCCGGATCT EDFATYYCQQSFS GGCACCGACTTCACCCTCACTATCTCTTCCTTGCAG TPLTFGGGTKVEI CCAGAAGACTTTGCCACGTATTACTGTCAGCAGTCC K TTTAGTACCCCTCTTACCTTCGGCGGAGGCACTAAG GTTGAGATTAAGSEQ ID NO 599 600

[0124] In some embodiments, provided herein is an anti-Activin E scFV antibody, wherein the amino acids have at least 95, 96, 97, 98, 99, or 100% sequence identity to SEQ ID NOS: 501; 503; 505; 507; 509; 511; 513; 515; 517; 519; 521; 523; 525; 527; 529; 531; 533; 535; 537; 539; 541; 543; 545; 547; 549; 551; 553; 555; 557; 559; 561; 563; 565; 567; 569; 571; 573; 575; 577; 579; 581; 583; 585; 587; 589; 591; 593; 595; 597; or 599.

[0125] In some embodiments, provided herein is an anti-Activin E scFV antibody encoded by a polynucleotide having at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to SEQ ID NOS: 502; 504; 506; 508; 510; 512; 514; 516; 518; 520; 522; 524; 526; 528; 530; 532; 534; 536; 538; 540; 542; 544; 546; 548; 550; 552; 554; 556; 558; 560; 562; 564; 566; 568; 570; 572; 574; 576; 578; 580; 582; 584; 586; 588; 590; 592; 594; 596; 598; or 600.

[0126] Table 5. Activity of the anti-Activin Antibodies As Measured by SPR.Clone ID Activin E Binding KD (M)AVE-01-D07 2.20E-08AVE-01-B08 2.90E-08AVE-02-A03 9.30E-09AVE-02-B04 3.10E-08AVE-06-B07 5.00E-08AVE-06-F07 4.38E-07AVE-06-A08 5.48E-09AVE-06-D08 3.57E-08 AVE-06-G08 4.38E-08 AVE-06-H08 7.69E-11 AVE-06-A09 3.13E-07 AVE-06-B09 9.38E-09 AVE-06-D09 1.16E-07 AVE-06-F09 3.83E-08 AVE-06-G09 6.67E-09 AVE-06-C10 1.18E-08 AVE-06-G10 1.17E-08 AVE-06-H10 3.75E-08 AVE-06-B11 3.75E-08 AVE-06-E11 3.00E-08 AVE-06-H11 3.75E-08 AVE-06-A12 3.75E-07 AVE-06-B12 2.19E-08 AVE-06-C12 2.13E-08 AVE-06-E12 2.91E-08 AVE-06-G12 2.20E-08 AVE-07-A01 3.67E-08 AVE-07-B01 9.69E-08 AVE-07-C01 8.75E-09 AVE-07-D01 2.91E-08 AVE-07-E01 7.78E-09 AVE-07-F01 2.56E-07 AVE-07-C02 1.13E-07 AVE-07-F02 8.44E-08 AVE-07-G02 1.22E-08 AVE-07-H03 2.00E-08 AVE-07-D04 7.81E-08 AVE-07-E06 1.84E-08 AVE-07-F06 1.39E-07 AVE-07-A07 1.50E-08 AVE-07-E07 1.63E-07 AVE-07-D08 9.20E-09 AVE-07-E08 1.04E-08AVE-07-H08 1.75E-08AVE-07-C10 1.55E-08AVE-07-D11 1.04E-08AVE-07-F11 2.29E-08AVE-07-G11 8.57E-09AVE-07-F12 9.23E-09AVE-07-G12 8.15E-09

[0127] Table 6. IC50 for each tested antibody.IC50 (nM) IC50 (nM)Antibody0.2 nM Activin E 0.02 nM Activin EhlgGl Isotype nd ndJ02 IgGl (anti-ALK7) 0.3139 0.3057AVE-06-H08 scFv-Fc 0.2703 0.04758AVE-06-A08 scFv-Fc nd ndAVE-06-G09 scFv-Fc nd ndAVE-07-E01 scFv-Fc nd ndAVE-07-G12 scFv-Fc nd ndAVE-07-G11 scFv-Fc nd ndAVE-07-C01 scFv-Fc nd ndAVE-07-D08 scFv-Fc nd ndNo treatment nd nd

[0128] Uses of Anti-Activin E antibodies.

[0129] Therapeutic Anti-Activin E antibodies.

[0130] Male C57BL / 6J mice with diet-induced obesity (DIO) were used in this study. Obesity was induced over 12-16 weeks through ad libitum access to a high-fat diet (HFD, 60% kcal from fat). Water was provided ad libitum throughout the study, and mice continued on HFD for the duration of the study.

[0131] Mice were randomized into four treatment groups: Group 1: Vehicle / Vehicle, Group 2: AVE-06-H08 mouse IgGl 10 mg / kg / Vehicle, Group 3: Vehicle / Semaglutide 40 pg / kg, and Group 4: AVE-06- H08 mouse IgGl 10 mg / kg / Semaglutide 40 nmol / kg.

[0132] All dosing was administered for the duration of the study. AVE-06-H08 mouse IgGl and vehicle were administered twice weekly via subcutaneous (SC) injection at a dose volume of 5 mL / kg. Semaglutide was administered SC once daily.

[0133] Dual-energy X-ray absorptiometry (DEXA) scans were performed at baseline (week 0) and at week 2 to assess body composition. For each DEXA scan, mice were anesthetized with ketamine / xylazine. Body weight was recorded twice weekly for all animals throughout the study.

[0134] FIG. 3A is a graph that shows the establishment of Activin E signaling assay in differentiated human adipocytes, and FIG. 3B is a graph that shows the antagonism of Activin E signaling in human adipocytes by AVE-06-H08 at 100 nM Activin E using the antibodies disclosed herein.

[0135] FIG. 4A to 4G show a Diet Induced Obesity (DIO) mouse model study plan and results. FIG. 4A shows the DIO mouse model study plan. FIG. 4B is a graph that shows baseline and vehicle corrected change in body weight post dose. 2-way ANOVA used for statistical measures to compare mean body weight at each timepoint to the vehicle only group. FIG. 4C is a graph that shows body composition analysis of total fat mass. Statistics calculated using 2-way ANOVA, and comparing to baseline value. FIG. 4D is a graph that shows body composition analysis of total lean mass. Statistics calculated using 2-way ANOVA, and comparing to baseline value. FIG. 4E is a graph that shows weight of various fat depots at terminal end point. One-way ANOVA used for statistical analysis. FIG. 4F is a graph that shows a histological analysis of eWAT adipose tissue from terminal endpoint, measuring adipocyte minimum diameter and area. One-way ANOVA used for statistical analysis. FIG. 4G shows representative images of adipocyte histology. One-way ANOVA used for statistical analysis. Prevention of weight and fat regain in diet-induced obesity (DIO) mouse model. Male C57BL / 6J mice with diet-induced obesity were used for this study. Obesity induction occurred over 12-16 weeks; during this time mice were allowed ad libitum access to a high-fat diet (HFD, 60% kcal from fat) and water. Mice were fed HFD for the entire duration of the study.

[0136] Mice were randomized into 3 weight-matched treatment groups: Group 1: Vehicle / Vehicle, Group 2: Semaglutide 40 pg per kg / Vehicle, Group 3: Semaglutide 40 pg per kg / AVE-06-H08 mouse IgGl 10 mg per kg.

[0137] Semaglutide was administered daily for the first 14 consecutive days of the study via subcutaneous (SC) injection at a dose volume of 2 pL per gram of body weight. AVE-06-H08 was administered SC at a volume of 2.8 pL per gram of body weight twice weekly beginning at day 10 through the end of the study, for a total of 8. Semaglutide treatment was stopped after day 14 and was replaced with vehicle treatments for groups 1 and 2 on the same days as AVE-06-H08 treatment for group 3.

[0138] Body weights were collected daily for the first 14 consecutive days, and then Monday-Friday for the remainder of the study. Food intake measurements were collected twice per week for each cage and then divided by the number of mice per cage to obtain individual food intake values.

[0139] On the first day of the study (day 1), animals were fasted for 4 hours at the start of the light phase. Upon euthanasia, epididymal (bilateral), mesenteric, and inguinal (bilateral) fat depots were collected and weighed. The liver was inspected for fatty liver characteristics and weighed. The left quadriceps muscle was collected for measurement of weight.

[0140] Data were analyzed using one- or two-way ANOVA (when appropriate) using time and treatment as factors. Holm-Sidak's multiple comparisons post hoc analysis was used, when appropriate, to identifytreatment group differences. All data are presented as mean ± S. E. M., and p values of < 0.05 were considered statistically significant.

[0141] FcRn Binding Affinity. FcRn binding affinity. FcRn binding affinity was measured using biolayer interferometry (BLI) on a ForteBio Octet Red384 instrument. Biotinylated FcRn:beta-2-microglobulin heterodimer (Aero Biosystems, Cat# FCM-H5283) was prepared at 1 pg / mL in PBS + 0.01% Tween-20 pH 7.4, then captured on SA Biosensors (Sartorius, Cat# 18-5019) for 180 seconds to ~ 7 nm. Biosensors were then baselined in acetate buffer at pH 6 for 180 seconds followed by 5 -minute sample association and dissociation phases in the same buffer. Regeneration was performed by dipping biosensors in PBS + 0.01% Tween-20, pH 7.4 for 30 seconds 3 times. The resulting kinetic profiles were fit using a 1: 1 binding model with the Data Analysis HT software.

[0142] Table 7. Affinity of tested antibodies to human FcRn, as measured by biolayer interferometry. Alternate #1 and Alternate #2 refer to non-Activin E binding antibodies expressed in same IgG4 or IgG4 LS Fc as AVE-06-H08.Ratio IgG4 / IgG4 Clone ka (1 / Ms) kd (l / s) KD (M)LS AVE-06-H08 IgG4 7.02E+05 1.95E-03 2.78E-09 4.3 AVE-06-H08 IgG4 n / a 4.09E+05 2.68E-04 6.54E-10[LS]Alternate #1 IgG4 8.90E+05 1.27E-03 1.42E-09 2.1 Alternate #1 IgG4 [LS] 6.47E+05 4.40E-04 6.79E-10 n / a Alternate #2 IgG4 8.34E+05 8.05E-04 9.66E-10 1.9 Alternate #2 IgG4 [LS] 6.34E+05 3.18E-04 5.01E-10 n / a

[0143] FIGS. 5A to 5F show the study design and results for weight regain prevention in DIO mice. Semaglutide dosed daily, mAbs dosed twice per week. FIG. 5B are graphs that show the baseline and vehicle-corrected body weights. Arrow indicates initiation of BIW mAb dosing. 2-way AN OVA used for statistical analysis. FIG. 5C is a graph that shows the food intake, reported on per-mouse basis. FIG. 5D is a graph that shows the terminal liver weight. FIG. 5E is a graph that shows the terminal adipose depot weights. FIG. 5F is a graph that shows the Terminal quadriceps weight.

[0144] Table 8. Modified Fc region AVE-06-H08_IgG4.Name Amino Acid sequence SEQ ID NO: > AVE-06- EVQLLESGGGLVQPGGSLRLSCAASGFDFSKFAMSWVRQAP 601GKGLEWVSSITRGSETTYYADSVKGRFTISRDNSKNTLYLQH08_IgG4_MNSLRAEDTAVYYCATLGLGYYYYFDVWGQGTLVTVSSAS LS HC TKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVD HKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPK DTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAK TKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGL PSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTV DKSRWQEGNVFSCSVLHEALHSHYTQKSLSLSLG> AVE-06- DIQMTQSPSSLSASVGDRVTITCRASQPISSYVTWYQQKPGK 602APKLLIYSASHLRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYH08_IgG4_YCQQSYNAPPTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGT LS LC ASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0145] Obese Non-human Primate Pharmacokinetic Study. Male diet-induced obese (DIO) cynomolgus monkeys (Macaca fascicularis), aged 8-15 years, with a body weight >7.5 kg, BMI 35-70 kg / m2, blood glucose < 120 mg / dL, and blood insulin < 300 pU / mL were used in this study. Animals were housed under standard conditions with ad libitum access to water and a controlled diet. Food and water intake were monitored throughout the study, and daily cage-side clinical observations were performed.

[0146] A total of 6 animals were enrolled in the pharmacokinetics study. The animals received a single intravenous (IV) dose of AVE-06-H08_IgG4_LS at 10 mg / kg.

[0147] Serum samples were collected at predefined time points following dosing for a total of 8 weeks. At each time point, 4 mL of whole blood was collected from a peripheral vein and transferred into serum separation tubes (SST). Samples were centrifuged at 2500 x g for 10 minutes at 4°C, and the resulting serum was aliquoted into three 400 pL fractions and stored at -80°C until analysis.

[0148] Serum concentrations of AVE-06-H08_IgG4_LS were determined using a Human IgG4 ELISA kit. Monkey serum samples were diluted 1:10 in assay buffer, and a standard curve was generated to quantify antibody concentrations at each time point. Antibody half-life was calculated based on a linear elimination model, using the serum concentration data obtained from the ELISA assay.

[0149] FIG. 6A shows the study design for PK study in obese mature nonhuman primates (NHPs). FIG.6B shows the non-human primate (NHP) selection criteria. FIG. 6C shows the serum concentration of AVE-06-H08_IgG4 at various timepoints. FIG. 6D shows the average serum concentration of AVE-06-H08_IgG4 with half-life calculated using linear elimination from days 14-56.

[0150] In some embodiments, the Anti-Activin E antibodies provided herein are useful for the treatment of a disease or condition involving an immune response.

[0151] Listing of Embodiments.

[0152] Embodiment 1. An anti-Activin E antibody or antigen binding domain thereof comprising comprises: a heavy chain variable domain (VH) complementarity determining region 1 (CDR1), VH CDR2, and VH CDR3 comprising an amino acid sequence of any one of the following SEQ ID NOs: 1, 2, 3; 11, 12, 13; 21, 22, 23; 31, 32, 33; 41, 42, 43; 51, 52, 53; 61, 62, 63; 71, 72, 73; 81, 82, 83; 91, 92, 93; 101, 102, 103; 111, 112, 113; 121, 122, 123; 131, 132, 133; 141, 142, 143; 151, 152, 153; 161, 162, 163; 171, 172, 173; 181, 182, 183; 191, 192, 193; 201, 202, 203; 211, 212, 213; 221, 222, 223; 231, 232, 233; 241, 242, 243; 251, 252, 253; 261, 262, 263; 271, 272, 273; 281, 282, 283; 291, 292, 293; 301, 302, 303; 311, 312, 313; 321, 322, 323; 331, 332, 333; 341, 342, 343; 351, 352, 353; 361, 362, 363; 371, 372, 373; 381, 382, 383; 391, 392, 393; 401, 402, 403; 411, 412, 413; 421, 422, 423; 431, 432, 433; 441, 442, 443; 451, 452, 453; 461, 462, 463; 471, 472, 473; 481, 482, 483; or 491, 492, 493, respectively; and a light chain variable domain (VL) CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of any one of the following SEQ ID NOs: 4, 5, 6; 14, 15, 16; 24, 25, 26; 34, 35, 36; 44, 45, 46; 54, 55, 56; 64, 65, 66; 74, 75, 76; 84, 85, 86; 94, 95, 96; 104, 105, 106; 114, 115, 116; 124, 125, 126; 134, 135, 136; 144, 145, 146; 154, 155, 156; 164, 165, 166; 174, 175, 176; 184, 185, 186; 194, 195, 196; 204, 205, 206; 214, 215, 216; 224, 225, 226; 234, 235, 236; 244, 245, 246; 254, 255, 256; 264, 265, 266; 274, 275, 276; 284, 285, 286; 294, 295, 296; 304, 305, 306; 314, 315, 316; 324, 325, 326; 334, 335, 336; 344, 345, 346; 354, 355, 356; 364, 365, 366; 374, 375, 376; 384, 385, 386; 394, 395, 396; 404, 405, 406; 414, 415, 416; 424, 425, 426; 434, 435, 436; 444, 445, 446; 454, 455, 456; 464, 465, 466; 474, 475, 476; 484, 485, 486; or 494, 495, 496, respectively.

[0153] Embodiment 2. The antibody of embodiment 1, wherein the antibody comprises: a VH and VL pair comprising at least 95, 96, 97, 98, 99, or 100% sequence identify to SEQ ID NOS; 7, 8; 17, 18; 27, 28; 37, 38; 47, 48; 57, 58; 67, 68; 77, 78; 87, 88; 97, 98; 107, 108; 117, 118; 127, 128; 137, 138; 147, 148; 157, 158; 167, 168; 177, 178; 187, 188; 197, 198; 207, 208; 217, 218; 227, 228; 237, 238; 247, 248; 257, 258; 267, 268; 277, 278; 287, 288; 297, 298; 307, 308; 317, 318; 327, 328; 337, 338; 347, 348; 357, 358; 367, 368; 377, 378; 387, 388; 397, 398; 407, 408; 417, 418; 427, 428; 437, 438; 447, 448; 457, 458; 467, 468; 477, 478; 487, 488; 497, 498; or 601, 602.

[0154] Embodiment 3. The antibody of embodiment 1, wherein the antibody comprises: a heavy chain and light chain variable domains are encoded by a polynucleotide or polynucleotides comprising at least 95, 96, 97, 98, 99, or 100% sequence identify to SEQ ID NOS: 9, 10; 19, 20; 29, 30; 39, 40; 49, 50; 59, 60; 69, 70; 79, 80; 89, 90; 99, 100; 109, 110; 119, 120; 129, 130; 139, 140; 149, 150; 159, 160; 169, 170; 179, 180; 189, 190; 199, 200; 209, 210; 219, 220; 229, 230; 239, 240; 249, 250; 259, 260; 269, 270; 279, 280; 289, 290; 299, 300; 309, 310; 319, 320; 329, 330; 339, 340; 349, 350; 359, 360; 369, 370; 379, 380; 389, 390; 399, 400; 409, 410; 419, 420; 429, 430; 439, 440; 449, 450; 459, 460; 469, 470; 479, 480; 489, 490; or 499, 500.

[0155] Embodiment 4. The antibody of any one of embodiments 1 to 3, wherein the antibody is a monoclonal antibody.

[0156] Embodiment 5. The antibody of any one of embodiments 1 to 3, wherein the antibody is a full-length antibody.

[0157] Embodiment 6. The antibody of any one of embodiments 1 to 3, wherein the antibody is an antibody fragment selected from F(ab’)2, Fab, Fab’, Fv, or scFv.

[0158] Embodiment 7. The antibody fragment of embodiment 6, wherein the antibody comprises an Fc domain selected from one of the following: human IgGl, human IgG2, human IgG3, and human IgG4.

[0159] Embodiment 8. A method of treating a disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody of any one of embodiments 1-7.

[0160] Embodiment 9. A single chain fragment variable (scFv) Activin E antagonist comprising: a heavy chain variable domain (VH) complementarity determining region 1 (CDR1), VH CDR2, and VH CDR3 comprising an amino acid sequence of any one of the following SEQ ID NOs: 1, 2, 3; 11, 12, 13; 21, 22, 23; 31, 32, 33; 41, 42, 43; 51, 52, 53; 61, 62, 63; 71, 72, 73; 81, 82, 83; 91, 92, 93; 101, 102, 103; 111, 112, 113; 121, 122, 123; 131, 132, 133; 141, 142, 143; 151, 152, 153; 161, 162, 163; 171, 172, 173; 181, 182, 183; 191, 192, 193; 201, 202, 203; 211, 212, 213; 221, 222, 223; 231, 232, 233; 241, 242, 243; 251, 252, 253; 261, 262, 263; 271, 272, 273; 281, 282, 283; 291, 292, 293; 301, 302, 303; 311, 312, 313; 321, 322, 323; 331, 332, 333; 341, 342, 343; 351, 352, 353; 361, 362, 363; 371, 372, 373; 381, 382, 383; 391, 392, 393; 401, 402, 403; 411, 412, 413; 421, 422, 423; 431, 432, 433; 441, 442, 443; 451, 452, 453; 461, 462, 463; 471, 472, 473; 481, 482, 483; or 491, 492, 493; and a light chain variable domain (VL) CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of any one of the following SEQ ID NOs: 4, 5, 6; 14, 15, 16; 24, 25, 26; 34, 35, 36; 44, 45, 46; 54, 55, 56; 64, 65, 66; 74, 75, 76; 84, 85, 86; 94, 95, 96; 104, 105, 106; 114, 115, 116; 124, 125, 126; 134, 135, 136; 144, 145, 146; 154, 155, 156; 164, 165, 166; 174, 175, 176; 184, 185, 186; 194, 195, 196; 204, 205, 206; 214, 215, 216; 224, 225, 226; 234, 235, 236; 244, 245, 246; 254, 255, 256; 264, 265, 266; 274, 275, 276; 284, 285, 286; 294, 295, 296; 304, 305, 306; 314, 315, 316; 324, 325, 326; 334, 335, 336; 344, 345, 346; 354, 355, 356; 364, 365, 366; 374, 375, 376; 384, 385, 386; 394, 395, 396; 404, 405, 406; 414, 415, 416; 424, 425, 426; 434, 435, 436; 444, 445, 446; 454, 455, 456; 464, 465, 466; 474, 475, 476; 484, 485, 486; or 494, 495, 496, respectively.

[0161] Embodiment 10. The scFv of embodiment 9, wherein the scFv comprises at least 95, 96, 97, 98, 99, or 100% amino acid sequence identify to: 501; 503; 505; 507; 509; 511; 513; 515; 517; 519; 521; 523; 525; 527; 529; 531; 533; 535; 537; 539; 541; 543; 545; 547; 549; 551; 553; 555; 557; 559; 561; 563; 565; 567; 569; 571; 573; 575; 577; 579; 581; 583; 585; 587; 589; 591; 593; 595; 597; or 599.

[0162] Embodiment 11. The scFv of embodiment 9, wherein the scFv comprises at least 95, 96, 97, 98, 99, or 100% nucleic sequence identify to: 502; 504; 506; 508; 510; 512; 514; 516; 518; 520; 522; 524; 526; 528; 530; 532; 534; 536; 538; 540; 542; 544; 546; 548; 550; 552; 554; 556; 558; 560; 562; 564; 566; 568; 570; 572; 574; 576; 578; 580; 582; 584; 586; 588; 590; 592; 594; 596; 598; or 600.

[0163] Embodiment 12. The scFv of embodiment 9, wherein the scFv is a tandem scFv.

[0164] Embodiment 13. A method of treating a disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody of any one of embodiments 1-12.

[0165] Embodiment 14. The method of embodiment 13, where the disease is selected from at least one of: a metabolic disorder, type 2 diabetes, obesity, an elevated triglyceride level, lipodystrophy, liver inflammation, fatty liver disease, hypercholesterolemia, an elevated liver enzyme, nonalcoholic steatohepatitis (NASH), a cardiovascular disease, cardiomyopathy, high blood pressure, or heart failure.

[0166] Embodiment 15. The method of embodiment 13 or embodiment 14, wherein the subject is human.

[0167] Embodiment 16. A nucleic acid comprising an anti-Activin E antibody or antigen binding domain thereof, comprising: a heavy chain variable domain (VH) complementarity determining region 1 (CDR1), VH CDR2, and VH CDR3 comprising an amino acid sequence of any one of the following SEQ ID NOs: 1, 2, 3; 11, 12, 13; 21, 22, 23; 31, 32, 33; 41, 42, 43; 51, 52, 53; 61, 62, 63; 71, 72, 73; 81, 82, 83; 91, 92, 93; 101, 102, 103; 111, 112, 113; 121, 122, 123; 131, 132, 133; 141, 142, 143; 151, 152, 153; 161, 162, 163; 171, 172, 173; 181, 182, 183; 191, 192, 193; 201, 202, 203; 211, 212, 213; 221, 222, 223; 231, 232, 233; 241, 242, 243; 251, 252, 253; 261, 262, 263; 271, 272, 273; 281, 282, 283; 291, 292, 293; 301, 302, 303; 311, 312, 313; 321, 322, 323; 331, 332, 333; 341, 342, 343; 351, 352, 353; 361, 362, 363; 371, 372, 373; 381, 382, 383; 391, 392, 393; 401, 402, 403; 411, 412, 413; 421, 422, 423; 431, 432, 433; 441, 442, 443; 451, 452, 453; 461, 462, 463; 471, 472, 473; 481, 482, 483; or 491, 492, 493; and a light chain variable domain (VL) CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of any one of the following SEQ ID NOs: 4, 5, 6; 14, 15, 16; 24, 25, 26; 34, 35, 36; 44, 45, 46; 54, 55, 56; 64, 65, 66; 74, 75, 76; 84, 85, 86; 94, 95, 96; 104, 105, 106; 114, 115, 116; 124, 125, 126; 134, 135, 136; 144, 145, 146; 154, 155, 156; 164, 165, 166; 174, 175, 176; 184, 185, 186; 194, 195, 196; 204, 205, 206; 214, 215, 216; 224, 225, 226; 234, 235, 236; 244, 245, 246; 254, 255, 256; 264, 265, 266; 274, 275, 276; 284, 285, 286; 294, 295, 296; 304, 305, 306; 314, 315, 316; 324, 325, 326; 334, 335, 336; 344, 345, 346; 354, 355, 356; 364, 365, 366; 374, 375, 376; 384, 385, 386; 394, 395, 396; 404, 405, 406; 414, 415, 416; 424, 425, 426; 434, 435, 436; 444, 445, 446; 454, 455, 456; 464, 465, 466; 474, 475, 476; 484, 485, 486; or 494, 495, 496, respectively.

[0168] Embodiment 17. The nucleic acid of embodiment 16, wherein the antibody or antigen binding domain thereof comprises a heavy chain and light chain variable domain encoding polynucleotide having at least 95, 96, 97, 98, 99, or 100% sequence identify to SEQ ID NOS: 9, 10; 19, 20; 29, 30; 39, 40; 49, 50; 59, 60; 69, 70; 79, 80; 89, 90; 99, 100; 109, 110; 119, 120; 129, 130; 139, 140; 149, 150; 159, 160; 169, 170; 179, 180; 189, 190; 199, 200; 209, 210; 219, 220; 229, 230; 239, 240; 249, 250; 259, 260; 269, 270; 279, 280; 289, 290; 299, 300; 309, 310; 319, 320; 329, 330; 339, 340; 349, 350; 359, 360; 369, 370; 379, 380; 389, 390; 399, 400; 409, 410; 419, 420; 429, 430; 439, 440; 449, 450; 459, 460; 469, 470; 479, 480; 489, 490; 499, 500; or 601, 602.

[0169] Embodiment 18. The nucleic acid of embodiment 16, wherein the antibody is a monoclonal, bispecific, multivalent, multi-specific, diabody, chimeric, scFv antibody, or domain thereof.

[0170] Embodiment 19. The nucleic acid of embodiment 18, wherein the scFv encodes a polypeptide that comprises at least 95, 96, 97, 98, 99, or 100% amino acid sequence identify to: 501; 503; 505; 507; 509; 511; 513; 515; 517; 519; 521; 523; 525; 527; 529; 531; 533; 535; 537; 539; 541; 543; 545;547; 549; 551; 553; 555; 557; 559; 561; 563; 565; 567; 569; 571; 573; 575; 577; 579; 581; 583; 585; 587; 589; 591; 593; 595; 597; or 599.

[0171] Embodiment 20. The nucleic acid of embodiment 18, wherein the scFv comprises at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% nucleic sequence identify to: 502; 504; 506; 508; 510; 512; 514; 516; 518; 520; 522; 524; 526; 528; 530; 532; 534; 536; 538; 540; 542; 544; 546; 548; 550; 552; 554; 556; 558; 560; 562; 564; 566; 568; 570; 572; 574; 576; 578; 580; 582; 584; 586; 588; 590; 592; 594; 596; 598; or 600.

[0172] Embodiment 21. The nucleic acid of embodiment 16, wherein an antibody binding domain is fused to an Fc domain of any one of the following: human IgGl, human IgG2, human IgG3, and human IgG4.

[0173] Embodiment 22. The nucleic acid of any one of embodiments 16 to 21, wherein the nucleic acid sequence is optimized for expression in a bacterial, fungal, mammalian, insect, or plant cell.

[0174] Embodiment 23. A vector comprising the nucleic acid of embodiment 16.

[0175] Embodiment 24. A host cell comprising nucleic acid the vector of embodiment 23.

[0176] Embodiment 25. A method of treating a subject having or at risk of developing a metabolic disorder, type 2 diabetes, obesity, an elevated triglyceride level, lipodystrophy, liver inflammation, fatty liver disease, hypercholesterolemia, an elevated liver enzyme, nonalcoholic steatohepatitis (NASH), a cardiovascular disease, cardiomyopathy, high blood pressure, and / or heart failure, the method comprising administering an anti-Inhibin E antibody administering an antibody, scFv, or antigen binding domain thereof of any one of embodiments 1 to 8 or any the nucleic acid of one of embodiments 16 to 22 to the subject.

[0177] Embodiment 26. The method of embodiment 25, wherein the anti-Activin antibody or binding domain thereof comprises a variable heavy chain and light chain nucleic acid sequence having at least 95, 96, 97, 98, 99, or 100% sequence identify to SEQ ID NOS: 9, 10; 19, 20; 29, 30; 39, 40; 49, 50; 59, 60; 69, 70; 79, 80; 89, 90; 99, 100; 109, 110; 119, 120; 129, 130; 139, 140; 149, 150; 159, 160; 169, 170; 179, 180; 189, 190; 199, 200; 209, 210; 219, 220; 229, 230; 239, 240; 249, 250; 259, 260; 269, 270; 279, 280; 289, 290; 299, 300; 309, 310; 319, 320; 329, 330; 339, 340; 349, 350; 359, 360; 369, 370; 379, 380; 389, 390; 399, 400; 409, 410; 419, 420; 429, 430; 439, 440; 449, 450; 459, 460; 469, 470; 479, 480; 489, 490; 499, 500; or 601, 602.

[0178] Embodiment 1. The method of embodiment 25, wherein the anti-Activin antibody or binding domain thereof comprises an scFv comprising at least 95, 96, 97, 98, 99, or 100% amino acid sequence identify to: 501; 503; 505; 507; 509; 511; 513; 515; 517; 519; 521; 523; 525; 527; 529; 531; 533; 535; 537; 539; 541; 543; 545; 547; 549; 551; 553; 555; 557; 559; 561; 563; 565; 567; 569; 571; 573; 575; 577; 579; 581; 583; 585; 587; 589; 591; 593; 595; 597; or 599.

[0179] Embodiment 28. The method of any one of embodiments 25 to 27, wherein when the subject is administered a therapeutic agent that treats or inhibits metabolic disorders or cardiovascular diseases in a standard dosage amount.

[0180] Embodiment 29. The method of any one of embodiments 25 to 28, wherein when the subject is administered a therapeutic agent that treats or inhibits metabolic disorders or cardiovascular diseases that is the same as or lower than a standard dosage amount.

[0181] Embodiment 30. A method of treating a subject with a therapeutic agent that treats or inhibits a metabolic disorder, type 2 diabetes, obesity, an elevated triglyceride level, lipodystrophy, liver inflammation, fatty liver disease, hypercholesterolemia, an elevated liver enzyme, nonalcoholic steatohepatitis (NASH), a cardiovascular disease, cardiomyopathy, high blood pressure, or heart failure, the method comprising administering an antibody or antigen binding domain thereof any one of embodiments 1 to 8, or any the nucleic acid of one of embodiments 16 to 22 to the subject.

[0182] Embodiment 31. The method of embodiment 30, wherein the subject is administered or continued to be administered a therapeutic agent that treats or inhibits the metabolic disorder, type 2 diabetes, obesity, an elevated triglyceride level, lipodystrophy, liver inflammation, fatty liver disease, hypercholesterolemia, an elevated liver enzyme, nonalcoholic steatohepatitis (NASH), a cardiovascular disease, cardiomyopathy, high blood pressure, or heart failure in a standard dosage amount; or the subject is administered or continued to be administered the therapeutic agent that treats or inhibits the metabolic disorder, type 2 diabetes, obesity, an elevated triglyceride level, lipodystrophy, liver inflammation, fatty liver disease, hypercholesterolemia, an elevated liver enzyme, nonalcoholic steatohepatitis (NASH), a cardiovascular disease, cardiomyopathy, high blood pressure, or heart failure in an amount that is the same as or lower than a standard dosage amount.

[0183] Embodiment 32. The method of embodiment 30 or embodiment 31, wherein the metabolic disorder is selected from at least one of: type 2 diabetes, and the therapeutic agent is chosen from metformin, insulin, glyburide, glipizide, glimepiride, repaglinide, nateglinide, thiazolidinediones, rosiglitazone, pioglitazone, sitagliptin, saxagliptin, linagliptin, exenatide, liraglutide, semaglutide, canagliflozin, dapagliflozin, and empagliflozin, or any combination thereof; obesity, and the therapeutic agent is chosen from orlistat, phentermine, topiramate, bupropion, naltrexone, and liraglutide, or any combination thereof: elevated triglyceride, and the therapeutic agent is chosen from rosuvastatin, simvastatin, atorvastatin, fenofibrate, gemfibrozil, fenofibric acid, niacin, and an omega-3 fatty acid, or any combination thereof, lipodystrophy, and the therapeutic agent is chosen from tesamorelin, metformin, poly-L-lactic acid, calcium hydroxyapatite, polymethylmethacrylate, bovine collagens, human collagens, silicone, and hyaluronic acid, or any combination thereof; liver inflammation, and the therapeutic agent is a hepatitis therapeutic or a hepatitis vaccine; fatty liver disease include, and the subject is administered bariatric surgery and / or dietary intervention; hypercholesterolemia, and the therapeutic agent is chosen from: atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin calcium, simvastatin, cholestyramine, colesevelam, and colestipol, alirocumab, evolocumab, niaspan, niacor, fenofibrate, gemfibrozil, and bempedoic, or any combination thereof; an elevated liver enzyme, and the therapeutic agent is chosen from coffee, folic acid, potassium, vitamin B6, a statin, and fiber, or any combination thereof; or nonalcoholic steatohepatitis (NASH) and the therapeutic agent is obeticholic acid, Selonsertib, Elafibranor, Cenicriviroc, GR MD 02, MGL 3196, IMM124E, arachidyl amido cholanoic acid, GS0976,Emricasan, Volixibat, NGM282, GS9674, Tropifexor, MN 001, LMB763, BI 1467335, MSDC 0602, PF 05221304, DF102, Saroglitazar, BMS986036, Lanifibranor, Semaglutide, Nitazoxanide, GRI 0621, EYP001, VK2809, Nalmefene, LIK066, MT 3995, Elobixibat, Namodenoson, Foralumab, SAR425899, Sotagliflozin, EDP 305, Isosabutate, Gemcabene, TERN 101, KBP 042, PF 06865571, DUR928, PF 06835919, NGM313, BMS 986171, Namacizumab, CER 209, ND L02 s0201, RTU 1096, DRX 065, IGNIS DGAT2Rx, INT 767, NC 001, Seladepar, PXL770, TERN 201, NV556, AZD2693, SP 1373, VK0214, Hepastem, TGFTX4, RLBN1127, GKT 137831, RYI 018, CB4209-CB4211, and JH 0920.

[0184] Embodiment 33. The method of embodiment 30, wherein the cardiovascular disease is selected from at least one of: high blood pressure, and the therapeutic agent is chosen from chlorthalidone, chlorothiazide, hydrochlorothiazide, indapamide, metolazone, acebutolol, atenolol, betaxolol, bisoprolol fumarate, carteolol hydrochloride, metoprolol tartrate, metoprolol succinate, nadolol, benazepril hydrochloride, captopril, enalapril maleate, fosinopril sodium, lisinopril, moexipril, perindopril, quinapril hydrochloride, ramipril, trandolapril, candesartan, eprosartan mesylate, irbesartan, losartan potassium, telmisartan, valsartan, amlodipine besylate, bepridil, diltiazem hydrochloride, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, verapamil hydrochloride, doxazosin mesylate, prazosin hydrochloride, terazosin hydrochloride, methyldopa, carvedilol labetalol hydrochloride, alpha methyldopa, clonidine hydrochloride, guanabenz acetate, guanfacine hydrochloride, guanadrel, guanethidine monosulfate, reserpine, hydralazine hydrochloride, and minoxidil, or any combination thereof; cardiomyopathy, and the therapeutic agent is an ACE inhibitor, an angiotensin II receptor blocker, a beta blocker, a calcium channel blocker, digoxin, an antiarrhythmic, an aldosterone blocker, a diuretic, an anticoagulant, a blood thinner, and a corticosteroid; or heart failure, and the therapeutic agent is an ACE inhibitor, an angiotensin-2 receptor blocker, a beta blocker, a mineralocorticoid receptor antagonist, a diuretic, ivabradine, sacubitril valsartan, hydralazine with nitrate, and digoxin. The present disclosure also includes methods of treating a subject with a therapeutic agent that treats or inhibits a metabolic disorder comprising administering or continuing to administer to the subject the therapeutic agent that treats or inhibits the metabolic disorder in a standard dosage amount, and administering to the subject an inhibitory anti-Activin E antibody, scFv, or binding fragment thereof.

[0185] The present disclosure also includes methods of treating a subject with a therapeutic agent that treats or inhibits a cardiovascular disease, wherein the subject is suffering from a cardiovascular disease, comprising administering or continuing to administer to the subject the therapeutic agent that treats or inhibits the cardiovascular disease in a standard dosage amount, and administering to the subject an inhibitory anti-Activin E antibody, scFv, or binding fragment thereof.

[0186] For subjects that have an increased risk of developing a metabolic disorder, such as type 2 diabetes, lipodystrophy, liver inflammation, fatty liver disease, hypercholesterolemia, elevated liver enzymes (such as, for example, ALT and / or AST), obesity, high blood pressure, and / or elevated triglyceride level (hypertriglyceridemia), and / or a cardiovascular disease, such as cardiomyopathy, heart failure, and high blood pressure. These subjects can be treated with an inhibitory anti-Activin E antibody, scFv, or binding fragment thereof of the present disclosure.

[0187] In certain embodiments of the disclosure, the metabolic disorder is type 2 diabetes, obesity, NASH, and / or elevated triglyceride level. In any of the embodiments disclosed herein, the metabolic disorder is type 2 diabetes. In any of the embodiments disclosed herein, the metabolic disorder is obesity. In any of the embodiments disclosed herein, the metabolic disorder is NASH. In any of the embodiments disclosed herein, the metabolic disorder is elevated triglyceride level. In any of the embodiments disclosed herein, the metabolic disorder is lipodystrophy. In any of the embodiments disclosed herein, the metabolic disorder is liver inflammation. In any of the embodiments disclosed herein, the metabolic disorder is fatty liver disease. In any of the embodiments disclosed herein, the metabolic disorder is hypercholesterolemia. In any of the embodiments disclosed herein, the metabolic disorder is elevated liver enzymes (such as, for example, ALT and / or AST).

[0188] In addition, other metabolic disorders / conditions associated with body fat distribution also include, but are not limited to: type 2 diabetes, hyperlipidemia or dyslipidemia (high or altered circulating levels of low-density lipoprotein cholesterol (LDL-C), triglycerides, very low-density lipoprotein cholesterol (VLDL-C), apolipoprotein B or other lipid fractions), obesity (particularly abdominal obesity), lipodystrophy (such as an inability to deposit fat in adipose depots regionally (partial lipodystrophy) or in the whole body (lipoatrophy)), insulin resistance or higher or altered insulin levels at fasting or during a glucose or insulin challenge, liver fat deposition or fatty liver disease and their complications (such as, for example, cirrhosis, fibrosis, or inflammation of the liver), higher or elevated or altered liver enzyme levels or other markers of liver damage, inflammation or fat deposition, higher blood pressure and / or hypertension, higher blood sugar or glucose or hyperglycemia, metabolic syndrome, coronary artery disease, and other atherosclerotic conditions, and the complications of each of the aforementioned conditions.

[0189] Administration of Therapeutic Anti-Activin E antibodies.

[0190] The in vivo administration of the therapeutic Anti-Activin E antibodies described herein may be carried out intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, intrathecally, intraventricularly, intranasally, transmucosally, through implantation, or through inhalation. Intravenous administration may be carried out via injection or infusion. In some embodiments, the Anti-Activin E antibodies of the disclosure are administered intravenously. In some embodiments, the Anti-Activin E antibodies of the disclosure are administered subcutaneously. Administration of the therapeutic Anti-Activin E antibodies may be performed with any suitable excipients, carriers, or other agents to provide suitable or improved tolerance, transfer, delivery, and the like.

[0191] It is contemplated that any embodiment discussed in this specification can be implemented with respect to any method, kit, reagent, or composition of the invention, and vice versa. Furthermore, compositions of the invention can be used to achieve methods of the invention.

[0192] It will be understood that particular embodiments described herein are shown by way of illustration and not as limitations of the invention. The principal features of this invention can be employed in various embodiments without departing from the scope of the invention. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specificprocedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the claims.

[0193] All publications and patent applications mentioned in the specification are indicative of the level of skill of those skilled in the art to which this invention pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0194] The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and / or the specification may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.” The use of the term “or” in the claims is used to mean “and / or” unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and / or.” Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among the study subjects.

[0195] As used in this specification and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. In embodiments of any of the compositions and methods provided herein, “comprising” may be replaced with “consisting essentially of’ or “consisting of’. As used herein, the phrase “consisting essentially of’ requires the specified integer(s) or steps as well as those that do not materially affect the character or function of the claimed invention. As used herein, the term “consisting” is used to indicate the presence of the recited integer (e.g., a feature, an element, a characteristic, a property, a method / process step or a limitation) or group of integers (e.g., feature(s), element(s), characteristic(s), propertie(s), method / process steps or limitation(s)) only.

[0196] The term “or combinations thereof’ as used herein refers to all permutations and combinations of the listed items preceding the term. For example, “A, B, C, or combinations thereof’ is intended to include at least one of: A, B, C, AB, AC, BC, or ABC, and if order is important in a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing with this example, expressly included are combinations that contain repeats of one or more item or term, such as BB, AAA, AB, BBC, AAABCCCC, CBBAAA, CABABB, and so forth. The skilled artisan will understand that typically there is no limit on the number of items or terms in any combination, unless otherwise apparent from the context.

[0197] As used herein, words of approximation such as, without limitation, “about”, “substantial” or “substantially” refers to a condition that when so modified is understood to not necessarily be absolute or perfect but would be considered close enough to those of ordinary skill in the art to warrant designating the condition as being present. The extent to which the description may vary will depend on how great a change can be instituted and still have one of ordinary skilled in the art recognize the modified feature as still having the required characteristics and capabilities of the unmodified feature. In general, but subject to thepreceding discussion, a numerical value herein that is modified by a word of approximation such as “about” may vary from the stated value by at least ±1, 2, 3, 4, 5, 6, 7, 10, 12 or 15%.

[0198] Additionally, the section headings herein are provided for consistency with the suggestions under 37 CFR 1.77 or otherwise to provide organizational cues. These headings shall not limit or characterize the invention(s) set out in any claims that may issue from this disclosure. Specifically, and by way of example, although the headings refer to a “Field of Invention,” such claims should not be limited by the language under this heading to describe the so-called technical field. Further, a description of technology in the “Background of the Invention” section is not to be construed as an admission that technology is prior art to any invention(s) in this disclosure. Neither is the “Summary” to be considered a characterization of the invention(s) set forth in issued claims. Furthermore, any reference in this disclosure to “invention” in the singular should not be used to argue that there is only a single point of novelty in this disclosure. Multiple inventions may be set forth according to the limitations of the multiple claims issuing from this disclosure, and such claims accordingly define the invention(s), and their equivalents, that are protected thereby. In all instances, the scope of such claims shall be considered on their own merits in light of this disclosure, but should not be constrained by the headings set forth herein.

[0199] For each of the claims, each dependent claim can depend both from the independent claim and from each of the prior dependent claims for each and every claim so long as the prior claim provides a proper antecedent basis for a claim term or element.

[0200] To aid the Patent Office, and any readers of any patent issued on this application in interpreting the claims appended hereto, applicants wish to note that they do not intend any of the appended claims to invoke paragraph 6 of 35 U. S. C. § 112, U. S. C. § 112 paragraph (f), or equivalent, as it exists on the date of filing hereof unless the words “means for” or “step for” are explicitly used in the particular claim.

[0201] All of the compositions and / or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and / or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

Claims

WHAT IS CLAIMED IS:

1. An anti-Activin E antibody or antigen binding domain thereof comprising comprises:a heavy chain variable domain (VH) complementarity determining region 1 (CDR1), VH CDR2, and VH CDR3 comprising an amino acid sequence of any one of the following SEQ ID NOs: 1, 2, 3; 11, 12, 13; 21, 22, 23; 31, 32, 33; 41, 42, 43; 51, 52, 53; 61, 62, 63; 71, 72, 73; 81, 82, 83; 91, 92, 93; 101, 102, 103; 111, 112, 113; 121, 122, 123; 131, 132, 133; 141, 142, 143; 151, 152, 153; 161, 162, 163; 171, 172, 173; 181, 182, 183; 191, 192, 193; 201, 202, 203; 211, 212, 213; 221, 222, 223; 231, 232, 233; 241, 242, 243; 251, 252, 253; 261, 262, 263; 271, 272, 273; 281, 282, 283; 291, 292, 293; 301, 302, 303; 311, 312, 313; 321, 322, 323; 331, 332, 333; 341, 342, 343; 351, 352, 353; 361, 362, 363; 371, 372, 373; 381, 382, 383; 391, 392, 393; 401, 402, 403; 411, 412, 413; 421, 422, 423; 431, 432, 433; 441, 442, 443; 451, 452, 453; 461, 462, 463; 471, 472, 473; 481, 482, 483; or 491, 492, 493, respectively; anda light chain variable domain (VL) CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of any one of the following SEQ ID NOs: 4, 5, 6; 14, 15, 16; 24, 25, 26; 34, 35, 36; 44, 45, 46; 54, 55, 56; 64, 65, 66; 74, 75, 76; 84, 85, 86; 94, 95, 96; 104, 105, 106; 114, 115, 116; 124, 125, 126; 134, 135, 136; 144, 145, 146; 154, 155, 156; 164, 165, 166; 174, 175, 176; 184, 185, 186; 194, 195, 196; 204, 205, 206; 214, 215, 216; 224, 225, 226; 234, 235, 236; 244, 245, 246; 254, 255, 256; 264, 265, 266; 274, 275, 276; 284, 285, 286; 294, 295, 296; 304, 305, 306; 314, 315, 316; 324, 325, 326; 334, 335, 336; 344, 345, 346; 354, 355, 356; 364, 365, 366; 374, 375, 376; 384, 385, 386; 394, 395, 396; 404, 405, 406; 414, 415, 416; 424, 425, 426; 434, 435, 436; 444, 445, 446; 454, 455, 456; 464, 465, 466; 474, 475, 476; 484, 485, 486; or 494, 495, 496, respectively.

2. The antibody of claim 1, wherein the antibody comprises:a VH and VL pair comprising at least 95, 96, 97, 98, 99, or 100% sequence identify to SEQ ID NOS; 7, 8; 17, 18; 27, 28; 37, 38; 47, 48; 57, 58; 67, 68; 77, 78; 87, 88; 97, 98; 107, 108; 117, 118; 127, 128; 137, 138; 147, 148; 157, 158; 167, 168; 177, 178; 187, 188; 197, 198; 207, 208; 217, 218; 227, 228; 237, 238; 247, 248; 257, 258; 267, 268; 277, 278; 287, 288; 297, 298; 307, 308; 317, 318; 327, 328; 337, 338; 347, 348; 357, 358; 367, 368; 377, 378; 387, 388; 397, 398; 407, 408; 417, 418; 427, 428; 437, 438; 447, 448; 457, 458; 467, 468; 477, 478; 487, 488; 497, 498; or 601, 602.

3. The antibody of claim 1, wherein the antibody comprises:a heavy chain and light chain variable domains are encoded by a polynucleotide or polynucleotides comprising at least 95, 96, 97, 98, 99, or 100% sequence identify to SEQ ID NOS: 9, 10; 19, 20; 29, 30; 39, 40; 49, 50; 59, 60; 69, 70; 79, 80; 89, 90; 99, 100; 109, 110; 119, 120; 129, 130; 139, 140; 149, 150; 159, 160; 169, 170; 179, 180; 189, 190; 199, 200; 209, 210; 219, 220; 229, 230; 239, 240; 249, 250; 259, 260; 269, 270; 279, 280; 289, 290; 299, 300; 309, 310; 319, 320; 329, 330; 339, 340; 349, 350; 359, 360; 369, 370; 379, 380; 389, 390; 399, 400; 409, 410; 419, 420; 429, 430; 439, 440; 449, 450; 459, 460; 469, 470; 479, 480; 489, 490; or 499, 500.

4. The antibody of any one of claims 1 to 3, wherein the antibody is a monoclonal antibody.

5. The antibody of any one of claims 1 to 3, wherein the antibody is a full-length antibody.

6. The antibody of any one of claims 1 to 3, wherein the antibody is an antibody fragment selected from F(ab’)2, Fab, Fab’, Fv, or scFv.

7. The antibody fragment of claim 6, wherein the antibody comprises an Fc domain selected from one of the following: human IgGl, human IgG2, human IgG3, and human IgG4.

8. A method of treating a disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody of any one of claims 1-7.

9. A single chain fragment variable (scFv) Activin E antagonist comprising:a heavy chain variable domain (VH) complementarity determining region 1 (CDR1), VH CDR2, and VH CDR3 comprising an amino acid sequence of any one of the following SEQ ID NOs: 1, 2, 3; 11, 12, 13; 21, 22, 23; 31, 32, 33; 41, 42, 43; 51, 52, 53; 61, 62, 63; 71, 72, 73; 81, 82, 83; 91, 92, 93; 101, 102, 103; 111, 112, 113; 121, 122, 123; 131, 132, 133; 141, 142, 143; 151, 152, 153; 161, 162, 163; 171, 172, 173; 181, 182, 183; 191, 192, 193; 201, 202, 203; 211, 212, 213; 221, 222, 223; 231, 232, 233; 241, 242, 243; 251, 252, 253; 261, 262, 263; 271, 272, 273; 281, 282, 283; 291, 292, 293; 301, 302, 303; 311, 312, 313; 321, 322, 323; 331, 332, 333; 341, 342, 343; 351, 352, 353; 361, 362, 363; 371, 372, 373; 381, 382, 383; 391, 392, 393; 401, 402, 403; 411, 412, 413; 421, 422, 423; 431, 432, 433; 441, 442, 443; 451, 452, 453; 461, 462, 463; 471, 472, 473; 481, 482, 483; or 491, 492, 493; anda light chain variable domain (VL) CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of any one of the following SEQ ID NOs: 4, 5, 6; 14, 15, 16; 24, 25, 26; 34, 35, 36; 44, 45, 46; 54, 55, 56; 64, 65, 66; 74, 75, 76; 84, 85, 86; 94, 95, 96; 104, 105, 106; 114, 115, 116; 124, 125, 126; 134, 135, 136; 144, 145, 146; 154, 155, 156; 164, 165, 166; 174, 175, 176; 184, 185, 186; 194, 195, 196; 204, 205, 206; 214, 215, 216; 224, 225, 226; 234, 235, 236; 244, 245, 246; 254, 255, 256; 264, 265, 266; 274, 275, 276; 284, 285, 286; 294, 295, 296; 304, 305, 306; 314, 315, 316; 324, 325, 326; 334, 335, 336; 344, 345, 346; 354, 355, 356; 364, 365, 366; 374, 375, 376; 384, 385, 386; 394, 395, 396; 404, 405, 406; 414, 415, 416; 424, 425, 426; 434, 435, 436; 444, 445, 446; 454, 455, 456; 464, 465, 466; 474, 475, 476; 484, 485, 486; or 494, 495, 496, respectively.

10. The scFv of claim 9, wherein the scFv comprises at least 95, 96, 97, 98, 99, or 100% amino acid sequence identify to: 501; 503; 505; 507; 509; 511; 513; 515; 517; 519; 521; 523; 525; 527; 529; 531; 533; 535; 537; 539; 541; 543; 545; 547; 549; 551; 553; 555; 557; 559; 561; 563; 565; 567; 569; 571; 573; 575; 577; 579; 581; 583; 585; 587; 589; 591; 593; 595; 597; or 599.

11. The scFv of claim 9, wherein the scFv comprises at least 95, 96, 97, 98, 99, or 100% nucleic sequence identify to: 502; 504; 506; 508; 510; 512; 514; 516; 518; 520; 522; 524; 526; 528; 530; 532; 534; 536; 538; 540; 542; 544; 546; 548; 550; 552; 554; 556; 558; 560; 562; 564; 566; 568; 570; 572; 574; 576; 578; 580; 582; 584; 586; 588; 590; 592; 594; 596; 598; or 600.

12. The scFv of claim 9, wherein the scFv is a tandem scFv.

13. A method of treating a disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody of any one of claims 1-12.

14. The method of claim 13, where the disease is selected from at least one of: a metabolic disorder, type 2 diabetes, obesity, an elevated triglyceride level, lipodystrophy, liver inflammation, fatty liverdisease, hypercholesterolemia, an elevated liver enzyme, nonalcoholic steatohepatitis (NASH), a cardiovascular disease, cardiomyopathy, high blood pressure, or heart failure.

15. The method of claim 13 or claim 14, wherein the subject is human.

16. A nucleic acid comprising an anti-Activin E antibody or antigen binding domain thereof, comprising:a heavy chain variable domain (VH) complementarity determining region 1 (CDR1), VH CDR2, and VH CDR3 comprising an amino acid sequence of any one of the following SEQ ID NOs: 1, 2, 3; 11, 12, 13; 21, 22, 23; 31, 32, 33; 41, 42, 43; 51, 52, 53; 61, 62, 63; 71, 72, 73; 81, 82, 83; 91, 92, 93; 101, 102, 103; 111, 112, 113; 121, 122, 123; 131, 132, 133; 141, 142, 143; 151, 152, 153; 161, 162, 163; 171, 172, 173; 181, 182, 183; 191, 192, 193; 201, 202, 203; 211, 212, 213; 221, 222, 223; 231, 232, 233; 241, 242, 243; 251, 252, 253; 261, 262, 263; 271, 272, 273; 281, 282, 283; 291, 292, 293; 301, 302, 303; 311, 312, 313; 321, 322, 323; 331, 332, 333; 341, 342, 343; 351, 352, 353; 361, 362, 363; 371, 372, 373; 381, 382, 383; 391, 392, 393; 401, 402, 403; 411, 412, 413; 421, 422, 423; 431, 432, 433; 441, 442, 443; 451, 452, 453; 461, 462, 463; 471, 472, 473; 481, 482, 483; or 491, 492, 493; anda light chain variable domain (VL) CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of any one of the following SEQ ID NOs: 4, 5, 6; 14, 15, 16; 24, 25, 26; 34, 35, 36; 44, 45, 46; 54, 55, 56; 64, 65, 66; 74, 75, 76; 84, 85, 86; 94, 95, 96; 104, 105, 106; 114, 115, 116; 124, 125, 126; 134, 135, 136; 144, 145, 146; 154, 155, 156; 164, 165, 166; 174, 175, 176; 184, 185, 186; 194, 195, 196; 204, 205, 206; 214, 215, 216; 224, 225, 226; 234, 235, 236; 244, 245, 246; 254, 255, 256; 264, 265, 266; 274, 275, 276; 284, 285, 286; 294, 295, 296; 304, 305, 306; 314, 315, 316; 324, 325, 326; 334, 335, 336; 344, 345, 346; 354, 355, 356; 364, 365, 366; 374, 375, 376; 384, 385, 386; 394, 395, 396; 404, 405, 406; 414, 415, 416; 424, 425, 426; 434, 435, 436; 444, 445, 446; 454, 455, 456; 464, 465, 466; 474, 475, 476; 484, 485, 486; or 494, 495, 496, respectively.

17. The nucleic acid of claim 16, wherein the antibody or antigen binding domain thereof comprises a heavy chain and light chain variable domain encoding polynucleotide having at least 95, 96, 97, 98, 99, or 100% sequence identify to SEQ ID NOS: 9, 10; 19, 20; 29, 30; 39, 40; 49, 50; 59, 60; 69, 70; 79, 80; 89, 90; 99, 100; 109, 110; 119, 120; 129, 130; 139, 140; 149, 150; 159, 160; 169, 170; 179, 180; 189, 190; 199, 200; 209, 210; 219, 220; 229, 230; 239, 240; 249, 250; 259, 260; 269, 270; 279, 280; 289, 290; 299, 300; 309, 310; 319, 320; 329, 330; 339, 340; 349, 350; 359, 360; 369, 370; 379, 380; 389, 390; 399, 400; 409, 410; 419, 420; 429, 430; 439, 440; 449, 450; 459, 460; 469, 470; 479, 480; 489, 490; 499, 500; or 601, 602.

18. The nucleic acid of claim 16, wherein the antibody is a monoclonal, bispecific, multivalent, multi-specific, diabody, chimeric, scFv antibody, or domain thereof.

19. The nucleic acid of claim 18, wherein the scFv encodes a polypeptide that comprises at least 95, 96, 97, 98, 99, or 100% amino acid sequence identify to: 501; 503; 505; 507; 509; 511; 513; 515; 517; 519; 521; 523; 525; 527; 529; 531; 533; 535; 537; 539; 541; 543; 545; 547; 549; 551; 553; 555; 557; 559; 561; 563; 565; 567; 569; 571; 573; 575; 577; 579; 581; 583; 585; 587; 589; 591; 593; 595; 597; or 599.

20. The nucleic acid of claim 18, wherein the scFv comprises at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% nucleic sequence identify to: 502; 504; 506; 508; 510; 512; 514; 516; 518; 520; 522; 524; 526; 528; 530; 532; 534; 536; 538; 540; 542; 544; 546; 548; 550; 552; 554; 556; 558; 560; 562; 564; 566; 568; 570; 572; 574; 576; 578; 580; 582; 584; 586; 588; 590; 592; 594; 596; 598; or 600.

21. The nucleic acid of claim 16, wherein an antibody binding domain is fused to an Fc domain of any one of the following: human IgGl, human IgG2, human IgG3, and human IgG4.

22. The nucleic acid of any one of claims 16 to 21, wherein the nucleic acid sequence is optimized for expression in a bacterial, fungal, mammalian, insect, or plant cell.

23. A vector comprising the nucleic acid of claim 16.

24. A host cell comprising nucleic acid the vector of claim 23.

25. A method of treating a subject having or at risk of developing a metabolic disorder, type 2 diabetes, obesity, an elevated triglyceride level, lipodystrophy, liver inflammation, fatty liver disease, hypercholesterolemia, an elevated liver enzyme, nonalcoholic steatohepatitis (NASH), a cardiovascular disease, cardiomyopathy, high blood pressure, and / or heart failure, the method comprising administering an anti-Inhibin E antibody administering an antibody, scFv, or antigen binding domain thereof of any one of claims 1 to 8 or any the nucleic acid of one of claims 16 to 22 to the subject.

26. The method of claim 25, wherein the anti-Activin antibody or binding domain thereof comprises a variable heavy chain and light chain nucleic acid sequence having at least 95, 96, 97, 98, 99, or 100% sequence identify to SEQ ID NOS: 9, 10; 19, 20; 29, 30; 39, 40; 49, 50; 59, 60; 69, 70; 79, 80; 89, 90; 99, 100; 109, 110; 119, 120; 129, 130; 139, 140; 149, 150; 159, 160; 169, 170; 179, 180; 189, 190; 199, 200; 209, 210; 219, 220; 229, 230; 239, 240; 249, 250; 259, 260; 269, 270; 279, 280; 289, 290; 299, 300; 309, 310; 319, 320; 329, 330; 339, 340; 349, 350; 359, 360; 369, 370; 379, 380; 389, 390; 399, 400; 409, 410; 419, 420; 429, 430; 439, 440; 449, 450; 459, 460; 469, 470; 479, 480; 489, 490; 499, 500; or 601, 602.

27. The method of claim 25, wherein the anti-Activin antibody or binding domain thereof comprises an scFv comprising at least 95, 96, 97, 98, 99, or 100% amino acid sequence identify to: 501; 503; 505; 507; 509; 511; 513; 515; 517; 519; 521; 523; 525; 527; 529; 531; 533; 535; 537; 539; 541; 543; 545; 547; 549; 551; 553; 555; 557; 559; 561; 563; 565; 567; 569; 571; 573; 575; 577; 579; 581; 583; 585; 587; 589; 591; 593; 595; 597; or 599.

28. The method of any one of claims 25 to 27, wherein when the subject is administered a therapeutic agent that treats or inhibits metabolic disorders or cardiovascular diseases in a standard dosage amount.

29. The method of any one of claims 25 to 28, wherein when the subject is administered a therapeutic agent that treats or inhibits metabolic disorders or cardiovascular diseases that is the same as or lower than a standard dosage amount.

30. A method of treating a subject with a therapeutic agent that treats or inhibits a metabolic disorder, type 2 diabetes, obesity, an elevated triglyceride level, lipodystrophy, liver inflammation, fatty liver disease, hypercholesterolemia, an elevated liver enzyme, nonalcoholic steatohepatitis (NASH), a cardiovascular disease, cardiomyopathy, high blood pressure, or heart failure, the method comprisingadministering an antibody or antigen binding domain thereof any one of claims 1 to 8, or any the nucleic acid of one of claims 16 to 22 to the subject.

31. The method of claim 30, wherein the subject is administered or continued to be administered a therapeutic agent that treats or inhibits the metabolic disorder, type 2 diabetes, obesity, an elevated triglyceride level, lipodystrophy, liver inflammation, fatty liver disease, hypercholesterolemia, an elevated liver enzyme, nonalcoholic steatohepatitis (NASH), a cardiovascular disease, cardiomyopathy, high blood pressure, or heart failure in a standard dosage amount; or the subject is administered or continued to be administered the therapeutic agent that treats or inhibits the metabolic disorder, type 2 diabetes, obesity, an elevated triglyceride level, lipodystrophy, liver inflammation, fatty liver disease, hypercholesterolemia, an elevated liver enzyme, nonalcoholic steatohepatitis (NASH), a cardiovascular disease, cardiomyopathy, high blood pressure, or heart failure in an amount that is the same as or lower than a standard dosage amount.

32. The method of claim 30 or claim 31, wherein the metabolic disorder is selected from at least one of:type 2 diabetes, and the therapeutic agent is chosen from metformin, insulin, glyburide, glipizide, glimepiride, repaglinide, nateglinide, thiazolidinediones, rosiglitazone, pioglitazone, sitagliptin, saxagliptin, linagliptin, exenatide, liraglutide, semaglutide, canagliflozin, dapagliflozin, and empagliflozin, or any combination thereof;obesity, and the therapeutic agent is chosen from orlistat, phentermine, topiramate, bupropion, naltrexone, and liraglutide, or any combination thereof:elevated triglyceride, and the therapeutic agent is chosen from rosuvastatin, simvastatin, atorvastatin, fenofibrate, gemfibrozil, fenofibric acid, niacin, and an omega-3 fatty acid, or any combination thereof, lipodystrophy, and the therapeutic agent is chosen from tesamorelin, metformin, poly-L-lactic acid, calcium hydroxyapatite, polymethylmethacrylate, bovine collagens, human collagens, silicone, and hyaluronic acid, or any combination thereof;liver inflammation, and the therapeutic agent is a hepatitis therapeutic or a hepatitis vaccine;fatty liver disease include, and the subject is administered bariatric surgery and / or dietary intervention; hypercholesterolemia, and the therapeutic agent is chosen from: atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin calcium, simvastatin, cholestyramine, colesevelam, and colestipol, alirocumab, evolocumab, niaspan, niacor, fenofibrate, gemfibrozil, and bempedoic, or any combination thereof;an elevated liver enzyme, and the therapeutic agent is chosen from coffee, folic acid, potassium, vitamin B6, a statin, and fiber, or any combination thereof; ornonalcoholic steatohepatitis (NASH) and the therapeutic agent is obeticholic acid, Selonsertib, Elafibranor, Cenicriviroc, GR MD 02, MGL 3196, IMM124E, arachidyl amido cholanoic acid, GS0976, Emricasan, Volixibat, NGM282, GS9674, Tropifexor, MN 001, LMB763, BI 1467335, MSDC 0602, PF 05221304, DF102, Saroglitazar, BMS986036, Lanifibranor, Semaglutide, Nitazoxanide, GRI 0621, EYP001, VK2809, Nalmefene, LIK066, MT 3995, Elobixibat, Namodenoson, Foralumab, SAR425899,Sotagliflozin, EDP 305, Isosabutate, Gemcabene, TERN 101, KBP 042, PF 06865571, DUR928, PF 06835919, NGM313, BMS 986171, Namacizumab, CER 209, ND L02 s0201, RTU 1096, DRX 065, IGNIS DGAT2Rx, INT 767, NC 001, Seladepar, PXL770, TERN 201, NV556, AZD2693, SP 1373, VK0214, Hepastem, TGFTX4, RLBN1127, GKT 137831, RYI 018, CB4209-CB4211, and JH 0920.

33. The method of claim 30, wherein the cardiovascular disease is selected from at least one of: high blood pressure, and the therapeutic agent is chosen from chlorthalidone, chlorothiazide, hydrochlorothiazide, indapamide, metolazone, acebutolol, atenolol, betaxolol, bisoprolol fumarate, carteolol hydrochloride, metoprolol tartrate, metoprolol succinate, nadolol, benazepril hydrochloride, captopril, enalapril maleate, fosinopril sodium, lisinopril, moexipril, perindopril, quinapril hydrochloride, ramipril, trandolapril, candesartan, eprosartan mesylate, irbesartan, losartan potassium, telmisartan, valsartan, amlodipine besylate, bepridil, diltiazem hydrochloride, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, verapamil hydrochloride, doxazosin mesylate, prazosin hydrochloride, terazosin hydrochloride, methyldopa, carvedilol labetalol hydrochloride, alpha methyldopa, clonidine hydrochloride, guanabenz acetate, guanfacine hydrochloride, guanadrel, guanethidine monosulfate, reserpine, hydralazine hydrochloride, and minoxidil, or any combination thereof;cardiomyopathy, and the therapeutic agent is an ACE inhibitor, an angiotensin II receptor blocker, a beta blocker, a calcium channel blocker, digoxin, an antiarrhythmic, an aldosterone blocker, a diuretic, an anticoagulant, a blood thinner, and a corticosteroid; orheart failure, and the therapeutic agent is an ACE inhibitor, an angiotensin-2 receptor blocker, a beta blocker, a mineralocorticoid receptor antagonist, a diuretic, ivabradine, sacubitril valsartan, hydralazine with nitrate, and digoxin.

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