Methods of treating nausea and vomiting disorders using anti-GFRAL antibodies

Abstract

The present disclosure relates generally to methods of treating, preventing, or reducing nausea, vomiting, or a combination thereof, hyperemesis gravidarum (HG), nausea gravidarum and vomiting (NVP), or sequelae thereof in a human subject in need thereof, the methods comprise administering to the human subject a therapeutically effective amount of an antibody that specifically binds to a human glial cell line derived neurotrophic factor family receptor alpha-like (GFRAL).

Description

Cross-references to related applications

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 516,724, filed July 31, 2023, the contents of which are incorporated herein by reference in their entirety.

[0002] sequence list This application includes a sequence list submitted electronically in XML format and hereby incorporated herein by reference in its entirety. The XML copy was created on July 26, 2024, named 47702-0116WO1_SL.xml, and is 848,585 bytes in size.

[0003] I. Technical Field This disclosure generally relates to methods for treating, preventing, or reducing nausea, vomiting, or a combination thereof, hyperemesis gravidarum (HG), nausea and vomiting during pregnancy (NVP), or their sequelae, in human subjects in need, said methods comprising administering to said human subject a therapeutically effective amount of an antibody that specifically binds to human glial cell line-derived neurotrophic factor family receptor α-like (GFRAL).

[0004] II. Background Technology Growth differentiation factor 15 (GDF15) is a protein belonging to the transforming growth factor β (TGF-β) superfamily. GDF15 is also known as TGF-PL, MIC-1, PDF, PLAB, NAG-1, and PTGFB. GDF15 mRNA has been reported to be most abundant in the liver, with lower levels observed in some other tissues. Its expression in the liver can be significantly upregulated in damage to organs such as the liver, kidneys, heart, and lungs. GDF15 is also upregulated during pregnancy and produced in the placenta.

[0005] GDF15 has been reported to play a role in regulating inflammatory and apoptotic pathways in damaged tissues and during disease processes, including nausea and vomiting.

[0006] There is an urgent need for effective treatments for nausea and vomiting during pregnancy (NVP), hyperemesis gravidarum (HG), and other vomiting disorders.

[0007] III. Summary of the Invention This article provides a method for treating HG in human subjects in need, the method comprising administering a therapeutically effective amount of an antibody that specifically binds to human GFRAL to the human subject.

[0008] This article also provides a method for treating NVP in human subjects in need, the method comprising administering to the human subject a therapeutically effective amount of an antibody that specifically binds to human GFRAL. In some cases, NVP is mild. In other cases, NVP is moderate. In still other cases, NVP is severe.

[0009] This article also provides a method for treating nausea and / or vomiting in human subjects in need, the method comprising administering to the human subject a therapeutically effective amount of an antibody that specifically binds to human GDNF family receptor α-like (GFRAL).

[0010] This article also provides a method for reducing nausea and / or vomiting in human subjects in need, the method comprising administering to the human subject a therapeutically effective amount of an antibody that specifically binds to human GDNF family receptor α-like (GFRAL).

[0011] In some cases, administration is subcutaneous. In some cases, administration is intravenous. In some cases, the above methods include administration of one or more of the following: doxylamine, pyridoxine, ondansetron, dopamine antagonists (e.g., metoclopramide, promethazine), diphenhydramine, droperidol, methylprednisolone, mirtazapine, steroid therapy, antiemetics, vitamin B1, folic acid, vitamin K, vitamin D, magnesium, and ginger. In some cases, the above methods also include prior therapy, which includes administering one or more of the following to a human subject: dolamine, pyridoxine, ondansetron, dopamine antagonists (e.g., metoclopramide, promethazine), diphenhydramine, fluphenazine, methylprednisolone, mirtazapine, steroid therapy, antiemetics, vitamin B1, folic acid, vitamin K, vitamin D, magnesium, and ginger. In some cases, the human subject does not respond to prior therapy.

[0012] In some cases, the therapeutically effective dose of the antibody is approximately 100 mg, optionally wherein the therapeutically effective dose of the antibody is 100 mg.

[0013] In other cases, the therapeutically effective dose of the antibody is approximately 75 mg, optionally wherein the therapeutically effective dose of the antibody is 75 mg. In some cases, the therapeutically effective dose of the antibody is administered to a human subject only once (single dose). In other cases, the therapeutically effective dose of the antibody is administered twice or as needed to obtain a clinically beneficial effect in the patient. In some cases, the therapeutically effective dose of the antibody is administered subcutaneously. In other cases, the therapeutically effective dose of the antibody is administered intravenously.

[0014] In some cases, the therapeutically effective dose of the antibody is approximately 30 mg, optionally where the therapeutically effective dose of the antibody is 30 mg.

[0015] In some cases, the therapeutically effective dose of the antibody is approximately 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 180 mg, or 200 mg or more. In other cases, the therapeutically effective dose of the antibody is 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 180 mg, or 200 mg. In some cases, a therapeutically effective dose of antibody is administered once or as needed to achieve a clinically beneficial effect in the patient. In other cases, a therapeutically effective dose of antibody is administered via subcutaneous or intravenous injection.

[0016] In some cases, the method includes administering a therapeutically effective amount of antibody to a human subject in more than one dose (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 doses). Optionally, the therapeutically effective amount of antibody is administered as needed to obtain a clinically beneficial effect in the patient.

[0017] In some cases, the method involves administering more than one dose of the antibody to a human subject, wherein each dose is administered at intervals of about one week, two weeks, three weeks, four weeks, five weeks, six weeks or longer, or as needed (i.e., variable intervals), to obtain a clinically beneficial effect in the patient.

[0018] In some cases, the method is used to treat subjects diagnosed with HG, and a therapeutically effective amount of antibody is administered only once during pregnancy. In other cases, a therapeutically effective amount of antibody is administered two or three times during pregnancy, with intervals between administrations of approximately one, two, three, four, five, six, seven, eight weeks, or longer. Optionally, a therapeutically effective amount of antibody is administered as needed to obtain a clinically beneficial effect in the patient.

[0019] In some cases, biological samples obtained from human subjects showed elevated levels of GDF15 compared to control levels in control biological samples obtained from one or more humans who did not experience nausea and vomiting during pregnancy, hyperemesis gravidarum, nausea, or vomiting. In some cases, the biological samples were serum, plasma, or blood.

[0020] In some cases, antibodies inhibit the binding of human GFRAL to human RET.

[0021] In some cases, antibodies do not inhibit the binding of human GDF15 to human GFRAL.

[0022] In some cases, the antibody inhibits the binding of human GFRAL to human RET but does not inhibit the binding of human GDF15 to human GFRAL.

[0023] In some cases, antibodies inhibit the binding of human GDF15 to human GFRAL.

[0024] In some cases, the antibody specifically binds to amino acid residues 220-316 of the amino acid sequence shown in SEQ ID NO: 1797. In some cases, the antibody inhibits the binding of human RET to human GFRAL. In some cases, the antibody does not inhibit the binding of human GDF15 to human GFRAL. In some cases, the antibody inhibits the binding of human RET to human GFRAL and does not inhibit the binding of human GDF15 to human GFRAL.

[0025] In some cases, the antibody specifically binds to one or more residues selected from the group consisting of: Met214, Pro216, Pro217, Gln290, Cys291, Thr292, Cys293, Arg294, Thr295, Ile296, Thr297, Gln298, Ser299, Glu301, Lys305, Gln308, His309, His312, and Ser315 of the amino acid sequence shown in SEQ ID NO: 1797. In some cases, the antibody inhibits the binding of human RET to human GFRAL. In some cases, the antibody does not inhibit the binding of human GDF15 to human GFRAL. In some cases, the antibody inhibits the binding of human RET to human GFRAL and does not inhibit the binding of human GDF15 to human GFRAL.

[0026] In some cases, the antibody specifically binds to Thr297, Gln298, and Ser299 of the amino acid sequence shown in SEQ ID NO:1797.

[0027] In some cases, the antibody binds to GFRAL and contains a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH contains VH complementarity-determining regions (CDRs)1, VH CDR2, and VHCDR3 from the amino acid sequence shown in SEQ ID NO:1982, and the VL contains VL CDR1, VL CDR2, and VLCDR3 from the amino acid sequence shown in SEQ ID NO:1997.

[0028] In some cases, the antibody binds to GFRAL and contains VH and VL, wherein VH contains VH CDR1, VH CDR2, and VHCDR3, and VL contains VL CDR1, VL CDR2, and VL CDR3, wherein VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 contain or are composed of the amino acid sequences shown in SEQ ID NO:46, SEQ ID NO:137, SEQ ID NO:225, SEQ ID NO:301, SEQ ID NO:376, and SEQ ID NO:426, respectively.

[0029] In some cases, the antibody binds to GFRAL and contains VH and VL, wherein VH contains VH CDR1, VH CDR2, and VHCDR3, and VL contains VL CDR1, VL CDR2, and VL CDR3, wherein VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 contain or are composed of the amino acid sequences shown in SEQ ID NO:47, SEQ ID NO:138, SEQ ID NO:226, SEQ ID NO:302, SEQ ID NO:377, and SEQ ID NO:426, respectively.

[0030] In some cases, the antibody binds to GFRAL and contains VH and VL, wherein VH contains VH CDR1, VH CDR2, and VHCDR3, and VL contains VL CDR1, VL CDR2, and VL CDR3, wherein VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 contain or are composed of the amino acid sequences shown in SEQ ID NO:48, SEQ ID NO:137, SEQ ID NO:225, SEQ ID NO:301, SEQ ID NO:376, and SEQ ID NO:426, respectively.

[0031] In some cases, the antibody binds to GFRAL and contains VH and VL, wherein VH contains VH CDR1, VH CDR2 and VHCDR3, and VL contains VL CDR1, VL CDR2 and VL CDR3, wherein VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 contain or are composed of the amino acid sequences shown in SEQ ID NO:49, SEQ ID NO:139, SEQ ID NO:227, SEQ ID NO:303, SEQ ID NO:377 and SEQ ID NO:427, respectively.

[0032] In some cases, the antibody binds to GFRAL and contains VH and VL, wherein VH contains VH CDR1, VH CDR2, and VHCDR3, and VL contains VL CDR1, VL CDR2, and VL CDR3, wherein VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 contain or are composed of the amino acid sequences shown in SEQ ID NO:50, SEQ ID NO:140, SEQ ID NO:228, SEQ ID NO:304, SEQ ID NO:378, and SEQ ID NO:428, respectively.

[0033] In some cases, the antibody binds to GFRAL and contains VH and VL, wherein VH contains VH CDR1, VH CDR2 and VHCDR3, and VL contains VL CDR1, VL CDR2 and VL CDR3, wherein VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 contain or are composed of the amino acid sequences shown in SEQ ID NO:46, SEQ ID NO:141, SEQ ID NO:225, SEQ ID NO:301, SEQ ID NO:376 and SEQ ID NO:426, respectively.

[0034] In some cases, the antibody binds to GFRAL and comprises VH and VL, wherein VH comprises or consists of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the amino acid sequence shown in any of SEQ ID NO:1978-1988.

[0035] In some cases, the antibody binds to GFRAL and comprises VH and VL, wherein VL comprises or consists of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the amino acid sequence shown in any of SEQ ID NO:1990-2000.

[0036] In some cases, the antibody binds to GFRAL and comprises VH and VL, wherein VH comprises or consists of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the amino acid sequence shown in any one of SEQ ID NO:1978-1988, and VL comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the amino acid sequence shown in any one of SEQ ID NO:1990-2000.

[0037] In some cases, the antibody comprises VH and VL, wherein VH comprises or consists of the amino acid sequence shown in any of SEQ ID NO: 1978-1988.

[0038] In some cases, the antibody comprises VH and VL, wherein VL comprises or consists of the amino acid sequence shown in any of SEQ ID NO:1990-2000.

[0039] In some cases, the antibody binds to GFRAL and comprises VH and VL, wherein VH comprises or is composed of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the amino acid sequence shown in SEQ ID NO:1982.

[0040] In some cases, the antibody binds to GFRAL and comprises VH and VL, wherein VL comprises or is composed of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the amino acid sequence shown in SEQ ID NO:1997. In some cases, the antibody comprises VH and VL, wherein VL comprises or is composed of the amino acid sequence shown in SEQ ID NO:1997.

[0041] In some cases, the antibody binds to GFRAL and comprises VH and VL, wherein VH comprises or consists of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence shown in SEQ ID NO:3.

[0042] In some cases, the antibody binds to GFRAL and comprises VH and VL, wherein VL comprises or consists of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence shown in SEQ ID NO:4.

[0043] In some cases, the antibody binds to GFRAL and comprises VH and VL, wherein VH comprises or consists of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence shown in SEQ ID NO:3, and VL comprises or consists of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence shown in SEQ ID NO:4.

[0044] In some cases, the antibody contains VH and VL, wherein VH contains or is composed of the amino acid sequence shown in SEQ ID NO:3.

[0045] In some cases, the antibody comprises VH and VL, wherein VL comprises or is composed of the amino acid sequence shown in SEQ ID NO:4.

[0046] In some cases, the antibody comprises VH and VL, wherein VH comprises or is composed of the amino acid sequence shown in SEQ ID NO:3, and VL comprises the amino acid sequence shown in SEQ ID NO:4.

[0047] In some cases, the antibody comprises VH and VL, wherein VH comprises or consists of the amino acid sequence shown in SEQ ID NO:1982, and VL comprises or consists of the amino acid sequence shown in SEQ ID NO:1997.

[0048] In some cases, the antibody binds to GFRAL and comprises VH and VL, wherein VH comprises VH CDR1, VH CDR2 and VH CDR3 of the amino acid sequences shown in any one of SEQ ID NO:7 and 1957-1965, and VL comprises VL CDR1, VL CDR2 and VLCDR3 of the amino acid sequences shown in any one of SEQ ID NO:8 and 1967-1976. In some cases, the antibody comprises VH and VL, wherein VH comprises VH CDR1, VH CDR2, and VH CDR3, and VL comprises VL CDR1, VL CDR2, and VL CDR3, wherein VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VLCDR3 comprise or consist of the amino acid sequences shown below: (i) respectively, SEQ ID NO: 56, SEQ ID NO: 147, SEQ ID NO: 233, SEQ ID NO: 309, SEQ ID NO: 382, ​​and SEQ ID NO: 432; (ii) respectively, SEQ ID NO: 57, SEQ ID NO: 148, SEQ ID NO: 234, SEQ ID NO: 310, SEQ ID NO: 383, and SEQ ID NO: 432; (iii) respectively, SEQ ID NO: 58, SEQ ID NO: 147, SEQ ID NO: 148, SEQ ID NO: 234, SEQ ID NO: 310, SEQ ID NO: 383, and SEQ ID NO: 432. 233, SEQ ID NO: 309, SEQ ID NO: 382 and SEQ ID NO: 432; (iv) respectively, SEQ ID NO: 49, SEQ ID NO: 149, SEQ ID NO: 235, SEQ ID NO: 311, SEQ ID NO: 383 and SEQ ID NO: 433; (v) respectively, SEQ ID NO: 59, SEQ ID NO: 150, SEQ ID NO: 236, SEQ ID NO: 312, SEQ ID NO: 384 and SEQ ID NO: 434; or (vi) respectively, SEQ ID NO: 56, SEQ ID NO: 151, SEQ ID NO: 233, SEQ ID NO: 309, SEQ ID NO: 382 and SEQ ID NO: 432.In some cases, VH comprises or consists of an amino acid sequence having at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with the amino acid sequence shown in any one of SEQ ID NO:7 and 1957-1965, and VL comprises or consists of an amino acid sequence having at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with the amino acid sequence shown in any one of SEQ ID NO:8 and 1967-1976. In some cases, VH comprises or consists of an amino acid sequence from any one of SEQ ID NO:7 and 1957-1965, and VL comprises or consists of an amino acid sequence from any one of SEQ ID NO:8 and 1967-1976.

[0049] In some cases, the antibody binds to GFRAL and contains VH and VL, wherein VH contains VH CDR1, VH CDR2 and VH CDR3 from the amino acid sequence shown in SEQ ID NO:21, and VL contains VL CDR1, VL CDR2 and VL CDR3 from the amino acid sequence shown in SEQ ID NO:22. In some cases, the antibody comprises VH and VL, wherein VH comprises VHCDR1, VH CDR2, and VH CDR3, and VL comprises VL CDR1, VL CDR2, and VL CDR3, wherein VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise or consist of the amino acid sequences shown below: (i) respectively, SEQ ID NO: 86, SEQ ID NO: 177, SEQ ID NO: 261, SEQ ID NO: 337, SEQ ID NO: 401, and SEQ ID NO: 453; (ii) respectively, SEQ ID NO: 87, SEQ ID NO: 178, SEQ ID NO: 262, SEQ ID NO: 338, SEQ ID NO: 386, and SEQ ID NO: 453; (iii) respectively, SEQ ID NO: 88, SEQ ID NO: 179, SEQ ID NO: 179, SEQ ID NO: 170 ... (iv) SEQ ID NO: 261, SEQ ID NO: 337, SEQ ID NO: 401 and SEQ ID NO: 453 respectively; (v) SEQ ID NO: 89, SEQ ID NO: 168, SEQ ID NO: 263, SEQ ID NO: 339, SEQ ID NO: 386 and SEQ ID NO: 454 respectively; (v) SEQ ID NO: 90, SEQ ID NO: 180, SEQ ID NO: 264, SEQ ID NO: 340, SEQ ID NO: 402 and SEQ ID NO: 455 respectively; or (vi) SEQ ID NO: 86, SEQ ID NO: 181, SEQ ID NO: 261, SEQ ID NO: 337, SEQ ID NO: 401 and SEQ ID NO: 453 respectively. In some cases, VH contains or is composed of an amino acid sequence having at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with the amino acid sequence shown in SEQ ID NO:21, and VL contains or is composed of an amino acid sequence having at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with the amino acid sequence shown in SEQ ID NO:22.In some cases, VH contains the amino acid sequence of SEQ ID NO:21, or a composition thereof, and VL contains or is composed of the amino acid sequence of SEQ ID NO:22.

[0050] In some cases, the antibody binds to GFRAL and contains VH and VL, wherein VH contains VH CDR1, VH CDR2 and VH CDR3 from the amino acid sequence shown in SEQ ID NO:23, and VL contains VL CDR1, VL CDR2 and VL CDR3 from the amino acid sequence shown in SEQ ID NO:24. In some cases, the antibody comprises VH and VL, wherein VH comprises VHCDR1, VH CDR2, and VH CDR3, and VL comprises VL CDR1, VL CDR2, and VL CDR3, wherein VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise or consist of the amino acid sequences shown below: (i) respectively, SEQ ID NO: 91, SEQ ID NO: 182, SEQ ID NO: 265, SEQ ID NO: 341, SEQ ID NO: 385, and SEQ ID NO: 456; (ii) respectively, SEQ ID NO: 92, SEQ ID NO: 183, SEQ ID NO: 266, SEQ ID NO: 342, SEQ ID NO: 386, and SEQ ID NO: 456; (iii) respectively, SEQ ID NO: 93, SEQ ID NO: 182, SEQ ID NO: 456, SEQ ID NO: 941, SEQ ID NO: 385, and SEQ ID NO: 456. (iv) SEQ ID NO: 265, SEQ ID NO: 341, SEQ ID NO: 385 and SEQ ID NO: 456 respectively; (v) SEQ ID NO: 75, SEQ ID NO: 184, SEQ ID NO: 267, SEQ ID NO: 343, SEQ ID NO: 386 and SEQ ID NO: 457 respectively; (v) SEQ ID NO: 94, SEQ ID NO: 185, SEQ ID NO: 268, SEQ ID NO: 344, SEQ ID NO: 403 and SEQ ID NO: 458 respectively; or (vi) SEQ ID NO: 91, SEQ ID NO: 186, SEQ ID NO: 265, SEQ ID NO: 341, SEQ ID NO: 385 and SEQ ID NO: 456 respectively. In some cases, VH contains or is composed of an amino acid sequence having at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with the amino acid sequence shown in SEQ ID NO:23, and VL contains or is composed of an amino acid sequence having at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with the amino acid sequence shown in SEQ ID NO:24.In some cases, VH contains the amino acid sequence of SEQ ID NO: 23, or a composition thereof, and VL contains or is composed of the amino acid sequence of SEQ ID NO: 24.

[0051] In some cases, the antibody binds to GFRAL and comprises VH and VL, wherein VH comprises VH CDR1, VH CDR2 and VH CDR3 from the amino acid sequence shown in SEQ ID NO:25, and VL comprises VL CDR1, VL CDR2 and VL CDR3 from the amino acid sequence shown in SEQ ID NO:26. In some cases, the antibody comprises VH and VL, wherein VH comprises VHCDR1, VH CDR2, and VH CDR3, and VL comprises VL CDR1, VL CDR2, and VL CDR3, wherein VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise or consist of the amino acid sequences shown below: (i) respectively, SEQ ID NO: 95, SEQ ID NO: 187, SEQ ID NO: 269, SEQ ID NO: 345, SEQ ID NO: 404, and SEQ ID NO: 459; (ii) respectively, SEQ ID NO: 96, SEQ ID NO: 188, SEQ ID NO: 270, SEQ ID NO: 346, SEQ ID NO: 405, and SEQ ID NO: 459; (iii) respectively, SEQ ID NO: 97, SEQ ID NO: 187, SEQ ID NO: 188, SEQ ID NO: 270, SEQ ID NO: 346, SEQ ID NO: 405, and SEQ ID NO: 459. (iv) SEQ ID NO: 269, SEQ ID NO: 345, SEQ ID NO: 404 and SEQ ID NO: 459 respectively; (v) SEQ ID NO: 98, SEQ ID NO: 184, SEQ ID NO: 271, SEQ ID NO: 347, SEQ ID NO: 405 and SEQ ID NO: 460 respectively; (v) SEQ ID NO: 99, SEQ ID NO: 189, SEQ ID NO: 272, SEQ ID NO: 348, SEQ ID NO: 406 and SEQ ID NO: 461 respectively; or (vi) SEQ ID NO: 95, SEQ ID NO: 190, SEQ ID NO: 269, SEQ ID NO: 345, SEQ ID NO: 404 and SEQ ID NO: 459 respectively. In some cases, VH contains or is composed of an amino acid sequence having at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with the amino acid sequence shown in SEQ ID NO:25, and VL contains or is composed of an amino acid sequence having at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with the amino acid sequence shown in SEQ ID NO:26.In some cases, VH contains the amino acid sequence of SEQ ID NO:25, or a composition thereof, and VL contains or is composed of the amino acid sequence of SEQ ID NO:26.

[0052] In some cases, the antibody binds to GFRAL and contains VH and VL, wherein VH contains VH CDR1, VH CDR2 and VH CDR3 from the amino acid sequence shown in SEQ ID NO:37, and VL contains VL CDR1, VL CDR2 and VL CDR3 from the amino acid sequence shown in SEQ ID NO:38. In some cases, the antibody comprises VH and VL, wherein VH comprises VHCDR1, VH CDR2, and VH CDR3, and VL comprises VL CDR1, VL CDR2, and VL CDR3, wherein VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise or consist of the amino acid sequences shown below: (i) respectively, SEQ ID NO: 124, SEQ ID NO: 210, SEQ ID NO: 289, SEQ ID NO: 365, SEQ ID NO: 418, and SEQ ID NO: 474; (ii) respectively, SEQ ID NO: 73, SEQ ID NO: 211, SEQ ID NO: 290, SEQ ID NO: 366, SEQ ID NO: 419, and SEQ ID NO: 474; (iii) respectively, SEQ ID NO: 125, SEQ ID NO: 210, SEQ ID NO: 290, SEQ ID NO: 366, SEQ ID NO: 419, and SEQ ID NO: 474. SEQ ID NO: 289, SEQ ID NO: 365, SEQ ID NO: 418 and SEQ ID NO: 474 respectively; (iv) SEQ ID NO: 75, SEQ ID NO: 212, SEQ ID NO: 291, SEQ ID NO: 367, SEQ ID NO: 419 and SEQ ID NO: 475 respectively; (v) SEQ ID NO: 126, SEQ ID NO: 213, SEQ ID NO: 292, SEQ ID NO: 368, SEQ ID NO: 420 and SEQ ID NO: 476 respectively; or (vi) SEQ ID NO: 124, SEQ ID NO: 214, SEQ ID NO: 289, SEQ ID NO: 365, SEQ ID NO: 418 and SEQ ID NO: 474 respectively.In some cases, VH comprises or consists of an amino acid sequence having at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with the amino acid sequence shown in SEQ ID NO:37, and VL comprises or consists of an amino acid sequence having at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with the amino acid sequence shown in SEQ ID NO:38. In some cases, VH comprises the amino acid sequence of SEQ ID NO:37, or a composition thereof, and VL comprises or consists of the amino acid sequence of SEQ ID NO:38.

[0053] In some cases, VH comprises or is composed of the amino acid sequence of SEQ ID NO:39, and VL comprises or is composed of the amino acid sequence of SEQ ID NO:40. In some cases, the antibody comprises VH and VL, wherein VH comprises VH CDR1, VH CDR2, and VH CDR3 from the amino acid sequence shown in SEQ ID NO:39, and VL comprises VL CDR1, VL CDR2, and VL CDR3 from the amino acid sequence shown in SEQ ID NO:40. In some cases, the antibody comprises VH and VL, wherein VH comprises VH CDR1, VH CDR2, and VH CDR3, and VL comprises VL CDR1, VL CDR2, and VL CDR3, wherein (i) VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise or are composed of the amino acid sequences shown in SEQ ID NO: 127, SEQ ID NO: 215, SEQ ID NO: 293, SEQ ID NO: 369, SEQ ID NO: 421, and SEQ ID NO: 477, respectively; and (ii) VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise SEQ ID NO: 128, SEQ ID NO: 216, SEQ ID NO: 294, SEQ ID NO: 370, SEQ ID NO: 405, and SEQ ID NO: 477, respectively. (iii) The amino acid sequences shown in SEQ ID NO: 129, SEQ ID NO: 215, SEQ ID NO: 293, SEQ ID NO: 369, SEQ ID NO: 421 and SEQ ID NO: 477, respectively; (iv) The amino acid sequences shown in SEQ ID NO: 130, SEQ ID NO: 217, SEQ ID NO: 295, SEQ ID NO: 371, SEQ ID NO: 405 and SEQ ID NO: 478, respectively, of VH CDR1, VHCDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3, respectively.(v) VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 respectively contain or are composed of the amino acid sequences shown in SEQ ID NO:131, SEQ ID NO:218, SEQ ID NO:296, SEQ ID NO:372, SEQ ID NO:422, and SEQ ID NO:479; or (vi) VH CDR1, VH CDR2, VH CDR3, VL CDR1, VLCDR2, and VL CDR3 respectively contain the amino acid sequences shown in SEQ ID NO:127, SEQ ID NO:219, SEQ ID NO:293, SEQ ID NO:369, SEQ ID NO:421, and SEQ ID NO:477. In some cases, VH comprises or consists of an amino acid sequence having at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with the amino acid sequence shown in SEQ ID NO:39, and VL comprises or consists of an amino acid sequence having at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with the amino acid sequence shown in SEQ ID NO:40.

[0054] In some cases, the antibody specifically binds to amino acid residues 20-130 of the amino acid sequence shown in SEQ ID NO: 1797. In some cases, the antibody does not inhibit the binding of human GDF15 to human GFRAL.

[0055] In some cases, the antibody specifically binds to amino acid residues 131-210 of the amino acid sequence shown in SEQ ID NO: 1797. In some cases, the antibody inhibits the binding of human GDF15 to human GFRAL.

[0056] In some cases, the antibody specifically binds to: (a) one or more residues selected from the group consisting of GLY140, LEU148, ALA149, ALA146, VAL142, ASN145, VAL139, ALA135, GLU136, LEU152, LEU132, SER201, ALA204, LEU205, LYS153, ILE196, PRO197, and GLN200 of the GFRAL protein (SEQ ID NO: 1797), and optionally wherein the antibody inhibits the binding of the GFRAL protein to the GDF15 protein; (b) one or more residues selected from the group consisting of GFRAL protein (SEQ ID NO: 1797). 1797) of SER156, GLN147, SER150, TYR151, ALA154, CYS155, PHE174, TYR175, ALA137, CYS138, ASP141, VAL143, CYS144, LEU186, CYS189, CYS191, ALA192, GLN193, SER194, ASP195, CYS198, GLN199, LYS202, GLU203, HIS206, SER207, SER130, CYS131, LEU132, GLU133 and VAL134, and optionally wherein the antibody inhibits the binding of GFRAL protein to GDF15 protein; (c) one or more residues selected from the group consisting of: GFRAL protein (SEQ ID NO: SER156, GLN147, LEU148, ALA149, SER150, TYR151, LEU152, LYS153, ALA154, CYS155, PHE174, TYR175, GLU136, ALA137, CYS138, VAL139, GLY140, ASP141, VAL142, VAL143, CYS144, ASN145, ALA146, LEU186, CYS189, CYS19 (1797) 1. ALA192, GLN193, SER194, ASP195, ILE196, PRO197, CYS198, GLN199, GLN200, SER201, LYS202, GLU203, ALA204, LEU205, HIS206, SER207, SER130, CYS131, LEU132, GLU133, VAL134 and ALA135, and optionally, the antibodies therein inhibit the binding of GFRAL protein to GDF15 protein;(d) One or more residues selected from the group consisting of GLU136, ALA137, VAL139, GLY140, ASP141, VAL142, VAL143, CYS144, ASN145, ALA146, GLN147, PHE173, ASN177, ILE178, PRO179, ASN181, ILE182, and MET185 of the GFRAL protein (SEQ ID NO: 1797), and optionally wherein the antibody inhibits the binding of the GFRAL protein to the GDF15 protein; (e) One or more residues selected from the group consisting of GFRAL protein (SEQ ID NO: 1797). (f) residues selected from the group consisting of GFRAL protein (SEQ ID NO: 1797) including LEU132, GLU133, VAL134, ALA135, CYS138, LEU148, ALA149, SER150, TYR151, PHE174, TYR175, ALA169, ALA170, ILE171, ARG172, GLN176, PHE180, ALA183, GLN184, LEU186, ALA187, PHE188, and CYS189, and optionally wherein the antibody inhibits the binding of GFRAL protein to GDF15 protein; 1797) LEU132, GLU133, VAL134, ALA135, GLU136, ALA137, CYS138, VAL139, GLY140, ASP141, VAL142, VAL143, CYS144, ASN145, ALA146, GLN147, LEU148, ALA149, SER150, TYR151, PHE174, TYR175, A LA169, ALA170, ILE171, ARG172, PHE173, GLN176, ASN177, ILE178, PRO179, PHE180, ASN181, ILE182, ALA183, GLN184, MET185, LEU186, ALA187, PHE188, and CYS189, and optionally, the antibodies thereof inhibit the binding of GFRAL protein to GDF15 protein;Or (g) one or more residues selected from the group consisting of: MET214, PRO216, PRO217, GLN290, CYS291, THR292, CYS293, ARG294, THR295, ILE296, THR297, GLN298, SER299, GLU301, LYS305, GLN308, HIS309, HIS312 and SER315 of the GFRAL protein (SEQ ID NO: 1797), and optionally wherein the antibody inhibits the binding of the GFRAL protein to the RET protein.

[0057] In some cases, the antibody comprises VH and VL, wherein: (a) VH comprises VH CDR1, VH CDR2, and VH CDR3 of the amino acid sequences shown in any one of SEQ ID NO:15 and 1936-1941, and VL comprises VL CDR1, VL CDR2, and VLCDR3 of the amino acid sequences shown in any one of SEQ ID NO:16 and 1943-1947; (b) VH comprises VHCDR1, VH CDR2, and VH CDR3 of the amino acid sequences shown in any one of SEQ ID NO:1 and 1918-1927, and VL comprises VL CDR1, VL CDR2, and VL CDR3 of the amino acid sequences shown in any one of SEQ ID NO:2 and 1929-1934; or (c) VH comprises VH CDR1, VH CDR2, and VH CDR3 of the amino acid sequences shown in SEQ ID NO:11, and VL comprises VL CDR1, VL CDR2, and VL CDR3 of the amino acid sequences shown in SEQ ID NO:16 and 1943-1947. (c) VH comprises VHCDR1, VH CDR2, and VH CDR3 of the amino acid sequence shown in SEQ ID NO:12; and VL comprises VL CDR1, VL CDR2, and VL CDR3 of the amino acid sequence shown in SEQ ID NO:5, and VL comprises VL CDR1, VLCDR2, and VL CDR3 of the amino acid sequence shown in SEQ ID NO:6; (e) VH comprises VH CDR1, VH CDR2, and VH CDR3 of the amino acid sequence shown in SEQ ID NO:9, and VL comprises VL CDR1, VL CDR2, and VLCDR3 of the amino acid sequence shown in SEQ ID NO:10; (g) VH comprises VH CDR1, VH CDR2, and VH CDR3 of the amino acid sequence shown in SEQ ID NO:13, and VL comprises VL CDR1, VL CDR2, and VL CDR3 of the amino acid sequence shown in SEQ ID NO:14; and (i) VH comprises VL CDR1, VL CDR2, and VL CDR3 of the amino acid sequence shown in SEQ ID NO:12. (j) VH CDR1, VH CDR2 and VH CDR3 of the amino acid sequence shown in NO:17, and VL contains VL CDR1, VL CDR2 and VL CDR3 of the amino acid sequence shown in SEQ ID NO:18; (j) VH contains VH CDR1, VH CDR2 and VH CDR3 of the amino acid sequence shown in SEQ ID NO:19, and VL contains VL CDR1, VL CDR2 and VL CDR3 of the amino acid sequence shown in SEQ ID NO:20;(n) VH comprises VH CDR1, VH CDR2, and VH CDR3 from the amino acid sequence shown in SEQ ID NO:27, and VL comprises VL CDR1, VL CDR2, and VL CDR3 from the amino acid sequence shown in SEQ ID NO:28; (o) VH comprises VH CDR1, VH CDR2, and VH CDR3 from the amino acid sequence shown in SEQ ID NO:29, and VL comprises VLCDR1, VL CDR2, and VL CDR3 from the amino acid sequence shown in SEQ ID NO:30; (p) VH comprises VH CDR1, VH CDR2, and VH CDR3 from the amino acid sequence shown in SEQ ID NO:31, and VL comprises VL CDR1, VLCDR2, and VL CDR3 from the amino acid sequence shown in SEQ ID NO:32; (q) VH comprises VH CDR1, VH CDR2, and VH CDR3 from the amino acid sequence shown in SEQ ID NO:33. CDR3, and VL contains VL CDR1, VL CDR2, and VLCDR3 from the amino acid sequence shown in SEQ ID NO:34; (r) VH contains VH CDR1, VH CDR2, and VH CDR3 from the amino acid sequence shown in SEQ ID NO:35, and VL contains VL CDR1, VL CDR2, and VL CDR3 from the amino acid sequence shown in SEQ ID NO:36; (u) VH contains VH CDR1, VH CDR2, and VH CDR3 from the amino acid sequence shown in SEQ ID NO:480, and VL contains VL CDR1, VL CDR2, and VL CDR3 from the amino acid sequence shown in SEQ ID NO:481; (v) VH contains VH CDR1, VH CDR2, and VH CDR3 from the amino acid sequence shown in SEQ ID NO:482, and VL contains VL CDR1, VL CDR2, and VL CDR3 from the amino acid sequence shown in SEQ ID NO:483. CDR2 and VL CDR3; (w) VH comprises VH CDR1, VH CDR2, and VH CDR3 of the amino acid sequence shown in SEQ ID NO:484, and VL comprises VL CDR1, VL CDR2, and VL CDR3 of the amino acid sequence shown in SEQ ID NO:485; or (x) VH comprises VH CDR1, VH CDR2, and VH CDR3 of the amino acid sequence shown in SEQ ID NO:486, and VL comprises VL CDR1, VL CDR2, and VL CDR3 of the amino acid sequence shown in SEQ ID NO:487.

[0058] In some cases, the antibody is the one that competes with the antibodies in any of the tables in Tables 1-24 for binding to human GFRAL. In one case, the antibody competes with 3p10. In another case, the antibody competes with Hz3p10. In one case, the antibody competes with 5F12. In yet another case, the antibody competes with a humanized 5F12 antibody.

[0059] In some cases, antibodies consist of two heavy chains and two light chains.

[0060] In some cases, the antibody is a human IgG1, human IgG2, or human IgG4 antibody.

[0061] In some cases, the antibody is a human IgG1 antibody.

[0062] In some cases, antibodies contain the constant region of the human κ light chain.

[0063] In some cases, antibodies contain the constant region of the human λ light chain.

[0064] In some cases, antibodies are Fab, Fab′, F(ab′)2, Fv, scFv, (scFv)2, single-chain antibodies, dual variable region antibodies, single variable region antibodies, linear antibodies, double-chain antibodies, nanobodies, or V-region antibodies.

[0065] In some cases, the antibody binds to GFRAL and comprises a heavy chain containing an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the amino acid sequence shown in SEQ ID NO:2009 or 2010; and a light chain containing an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the amino acid sequence shown in SEQ ID NO:2011 or 2012.

[0066] In some cases, the antibody comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO: 2010 and a light chain containing the amino acid sequence shown in SEQ ID NO: 2012.

[0067] In some cases, the antibody comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO: 2009 and a light chain containing the amino acid sequence shown in SEQ ID NO: 2011.

[0068] In some cases, the antibody comprises a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 2010 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 2012.

[0069] In some cases, the antibody comprises a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 2009 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 2011.

[0070] In some cases, antibodies are humanized.

[0071] In some cases, human subjects (a) did not respond to prior administration of an antiemetic or (b) had unresolved nausea, vomiting, or a combination thereof after prior administration of an antiemetic.

[0072] This document also provides a method for treating HG in human subjects in need, the method comprising administering to the human subject a therapeutically effective amount of an antibody that specifically binds to human GFRAL. In some cases, the antibody comprises (i) VH, which comprises VH CDR1, VH CDR2, and VH CDR3 of the amino acid sequence shown in SEQ ID NO: 1982; and (ii) VL, which comprises VL CDR1, VL CDR2, and VLCDR3 of the amino acid sequence shown in SEQ ID NO: 1997. In some cases, the antibody comprises: (i) VH, which comprises VH CDR1 comprising or consisting of the amino acid sequence shown in SEQ ID NO:48, VH CDR2 comprising or consisting of the amino acid sequence shown in SEQ ID NO:137, and VH CDR3 comprising or consisting of the amino acid sequence shown in SEQ ID NO:225; and (ii) VL, which comprises VL CDR1 comprising or consisting of the amino acid sequence shown in SEQ ID NO:301, VL CDR2 comprising or consisting of the amino acid sequence shown in SEQ ID NO:376, and VL CDR3 comprising or consisting of the amino acid sequence shown in SEQ ID NO:426. In some cases, the antibody comprises: (i) VH comprising or consisting of the amino acid sequence shown in SEQ ID NO:1982; and (ii) VL comprising or consisting of the amino acid sequence shown in SEQ ID NO:1997. In some cases, the antibody comprises: (i) a heavy chain comprising the amino acid sequence shown in SEQ ID NO:2010 or composed thereof; and (ii) a light chain comprising the amino acid sequence shown in SEQ ID NO:2012 or composed thereof. In some cases, a therapeutically effective amount of the antibody is administered as a single dose. In some cases, the single dose is 30 mg. In some cases, the single dose is 75 mg. In some cases, the single dose is 100 mg. In some cases, the dose is administered subcutaneously. In other cases, the dose is administered intravenously. In some cases, a single dose is administered during the 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, 30th, 31st, 32nd, 33rd, 34th, 35th, or 36th week of pregnancy.

[0073] This document also provides a method for treating NVP in human subjects in need, the method comprising administering to the human subject a therapeutically effective amount of an antibody that specifically binds to human GFRAL. In some cases, the antibody comprises (i) VH, which comprises VH CDR1, VH CDR2, and VH CDR3 of the amino acid sequence shown in SEQ ID NO: 1982; and (ii) VL, which comprises VL CDR1, VL CDR2, and VLCDR3 of the amino acid sequence shown in SEQ ID NO: 1997. In some cases, the antibody comprises: (i) VH, which comprises VH CDR1 comprising or consisting of the amino acid sequence shown in SEQ ID NO:48, VH CDR2 comprising or consisting of the amino acid sequence shown in SEQ ID NO:137, and VH CDR3 comprising or consisting of the amino acid sequence shown in SEQ ID NO:225; and (ii) VL, which comprises VL CDR1 comprising or consisting of the amino acid sequence shown in SEQ ID NO:301, VL CDR2 comprising or consisting of the amino acid sequence shown in SEQ ID NO:376, and VL CDR3 comprising or consisting of the amino acid sequence shown in SEQ ID NO:426. In some cases, the antibody comprises: (i) VH comprising or consisting of the amino acid sequence shown in SEQ ID NO:1982; and (ii) VL comprising or consisting of the amino acid sequence shown in SEQ ID NO:1997. In some cases, the antibody comprises: (i) a heavy chain comprising the amino acid sequence shown in SEQ ID NO:2010 or composed thereof; and (ii) a light chain comprising the amino acid sequence shown in SEQ ID NO:2012 or composed thereof. In some cases, a therapeutically effective amount of the antibody is administered as a single dose. In some cases, the single dose is 30 mg. In some cases, the single dose is 75 mg. In some cases, the single dose is 100 mg. In some cases, the dose is administered subcutaneously. In other cases, the dose is administered intravenously. In some cases, a single dose is administered during the 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, 30th, 31st, 32nd, 33rd, 34th, 35th, or 36th week of pregnancy.

[0074] This document also provides a method for treating nausea and / or vomiting in a human subject in need, the method comprising administering to the human subject a therapeutically effective amount of an antibody that specifically binds to human GFRAL. In some cases, the antibody comprises (i) VH, which comprises VH CDR1, VH CDR2, and VHCDR3 of the amino acid sequence shown in SEQ ID NO: 1982; and (ii) VL, which comprises VL CDR1, VL CDR2, and VL CDR3 of the amino acid sequence shown in SEQ ID NO: 1997. In some cases, the antibody comprises: (i) VH, which comprises VH CDR1 comprising or consisting of the amino acid sequence shown in SEQ ID NO:48, VH CDR2 comprising or consisting of the amino acid sequence shown in SEQ ID NO:137, and VH CDR3 comprising or consisting of the amino acid sequence shown in SEQ ID NO:225; and (ii) VL, which comprises VL CDR1 comprising or consisting of the amino acid sequence shown in SEQ ID NO:301, VL CDR2 comprising or consisting of the amino acid sequence shown in SEQ ID NO:376, and VL CDR3 comprising or consisting of the amino acid sequence shown in SEQ ID NO:426. In some cases, the antibody comprises: (i) VH comprising or consisting of the amino acid sequence shown in SEQ ID NO:1982; and (ii) VL comprising or consisting of the amino acid sequence shown in SEQ ID NO:1997. In some cases, the antibody comprises: (i) a heavy chain comprising the amino acid sequence shown in SEQ ID NO:2010 or thereof; and (ii) a light chain comprising the amino acid sequence shown in SEQ ID NO:2012 or thereof. In some cases, a therapeutically effective amount of the antibody is administered as a single dose. In some cases, the single dose is 30 mg, 50 mg, 75 mg, or 100 mg. In some cases, the single dose is administered subcutaneously. In other cases, the single dose is administered intravenously. In one case, the single dose is 75 mg and is administered subcutaneously. In some cases, a single dose is administered during the 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th, 30th, 32nd, 34th, or 36th week of pregnancy.

[0075] This document also provides a method for reducing nausea and / or vomiting in human subjects in need, the method comprising administering to the human subject a therapeutically effective amount of an antibody that specifically binds to human GFRAL. In some cases, the antibody comprises (i) VH, which comprises VH CDR1, VH CDR2, and VHCDR3 of the amino acid sequence shown in SEQ ID NO: 1982; and (ii) VL, which comprises VL CDR1, VL CDR2, and VL CDR3 of the amino acid sequence shown in SEQ ID NO: 1997. In some cases, the antibody comprises: (i) VH, which comprises VH CDR1 comprising or consisting of the amino acid sequence shown in SEQ ID NO:48, VH CDR2 comprising or consisting of the amino acid sequence shown in SEQ ID NO:137, and VH CDR3 comprising or consisting of the amino acid sequence shown in SEQ ID NO:225; and (ii) VL, which comprises VL CDR1 comprising or consisting of the amino acid sequence shown in SEQ ID NO:301, VL CDR2 comprising or consisting of the amino acid sequence shown in SEQ ID NO:376, and VL CDR3 comprising or consisting of the amino acid sequence shown in SEQ ID NO:426. In some cases, the antibody comprises: (i) VH comprising or consisting of the amino acid sequence shown in SEQ ID NO:1982; and (ii) VL comprising or consisting of the amino acid sequence shown in SEQ ID NO:1997. In some cases, the antibody comprises: (i) a heavy chain comprising the amino acid sequence shown in SEQ ID NO:2010 or composed thereof; and (ii) a light chain comprising the amino acid sequence shown in SEQ ID NO:2012 or composed thereof. In some cases, a therapeutically effective amount of the antibody is administered as a single dose. In some cases, the single dose is 30 mg. In some cases, the single dose is 75 mg. In some cases, the single dose is 100 mg. In some cases, the dose is administered subcutaneously. In other cases, the dose is administered intravenously. In some cases, a single dose is administered during the 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, 30th, 31st, 32nd, 33rd, 34th, 35th, or 36th week of pregnancy.

[0076] This document also provides a method for treating HG in human subjects in need, the method comprising administering to the human subject a therapeutically effective amount of an antibody that specifically binds to human GFRAL. In some cases, the antibody comprises (i) VH, which comprises VH CDR1, VH CDR2, and VH CDR3 from the amino acid sequence shown in SEQ ID NO: 7; and (ii) VL, which comprises VL CDR1, VL CDR2, and VL CDR3 from the amino acid sequence shown in SEQ ID NO: 8. In some cases, the antibody comprises: (i) VH, which comprises VH CDR1 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 58, VH CDR2 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 147, and VH CDR3 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 233; and (ii) VL, which comprises VL CDR1 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 309, VL CDR2 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 382, ​​and VL CDR3 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 432. In some cases, the antibody comprises: (i) VH comprising or consisting of the amino acid sequence shown in SEQ ID NO: 7; and (ii) VL comprising or consisting of the amino acid sequence shown in SEQ ID NO: 8. In some cases, a therapeutically effective amount of the antibody is administered as a single dose. In some cases, the single dose is 30 mg. In some cases, the single dose is 75 mg. In some cases, the single dose is 100 mg. In some cases, the single dose is administered subcutaneously. In other cases, the single dose is administered intravenously. In some cases, the single dose is administered during weeks 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 of pregnancy. In some cases, a therapeutically effective amount of antibody is administered in more than one dose (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 doses).In some cases, the first dose is administered during the 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, 30th, 31st, 32nd, 33rd, 34th, 35th, or 36th week of pregnancy.

[0077] This article also provides a method for treating NVP in human subjects in need, the method comprising administering to the human subject a therapeutically effective amount of an antibody that specifically binds to human GFRAL. In some cases, the antibody comprises (i) VH, which comprises VH CDR1, VH CDR2, and VH CDR3 from the amino acid sequence shown in SEQ ID NO: 7; and (ii) VL, which comprises VL CDR1, VL CDR2, and VL CDR3 from the amino acid sequence shown in SEQ ID NO: 8. In some cases, the antibody comprises: (i) VH, comprising VH CDR1 comprising the amino acid sequence shown in SEQ ID NO: 58, VH CDR2 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 147, and VH CDR3 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 233, or both; and (ii) VL, comprising VL CDR1 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 309, VL CDR2 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 382, ​​and VLCDR3 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 432. In some cases, the antibody comprises: (i) VH comprising or consisting of the amino acid sequence shown in SEQ ID NO: 7; and (ii) VL comprising or consisting of the amino acid sequence shown in SEQ ID NO: 8. In some cases, a therapeutically effective amount of the antibody is administered as a single dose. In some cases, the single dose is 30 mg. In some cases, the single dose is 75 mg. In some cases, the single dose is 100 mg. In some cases, the single dose is administered subcutaneously. In other cases, the single dose is administered intravenously. In some cases, the single dose is administered during the 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, 30th, 31st, 32nd, 33rd, 34th, 35th, or 36th week of pregnancy. In some cases, a therapeutically effective amount of antibody is administered in more than one dose (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 doses).In some cases, the first dose is administered during the 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, 30th, 31st, 32nd, 33rd, 34th, 35th, or 36th week of pregnancy.

[0078] This article also provides a method for treating nausea and / or vomiting in a human subject in need, the method comprising administering to the human subject a therapeutically effective amount of an antibody that specifically binds to human GFRAL. In some cases, the antibody comprises (i) VH, which comprises VH CDR1, VH CDR2, and VHCDR3 from the amino acid sequence shown in SEQ ID NO: 7; and (ii) VL, which comprises VL CDR1, VL CDR2, and VLCDR3 from the amino acid sequence shown in SEQ ID NO: 8. In some cases, the antibody comprises: (i) VH, which comprises VH CDR1 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 58, VH CDR2 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 147, and VH CDR3 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 233; and (ii) VL, which comprises VL CDR1 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 309, VL CDR2 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 382, ​​and VL CDR3 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 432. In some cases, the antibody comprises: (i) VH comprising or consisting of the amino acid sequence shown in SEQ ID NO: 7; and (ii) VL comprising or consisting of the amino acid sequence shown in SEQ ID NO: 8. In some cases, a therapeutically effective amount of the antibody is administered as a single dose. In some cases, the single dose is 30 mg. In some cases, the single dose is 75 mg. In some cases, the single dose is 100 mg. In some cases, the single dose is administered subcutaneously. In other cases, the single dose is administered intravenously. In some cases, the single dose is administered during the 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, 30th, 31st, 32nd, 33rd, 34th, 35th, or 36th week of pregnancy. In some cases, a therapeutically effective amount of antibody is administered in more than one dose (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 doses).In some cases, the first dose is administered during the 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, 30th, 31st, 32nd, 33rd, 34th, 35th, or 36th week of pregnancy.

[0079] This article also provides a method for reducing nausea and / or vomiting in human subjects in need, the method comprising administering to the human subject a therapeutically effective amount of an antibody that specifically binds to human GFRAL. In some cases, the antibody comprises (i) VH, which comprises VH CDR1, VH CDR2, and VHCDR3 from the amino acid sequence shown in SEQ ID NO: 7; and (ii) VL, which comprises VL CDR1, VL CDR2, and VLCDR3 from the amino acid sequence shown in SEQ ID NO: 8. In some cases, the antibody comprises: (i) VH, which comprises VH CDR1 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 58, VH CDR2 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 147, and VH CDR3 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 233; and (ii) VL, which comprises VL CDR1 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 309, VL CDR2 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 382, ​​and VL CDR3 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 432. In some cases, the antibody comprises: (i) VH comprising or consisting of the amino acid sequence shown in SEQ ID NO: 7; and (ii) VL comprising or consisting of the amino acid sequence shown in SEQ ID NO: 8. In some cases, a therapeutically effective amount of the antibody is administered as a single dose. In some cases, the single dose is 30 mg. In some cases, the single dose is 75 mg. In some cases, the single dose is 100 mg. In some cases, the single dose is administered subcutaneously. In other cases, the single dose is administered intravenously. In some cases, the single dose is administered during the 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, 30th, 31st, 32nd, 33rd, 34th, 35th, or 36th week of pregnancy. In some cases, a therapeutically effective amount of antibody is administered in more than one dose (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 doses).In some cases, the first dose is administered during the 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, 30th, 31st, 32nd, 33rd, 34th, 35th, or 36th week of pregnancy.

[0080] In each of the above treatment methods, further treatment comprising one or more of the following may be administered to human subjects: dolrazemin (e.g., dolrazemin succinate), pyridoxine (e.g., pyridoxine hydrochloride (vitamin B6)), a dual-release formulation of dolrazemin and pyridoxine, ondansetron, dopamine antagonists (e.g., metoclopramide, promethazine), diphenhydramine, droperidol, methylprednisolone, mirtazapine, dimenhydrinate, chlorpromazine, prochlorperazine, steroid therapy, antiemetics, vitamin B1, folic acid, vitamin K, vitamin D, magnesium, and ginger. Further treatment may be provided before, substantially simultaneously with, or after administration of an antibody that specifically binds to human GFRAL.

[0081] A composition is also provided comprising any of the anti-GFRAL antibodies described herein and a combination of further treatment for HG or NVP. In some cases, the further treatment comprises one or more of the following: dolrazemin (e.g., dolrazemin succinate), pyridoxine (e.g., pyridoxine hydrochloride (vitamin B6)), a dual-release formulation of dolrazemin and pyridoxine, ondansetron, dopamine antagonists (e.g., metoclopramide, promethazine), diphenhydramine, droperidol, methylprednisolone, mirtazapine, dimenhydrinate, chlorpromazine, prochlorperazine, steroid therapy, antiemetics, vitamin B1, folic acid, vitamin K, vitamin D, magnesium, and ginger.

[0082] In another aspect, this disclosure features a method for (i) treating hyperemesis gravidarum in a human subject in need, (ii) treating nausea and vomiting (NVP) during pregnancy in a human subject in need, (iii) treating nausea and / or vomiting, or (iv) reducing nausea and / or vomiting in a human subject in need. The method comprises administering to a human subject a single dose of an antibody that specifically binds to human GDNF family receptor α-like (GFRAL), wherein the single dose is about 75 mg or 75 mg and said dose is administered subcutaneously to the subject. In some cases, the anti-GFRAL antibody comprises six CDRs of a 3P10 antibody (see Table 1). In some cases, the antibody comprises a VH containing the sequence shown in SEQ ID NO: 1982 and a VL containing the sequence shown in SEQ ID NO: 1997. In some cases, the antibody comprises a heavy chain containing the sequence shown in SEQ ID NO: 2010 and a light chain containing the sequence shown in SEQ ID NO: 2012.

[0083] IV. Description of the attached drawings Figure 1A-Figure 1B The alignment of the VH and VL sequences of the humanized 1C1 antibody is shown. SEQ ID NO is indicated in parentheses and bold text.

[0084] Figures 2A-2B The alignment of the VH and VL sequences of the humanized 25M22 antibody is shown. SEQ ID NO is indicated in parentheses and bold text.

[0085] Figures 3A-3B The alignment of the VH and VL sequences of the humanized 17J16 antibody is shown. SEQ ID NO is indicated in parentheses and bold text.

[0086] Figures 4A-4B The alignment of the VH and VL sequences of the humanized 5F12 antibody is shown. SEQ ID NO is indicated in parentheses and bold text.

[0087] Figures 5A-5B The alignment of the VH and VL sequences of the humanized 3P10 antibody is shown. SEQ ID NO is indicated in parentheses and bold text.

[0088] Figure 6 This is a graph showing the dose-dependent effect of hz3P10 on weight gain in mice after GDF15-Fc fusion protein-induced weight loss.

[0089] Figure 7 This is a graph showing the dose-dependent weight gain in transgenic GDF15-expressing mice treated with hz3P10.

[0090] Figure 8This is a graph showing the weight changes in mice carrying HT1080 tumors treated with hz3P10.

[0091] Figure 9 A is a graph showing serum GDF15 levels in a mouse tumor model compared to a control without tumors. Figure 9 B is a graph showing serum GDF15 levels in a patient-derived xenograft (PDX) mouse tumor model compared to a control group without tumors.

[0092] Figure 10 A- Figure 10 C represents the level of KLN205 (after treatment with 3P10 or IgG control) Figure 10 A), Renca ( Figure 10 B) and P16b16 ( Figure 10 C) A graph showing weight changes in a syngeneic mouse tumor model.

[0093] Figure 11 A- Figure 11 C represents the effect of gastric ( ) after treatment with hz3P10 or IgG control group. Figure 11 A) Ovary ( Figure 11 B) and liver ( Figure 11 C) A graph showing weight changes in a PDX mouse tumor model.

[0094] Figure 12 A- Figure 12 B represents the serum GDF15 levels in mice treated with cisplatin alone or in combination with hz3P10 and a control group. Figure 12 A) and weight change ( Figure 12 The chart in B).

[0095] Figure 13 This is a graph showing the change in body weight over time in rats that were given human GDF15-Fc fusion protein, followed by a single dose of hz3P10 or a mediator control two days later.

[0096] Figure 14 It is a chart showing the average daily body weight of rats treated weekly with cisplatin and hz3P10 or a mediator control.

[0097] Figure 15 A is a graph showing a simulated pharmacokinetic profile of 75 kg humans who received a single dose of 75 mg hz3P10 (1 mg / kg) over the first seven days, as well as actual serum concentrations measured in healthy volunteers who received a single dose of 10 mg, 30 mg, 100 mg, 200 mg, or 400 mg hz3P10. Figure 15B is a graph showing a simulated pharmacokinetic profile of 75 kg humans who received a single dose of 75 mg hz3P10 (1 mg / kg) over 30 weeks, as well as actual serum concentrations measured in healthy volunteers who received single doses of 10 mg, 30 mg, 100 mg, 200 mg, or 400 mg hz3P10.

[0098] V. Detailed Implementation This disclosure generally relates to methods for treating nausea and / or vomiting symptoms (such as HG and NVP) in human subjects in need, the methods comprising administering to the human subject a therapeutically effective amount of an antibody specifically bound to human GFRAL.

[0099] As used throughout this document, in the context of dosage, "about" means + / - 10% of the listed dosage. For example, "about 30 mg" means "27 mg to 33 mg"; "about 75 mg" means "67.5 mg to 82.5 mg"; and "about 100 mg" means "90 mg to 110 mg". As used throughout this document, in the context of duration, "about" means + / - one week. For example, "about 3 weeks" means "2 to 4 weeks" and "about 4 weeks" means "3 to 5 weeks".

[0100] Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0101] A. GFRAL, GDF15 and RET Human GDNF family receptor α-like (GFRAL, also known in the art as GDF15 receptor, C6orf144, chromosome 6 open reading frame 144, BA360D14.1, IVFI9356, and UNQ9356) is a 375-amino acid protein (excluding the signal peptide) that acts as a receptor for GDF15 signaling.

[0102] The following provides the amino acid sequence (SEQ ID NO:1797) of the full-length precursor human GFRAL, including the signal peptide sequence (lowercase residues): mivfiflamglsleneytsQTNNCTYLREQCLRDANGCKHAWRVMEDACNDSDPGDPCKMRNSSYCNLSIQYLVESNFQFKECLCTDDFYCTVNKLLGKKCINKSDNVKEDKFKWNLTTRSHHGFKGMWSCLEVAEACVGDVVCNAQLASYLKACSANGNPCDLKQCQAAIRFFYQNIPFNIAQMLAFCDCAQSDIPCQQSKEALHSKTCAVNMVPPPTCLSVIRSCQNDELCRRHYRTFQSKCWQRVTRKCHEDENCISTLSKQDLTCSGSDDCKAAYIDILGTVLQVQCTCRTITQSEESLCKIFQHMLHRKSCFNYPTLSNVKGMALYTRKHANKITLTGFHSPFNGEVIYAAMCMTVTCGILLLVMVKLRTSRISSKARDPSSIQIPGEL (SEQ ID NO: 1797).

[0103] The amino acid sequence of the mature human GFRAL polypeptide is provided below (SEQ ID NO: 1798): QTNNCTYLREQCLRDANGCKHAWRVMEDACNDSDPGDPCKMRNSSYCNLSIQYLVESNFQFKECLCTDDFYCTVNKLLGKKCINKSDNVKEDKFKWNLTTRSHHGFKGMWSCLEVAEACVGDVVCNAQLASYLKACSANGNPCDLKQCQAAIRFFYQNIPFNIAQMLAFCDCAQSDIPCQQSKEALHSKTCAVNMVPPPTCLSVIRSCQNDELCRRHYRTFQSKCWQRVTRKCHEDENCISTLSKQDLTCSGSDDCKAAYIDILGTVLQVQCTCRTITQSEESLCKIFQHMLHRKSCFNYPTLSNVKGMALYTRKHANKITLTGFHSPFNGEVIYAAMCMTVTCGILLLVMVKLRTSRISSKARDPSSIQIPGEL(SEQ ID NO: 1798).

[0104] Human GFRAL has an extracellular domain (e.g., residues 20-351 of the amino acid sequence shown in SEQ ID NO: 1797), a transmembrane domain (e.g., residues 352-371 of the amino acid sequence shown in SEQ ID NO: 1797), and a cytoplasmic domain (e.g., residues 372-394 of the amino acid sequence shown in SEQ ID NO: 1797).

[0105] GDF15 (also known in the art as MIC-1 (macrophage inhibitory cytokine-1), PDF (prostate differentiation factor), PLAB (placental bone morphogenetic protein), NAG-1 (non-steroidal anti-inflammatory drug (NSAID) activating gene), TGF-PL, and PTGFB) is a member of the transforming growth factor β (TGF-β) superfamily. GDF15, a 62 kDa intracellular precursor protein subsequently synthesized from furin-like proteases, is secreted as a 25 kDa disulfide-linked protein (see, for example, Fairlie et al.). J. Leukoc. Biol 65:2-5 (1999)). GDF15 mRNA is found in several tissues, including the liver, kidneys, pancreas, colon, and placenta, and GDF15 expression in the liver can be significantly upregulated during damage to organs such as the liver, kidneys, heart, and lungs. GDF15 is also upregulated during pregnancy and produced in the placenta.

[0106] The GDF15 precursor is a 308-amino acid polypeptide (NCBI reference sequence NP_004855.2; GI:153792495), containing a 29-amino acid signal peptide, a 167-amino acid predomain, and a 112-amino acid mature domain cleaved from the predomain by a furin-like protease.

[0107] The amino acid sequence of the precursor human GDF15 peptide (SEQ ID NO:1810) is provided below: MPGQELRTVNGSQMLLVLLVLSWLPHGGALSLAEASRASFPGPSELHSEDSRFRELRKRYEDLLLTLRANQSWEDSNTDLVPAPAVRILTPEVRLGSGGHLRISRAALPEGLPEASRLHRALFRLSPTASRSWDVTRPLRRQLSLARPQAPA LHLRLSPPPSQSDQLLAESSSARPQLELHLRPQAARGRRRARARNGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO: 1810).

[0108] GDF15 peptides of 308 amino acids are called "full-length" GDF15 peptides; GDF15 peptides of 112 amino acids (amino acids 197-308 of "full-length" GDF15) are "mature" GDF15 peptides. The amino acid sequence of a mature human GDF15 peptide (SEQ ID NO: 1811) is provided below: ARNGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO: 1811).

[0109] RET (also known in the art as the Ret proto-oncogene, cadherin-associated family member 16, rearranged during transfection, RET receptor tyrosine kinase, cadherin family member 12, proto-oncogene C-Ret, EC 2.7.10.1, CDHF12, CDHR16, RET51, PTC, hydroxyaryl protein kinase, RET conversion sequence, and receptor tyrosine kinase) is a receptor tyrosine kinase, a cell surface molecule that transduces signals for cell growth and differentiation. RET acts as a co-receptor and is known to be a primary signal transduction receptor for glial cell line-derived neurotrophic factor (GDNF) ligands (in humans, GDNF, artemin, neurturin, and persesphin) when binding to members of the GDNF receptor α (GFRα) co-receptor. RET proteins (e.g., RET-ECD) comprise four consecutive cadherin-like domains (CLD1-CLD4) followed by a proximal cysteine-rich domain (CRD). RET proteins are co-receptors with GFRAL and GDF15 proteins (e.g., acting as co-receptors with RET proteins). Receptor complexes include GFRAL proteins, such as the RET / GFRAL complex, the GFRAL / GDF15 complex, and the RET / GFRAL / GDF15 complex.

[0110] RET differs from TGFβ RI and TGFβ RII. SEQ ID NO: 1812 is the sequence of mature human RET9 lacking the signal peptide: The following provides the amino acid sequence (SEQ ID NO:1813) of the full-length precursor human RET protein, including the signal peptide sequence (lowercase residues): B. Antibodies that bind to human GFRAL This disclosure provides antibodies that bind to human GFRAL (also referred to herein as "anti-GFRAL antibodies") and that can be used in the treatment methods described herein. The antibodies described herein include those known in the art, such as those described in International Patent Application Publications No. WO 2017 / 172260 and No. WO 2022 / 207785, each of which is incorporated herein by reference in its entirety.

[0111] The antibodies described herein antagonize the effects of the GDF15 protein, including blocking the formation of the GDF15 / GFRAL protein complex or the GDF15 / GFRAL / RET protein complex or blocking GDF15 signaling, including as measured, for example, by several in vitro cell-based assays. Such assays may include (1) an ELK1-luciferase reporter gene assay (see, for example, Example 3 of International Patent Application Publication WO 2017 / 172260, which is incorporated herein by reference in its entirety); and / or (2) an ERK-phosphorylation assay in U2OS cells (see, for example, Example 4 of International Patent Application Publication WO 2017 / 172260, which is incorporated herein by reference in its entirety). Therefore, the antibodies described herein are expected to inhibit GDF15 activity in vivo (e.g., related to GDF15 signaling function). This property makes the disclosed antibody a viable therapeutic agent for treating diseases, conditions, or disorders caused by or otherwise associated with GDF15 proteins (such as those related to GDF15-induced signaling in a subject).

[0112] In some cases, the antibodies described herein inhibit the binding of human GFRAL to human RET. Methods for determining whether an antibody inhibits the binding of human GFRAL to human RET are known in the art, such as, for example, immunoprecipitation, immunohistochemistry, and ELISA (see, for example, International Patent Application Publication WO 2017 / 172260, which is incorporated herein by reference in its entirety). Exemplary antibodies that inhibit the binding of human GFRAL to human RET include Hz3P10, 3P10, 5F12, 2I23, 6N16, 1B3, 6G9, or 2B11 (see, for example, a working example of International Patent Application Publication WO 2017 / 172260, which is incorporated herein by reference in its entirety).

[0113] In some cases, the antibodies described herein do not inhibit the binding of human GFRAL to human GDF15. Methods for determining whether an antibody does not inhibit the binding of human GFRAL to human GDF15 are known in the art, such as, for example, immunoprecipitation, immunohistochemistry, and ELISA (see, for example, International Patent Application Publication WO 2017 / 172260, which is incorporated herein by reference in its entirety). Exemplary antibodies that do not inhibit the binding of human GFRAL to human GDF15 include 5F12, 3P10, Hz3P10, 6N16, 2B11, 1B3, 2I23, 1A3, P1B6, P1H8, and P8G4 (see, for example, working examples of International Patent Application Publication WO 2017 / 172260, which is incorporated herein by reference in its entirety). In some cases, the antibodies described herein (i) inhibit the binding of human GFRAL to human RET and (ii) do not inhibit the binding of human GFRAL to human GDF15.

[0114] In some cases, the antibodies described herein inhibit the binding of human GFRAL to human GDF15. Methods for determining whether an antibody inhibits the binding of human GFRAL to human GDF15 are known in the art, such as, for example, immunoprecipitation, immunohistochemistry, and ELISA (see, for example, International Patent Application Publication WO 2017 / 172260, which is incorporated herein by reference in its entirety). Exemplary antibodies that inhibit the binding of human GFRAL to human GDF15 include 2B8, 8C10, 25M22, 12A3, 19K19, 1C1, 8D8, 22N5, 2A9, 2B3, 24G2, 17J16, and 5A20 (see, for example, working examples of International Patent Application Publication WO 2017 / 172260, which is incorporated herein by reference in its entirety).

[0115] In some cases, the antibody comprises a VH, which includes VH CDR1, VH CDR2, and VH CDR3; and a VL, which includes VL CDR1, VL CDR2, and VL CDR3, wherein VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VLCDR3 are derived from any one of the VH and VL sequences of the antibody described herein, such as the VH and VL amino acid sequences depicted in Tables 1-24. In some cases, the antibody is a humanized form of the antibody described herein. In some cases, the humanized form of the antibody described herein includes VH, which includes VH CDR1, VH CDR2, and VH CDR3; and VL, which includes VL CDR1, VL CDR2, and VL CDR3, wherein VH CDR1, VH CDR2, and VH CDR3 are derived from the amino acid sequence of the VH of the antibody described herein, and VL CDR1, VL CDR2, and VL CDR3 are derived from the amino acid sequence of the VL of the antibody described herein (see Tables 1-24).

[0116] The antibody named 3P10 comprises a VH containing the sequence shown in SEQ ID NO: 3 and a VL containing the sequence shown in SEQ ID NO: 4 (see Table 1). An exemplary humanized form of antibody 3P10 comprises a VH containing the sequence shown in any one of SEQ ID NO: 1978-1988 and a VL containing the sequence shown in any one of SEQ ID NO: 1990-2000.

[0117] The antibody named Hz3P10 comprises a VH containing the sequence shown in SEQ ID NO: 1982 and a VL containing the sequence shown in SEQ ID NO: 1997 (see Table 1A). The antibody named Hz3P10 comprises a heavy chain containing the sequence shown in SEQ ID NO: 2010 and a light chain containing the sequence shown in SEQ ID NO: 2012 (see Table 1A).

[0118] The antibody named 5F12 contains a VH containing the sequence shown in SEQ ID NO: 7 and a VL containing the sequence shown in SEQ ID NO: 8 (see Table 2).

[0119] The antibody named 2I23 contains a VH containing the sequence shown in SEQ ID NO: 21 and a VL containing the sequence shown in SEQ ID NO: 22 (see Table 3).

[0120] The antibody named 6N16 contains a VH containing the sequence shown in SEQ ID NO: 23 and a VL containing the sequence shown in SEQ ID NO: 24 (see Table 4).

[0121] The antibody named 1B3 contains a VH containing the sequence shown in SEQ ID NO: 25 and a VL containing the sequence shown in SEQ ID NO: 26 (see Table 5).

[0122] The antibody named 6G9 contains a VH containing the sequence shown in SEQ ID NO: 37 and a VL containing the sequence shown in SEQ ID NO: 38 (see Table 6).

[0123] The antibody named 2B11 contains a VH containing the sequence shown in SEQ ID NO: 39 and a VL containing the sequence shown in SEQ ID NO: 40 (see Table 7).

[0124] The antibody named 17J16 contains a VH containing the sequence shown in SEQ ID NO: 13 and a VL containing the sequence shown in SEQ ID NO: 14 (see Table 8).

[0125] The antibody named 8D8 contains a VH containing the sequence shown in SEQ ID NO: 11 and a VL containing the sequence shown in SEQ ID NO: 12 (see Table 9).

[0126] The antibody named 2B3 comprises a VH containing the sequence shown in SEQ ID NO: 29 and a VL containing the sequence shown in SEQ ID NO: 30 (see Table 10).

[0127] The antibody named 24G2 contains a VH containing the sequence shown in SEQ ID NO: 35 and a VL containing the sequence shown in SEQ ID NO: 36 (see Table 11).

[0128] The antibody named 5A20 contains a VH containing the sequence shown in SEQ ID NO: 9 and a VL containing the sequence shown in SEQ ID NO: 10 (see Table 12).

[0129] The antibody named 2B8 comprises a VH containing the sequence shown in SEQ ID NO: 17 and a VL containing the sequence shown in SEQ ID NO: 18 (see Table 13).

[0130] The antibody named 8C10 contains a VH containing the sequence shown in SEQ ID NO: 31 and a VL containing the sequence shown in SEQ ID NO: 32 (see Table 14).

[0131] The antibody named 25M22 contains a VH containing the sequence shown in SEQ ID NO: 15 and a VL containing the sequence shown in SEQ ID NO: 16 (see Table 15).

[0132] The antibody named 12A3 contains a VH containing the sequence shown in SEQ ID NO: 5 and a VL containing the sequence shown in SEQ ID NO: 6 (see Table 16).

[0133] The antibody named 19K19 contains a VH containing the sequence shown in SEQ ID NO: 27 and a VL containing the sequence shown in SEQ ID NO: 28 (see Table 17).

[0134] The antibody named 1C1 contains a VH containing the sequence shown in SEQ ID NO: 1 and a VL containing the sequence shown in SEQ ID NO: 2 (see Table 18).

[0135] The antibody named 22N5 contains a VH containing the sequence shown in SEQ ID NO: 19 and a VL containing the sequence shown in SEQ ID NO: 20 (see Table 19).

[0136] The antibody named 2A9 comprises a VH containing the sequence shown in SEQ ID NO: 33 and a VL containing the sequence shown in SEQ ID NO: 34 (see Table 20).

[0137] The antibody named 1A3 comprises a VH containing the sequence shown in SEQ ID NO: 480 and a VL containing the sequence shown in SEQ ID NO: 481 (see Table 21).

[0138] The antibody named P1B6 comprises a VH containing the sequence shown in SEQ ID NO: 482 and a VL containing the sequence shown in SEQ ID NO: 483 (see Table 22).

[0139] The antibody named P8G4 contains a VH containing the sequence shown in SEQ ID NO: 486 and a VL containing the sequence shown in SEQ ID NO: 487 (see Table 23).

[0140] The antibody named P1H8 comprises a VH containing the sequence shown in SEQ ID NO: 484 and a VL containing the sequence shown in SEQ ID NO: 485 (see Table 24).

[0141] Table 1: Antibody 3P10 CDR sequence

[0142] Table 1A: Hz3P10 VH, VL, heavy chain (HC), and light chain (LC) sequences

[0143] Table 2: Antibody 5F12 CDR sequence

[0144] Table 3: Antibody 2I23 CDR sequence

[0145] Table 4: Antibody 6N16 CDR Sequence

[0146] Table 5: Antibody 1B3 CDR Sequence

[0147] Table 6: Antibody 6G9 CDR Sequence

[0148] Table 7: Antibody 2B11 CDR Sequence

[0149] Table 8: CDR sequence of antibody 17J16

[0150] Table 9: Antibody 8D8 CDR Sequence

[0151] Table 10: Antibody 2B3 CDR Sequence

[0152] Table 11: Antibody 24G2 CDR sequence

[0153] Table 12: Antibody 5A20 CDR sequence

[0154] Table 13: Antibody 2B8 CDR Sequence

[0155] Table 14: Antibody 8C10 CDR Sequence

[0156] Table 15: Antibody 25M22 CDR sequence

[0157] Table 16: Antibody 12A3 CDR Sequence

[0158] Table 17: Antibody 19K19 CDR Sequence

[0159] Table 18: Antibody 1C1 CDR Sequence

[0160] Table 19: CDR sequence of antibody 22N5

[0161] Table 20: Antibody 2A9 CDR Sequence

[0162] Table 21: Antibody 1A3 CDR Sequence

[0163] Table 22: Antibody P1B6 CDR Sequence

[0164] Table 23: Antibody P8G4 CDR Sequence

[0165] Table 24: Antibody P1H8 CDR Sequence

[0166] Antibody CDRs are defined by those skilled in the art using various methods / systems. These systems and / or definitions have been developed and refined over many years and include Kabat, Chothia, IMGT, AbM, and Contact. The Kabat definition is based on sequence variability and is commonly used. The Chothia definition is based on the location of structural loop regions. The IMGT system is based on sequence variability and the location of variable domains within the structure. The AbM definition is a balance between Kabat and Chothia. The Contact definition is based on the analysis of available antibody crystal structures. An exemplary system is a combination of Kabat and Chothia. Software programs (e.g., abYsis) are available and known to those skilled in the art for analyzing antibody sequences and determining CDRs. It should be understood that references in this disclosure to a specific antibody's VH CDR or VH CDR and / or VL CDR or VL CDR, including specific VH amino acid sequences and / or VL amino acid sequences, will encompass all CDR definitions as known to those skilled in the art.

[0167] In some cases, the humanized form of the antibody described herein comprises a VH containing VH CDR1, VHCDR2, and VH CDR3; and a VL containing VL CDR1, VL CDR2, and VL CDR3, wherein VH CDR1, VH CDR2, and VHCDR3 are derived from the amino acid sequence of the VH of the antibody described herein, and VL CDR1, VL CDR2, and VL CDR3 are derived from the amino acid sequence of the VL of the antibody described herein (see Tables 1-24). For example, in some cases, the antibody comprises (i) a VH containing VH CDR1, VH CDR2, and VH CDR3 from the amino acid sequence shown in SEQ ID NO:3; and (ii) a VL containing VL CDR1, VL CDR2, and VL CDR3 from the amino acid sequence shown in SEQ ID NO:4 (i.e., the six CDRs of antibody 3P10 in Table 1). As another example, in some cases, the antibody comprises (i) VH, which comprises VH CDR1, VH CDR2, and VH CDR3 of the amino acid sequence shown in SEQ ID NO:1982; and (ii) VL, which comprises VL CDR1, VL CDR2, and VL CDR3 of the amino acid sequence shown in SEQ ID NO:1997 (i.e., the six CDRs of the humanized 3P10 antibody in Table 1A). In another example, in some cases, the antibody comprises (i) VH, which comprises VH CDR1, VH CDR2, and VH CDR3 of the amino acid sequence shown in any one of SEQ ID NO:1978-1988; and (ii) VL, which comprises VL CDR1, VL CDR2, and VL CDR3 of the amino acid sequence shown in any one of SEQ ID NO:1990-2000 (i.e., the six CDRs of the humanized 3P10 antibody in Table 1A). In another instance, in some cases, the antibody comprises (i) VH, which comprises VH CDR1, VH CDR2, and VH CDR3 from the amino acid sequence shown in SEQ ID NO: 7; and (ii) VL, which comprises VL CDR1, VL CDR2, and VL CDR3 (i.e., the six CDRs of antibody 5F12) from the amino acid sequence shown in SEQ ID NO: 8.In another instance, in some cases, the antibody comprises (i) VH, which comprises VH CDR1, VH CDR2, and VH CDR3 of the amino acid sequences shown in any of SEQ ID NO: 1958-1965; and (ii) VL, which comprises VL CDR1, VL CDR2, and VLCDR3 (i.e., the six CDRs of the humanized 5F12 antibody) of the amino acid sequences shown in any of SEQ ID NO: 1967-1976.

[0168] In some cases, the antibody comprises (i) VH, which comprises VH CDR1, VH CDR2, and VH CDR3 as defined by any of the CDR definitions from any of the tables from Table 1 to Table 24; and (ii) VL, which comprises VL CDR1, VL CDR2, and VL CDR3 as defined by any of the CDR definitions from any of the tables from Table 1 to Table 24. For example, in some cases, the antibody comprises (i) VH, which comprises VH CDR1, VHCDR2, and VH CDR3 as defined by any of the CDR definitions from Table 1; and (ii) VL, which comprises VL CDR1, VLCDR2, and VL CDR3 as defined by any of the CDR definitions from Table 1. In another instance, in some cases, the antibody comprises (i) VH, which comprises VH CDR1, VH CDR2 and VH CDR3 as defined by any of the CDR definitions from Table 2; and (ii) VL, which comprises VL CDR1, VL CDR2 and VL CDR3 as defined by any of the CDR definitions from Table 2.

[0169] In some cases, the CDR of an antibody is named according to example. See Tables 1-24.

[0170] In some cases, the CDR of an antibody is named according to IMGT. See Tables 1-24.

[0171] In some cases, the CDR of an antibody is named according to Kabat. See Tables 1-24.

[0172] In some cases, the CDR of an antibody is named according to Chothia. See Tables 1-24.

[0173] In some cases, the CDR of an antibody is named according to the contact. See Tables 1-24.

[0174] In some cases, the CDR of an antibody is named according to the AbM designation. See Tables 1-24.

[0175] In some cases, the antibody comprises: (i) VH, which comprises VH CDR1 comprising the amino acid sequence shown in SEQ ID NO:46, VH CDR2 comprising the amino acid sequence shown in SEQ ID NO:137, and VH CDR3 comprising the amino acid sequence shown in SEQ ID NO:225; and (ii) VL, which comprises VL CDR1 comprising the amino acid sequence shown in SEQ ID NO:301, VL CDR2 comprising the amino acid sequence shown in SEQ ID NO:376, and VL CDR3 comprising the amino acid sequence shown in SEQ ID NO:426.

[0176] In some cases, the antibody comprises: (i) VH, which comprises VH CDR1 comprising the amino acid sequence shown in SEQ ID NO:47, VH CDR2 comprising the amino acid sequence shown in SEQ ID NO:138, and VH CDR3 comprising the amino acid sequence shown in SEQ ID NO:226; and (ii) VL, which comprises VL CDR1 comprising the amino acid sequence shown in SEQ ID NO:302, VL CDR2 comprising the amino acid sequence shown in SEQ ID NO:377, and VL CDR3 comprising the amino acid sequence shown in SEQ ID NO:426.

[0177] In some cases, the antibody comprises: (i) VH, which comprises VH CDR1 comprising the amino acid sequence shown in SEQ ID NO:48, VH CDR2 comprising the amino acid sequence shown in SEQ ID NO:137, and VH CDR3 comprising the amino acid sequence shown in SEQ ID NO:225; and (ii) VL, which comprises VL CDR1 comprising the amino acid sequence shown in SEQ ID NO:301, VL CDR2 comprising the amino acid sequence shown in SEQ ID NO:376, and VL CDR3 comprising the amino acid sequence shown in SEQ ID NO:426.

[0178] In some cases, the antibody comprises: (i) VH, which comprises VH CDR1 comprising the amino acid sequence shown in SEQ ID NO:49, VH CDR2 comprising the amino acid sequence shown in SEQ ID NO:139, and VH CDR3 comprising the amino acid sequence shown in SEQ ID NO:227; and (ii) VL, which comprises VL CDR1 comprising the amino acid sequence shown in SEQ ID NO:303, VL CDR2 comprising the amino acid sequence shown in SEQ ID NO:377, and VL CDR3 comprising the amino acid sequence shown in SEQ ID NO:427.

[0179] In some cases, the antibody comprises: (i) VH, which comprises VH CDR1 comprising the amino acid sequence shown in SEQ ID NO:50, VH CDR2 comprising the amino acid sequence shown in SEQ ID NO:140, and VH CDR3 comprising the amino acid sequence shown in SEQ ID NO:228; and (ii) VL, which comprises VL CDR1 comprising the amino acid sequence shown in SEQ ID NO:304, VL CDR2 comprising the amino acid sequence shown in SEQ ID NO:378, and VL CDR3 comprising the amino acid sequence shown in SEQ ID NO:428.

[0180] In some cases, the antibody comprises: (i) VH, which comprises VH CDR1 comprising the amino acid sequence shown in SEQ ID NO:46, VH CDR2 comprising the amino acid sequence shown in SEQ ID NO:141, and VH CDR3 comprising the amino acid sequence shown in SEQ ID NO:225; and (ii) VL, which comprises VL CDR1 comprising the amino acid sequence shown in SEQ ID NO:301, VL CDR2 comprising the amino acid sequence shown in SEQ ID NO:376, and VL CDR3 comprising the amino acid sequence shown in SEQ ID NO:426.

[0181] In some cases, the antibody contains a humanized framework region (FR) sequence, for example, as described herein. In some embodiments, the antibody described herein contains a VH containing the amino acid sequences VH FR1, VH FR2, VH FR3, and VH FR4 as described in International Patent Application Publication No. WO 2017 / 172260, which is incorporated herein by reference in its entirety; and / or (b) a VL containing the amino acid sequences VL FR1, VL FR2, VL FR3, and VL FR4 as described in International Patent Application Publication No. WO 2017 / 172260.

[0182] In some cases, the antibody comprises VH, which comprises VH CDR1, VH CDR2, and VH CDR3 of antibody 3P10 (or its humanized form), and wherein the VH comprises an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence shown in SEQ ID NO:3. In some cases, the antibody comprises VH, which comprises VHCDR1, VH CDR2, and VH CDR3 of antibody 3P10 (or its humanized form), and wherein the VH comprises an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the amino acid sequence shown in SEQ ID NO:1982.

[0183] In some cases, the antibody comprises a VL, wherein the VL comprises VL CDR1, VL CDR2, and VL CDR3 of antibody 3P10 (or its humanized form), and wherein the VL comprises an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 4. In some cases, the antibody comprises a VL, wherein the VL comprises VLCDR1, VL CDR2, and VL CDR3 of antibody 3P10 (or its humanized form), and wherein the VL comprises an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the amino acid sequence shown in SEQ ID NO: 1997.

[0184] In some cases, the antibody comprises: (i) VH, which comprises VHCDR1, VH CDR2 and VH CDR3 of antibody 3P10 (or its humanized form), and wherein VH comprises an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with the amino acid sequence shown in SEQ ID NO:3; and VL, which comprises VL CDR1, VL CDR2 and VLCDR3 of antibody 3P10 (or its humanized form), and wherein VL comprises an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with the amino acid sequence shown in SEQ ID NO:4. In some cases, the antibody comprises: (i) VH, which comprises VH CDR1, VH CDR2 and VH CDR3 of antibody 3P10 (or its humanized form), and wherein VH comprises an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with the amino acid sequence shown in SEQ ID NO:1982; and (ii) VL, which comprises VL CDR1, VL CDR2 and VL CDR3 of antibody 3P10 (or its humanized form), and wherein VL comprises an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with the amino acid sequence shown in SEQ ID NO:1997.

[0185] In some cases, the antibody contains a VH comprising the amino acid sequence shown in any of SEQ ID NO:1978-1988. In some cases, the antibody contains a VH comprising the amino acid sequence shown in SEQ ID NO:1982.

[0186] In some cases, the antibody comprises a VL containing the amino acid sequence shown in any of SEQ ID NO:1990-2000. In some cases, the antibody comprises a VL containing the amino acid sequence shown in SEQ ID NO:1997.

[0187] In some cases, the antibody comprises: (i) a VH comprising the amino acid sequence shown in any one of SEQ ID NO:1978-1988; and (ii) a VL comprising the amino acid sequence shown in any one of SEQ ID NO:1990-2000. In some cases, the antibody comprises: (i) a VH comprising the amino acid sequence shown in SEQ ID NO:1982; and (ii) a VL comprising the amino acid sequence shown in SEQ ID NO:1997.

[0188] In some cases, the antibody comprises a VH, which comprises VH CDR1, VH CDR2, and VH CDR3 of the antibody described in any one of Tables 1-24, and wherein the VH comprises an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the VH shown in any one of Tables 1-24, respectively. In some cases, the antibody comprises a VH, which comprises VHCDR1, VH CDR2, and VH CDR3 of the antibody described in Table 2, and wherein the VH comprises an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the VH shown in Table 2.

[0189] In some cases, the antibody comprises a VL, which comprises VL CDR1, VL CDR2, and VL CDR3 of the antibody described in any one of Tables 1-24, and wherein the VL comprises an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the VL shown in any one of Tables 1-24, respectively. In some cases, the antibody comprises a VL, which comprises VLCDR1, VL CDR2, and VL CDR3 of the antibody described in Table 2, and wherein the VL comprises an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the VL shown in Table 2.

[0190] In some cases, the antibody comprises: (i) a VH comprising VH CDR1, VH CDR2, and VH CDR3 of the antibody described in any one of Tables 1-24, wherein the VH comprises an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the VH shown in any one of Tables 1-24; and a VL comprising VL CDR1, VL CDR2, and VL CDR3 of the antibody described in any one of Tables 1-24, wherein the VL comprises an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the VL shown in any one of Tables 1-24. In some cases, the antibody comprises: (i) VH, which comprises VH CDR1, VHCDR2 and VH CDR3 of the antibody described in Table 2, and wherein VH comprises an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with VH shown in Table 2; and VL, which comprises VL CDR1, VL CDR2 and VL CDR3 of the antibody described in Table 2, and wherein VL comprises an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with VL shown in Table 2.

[0191] In some cases, the antibody contains a VH, which includes a humanized form of the VH described in any of the tables 1-24.

[0192] In some cases, the antibody comprises a VH, which is a humanized form of the amino acid sequence shown in SEQ ID NO:7. In some cases, the antibody comprises a VH, which is the amino acid sequence shown in any one of SEQ ID NO:1958-1965.

[0193] In some cases, the antibody contains a VL, which includes a humanized form of the VL described in any of the tables 1-24.

[0194] In some cases, the antibody comprises a VL containing a humanized form of the amino acid sequence shown in SEQ ID NO:8. In some cases, the antibody comprises a VL containing the amino acid sequence shown in any one of SEQ ID NO:1967-1976.

[0195] In some cases, the antibody comprises: (i) a humanized form of VH as described in any of the tables in Tables 1-24, and (ii) a humanized form of VL as described in any of the tables in Tables 1-24.

[0196] In some cases, the antibody comprises: (i) a humanized form of VH containing the amino acid sequence shown in SEQ ID NO:7; and (ii) a humanized form of VL containing the amino acid sequence shown in SEQ ID NO:8. In some cases, the antibody comprises: (i) a humanized form of VH containing the amino acid sequence shown in any one of SEQ ID NO:1958-1965; and (ii) a humanized form of VL containing the amino acid sequence shown in any one of SEQ ID NO:1967-1976.

[0197] In some cases, the antibody comprises a heavy chain containing VH comprising VH CDR1, VH CDR2, and VH CDR3 of the amino acid sequence shown in SEQ ID NO:1982, and wherein the heavy chain comprises an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the amino acid sequence shown in SEQ ID NO:2010.

[0198] In some cases, the antibody comprises a light chain containing a VL comprising VL CDR1, VL CDR2, and VL CDR3 of the amino acid sequence shown in SEQ ID NO:1997, and wherein the light chain comprises an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the amino acid sequence shown in SEQ ID NO:2012.

[0199] In some cases, the antibody comprises: (i) a heavy chain comprising VH comprising VH CDR1, VH CDR2, and VH CDR3 of the amino acid sequence shown in SEQ ID NO:1982, and wherein the heavy chain comprises an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the amino acid sequence shown in SEQ ID NO:2010; and (ii) a light chain comprising VL comprising VL CDR1, VL CDR2, and VL CDR3 of the amino acid sequence shown in SEQ ID NO:1997, and wherein the light chain comprises an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the amino acid sequence shown in SEQ ID NO:2012.

[0200] In some cases, the antibody comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:2010.

[0201] In some cases, the antibody comprises a light chain containing the amino acid sequence shown in SEQ ID NO:2012.

[0202] In some cases, the antibody comprises: (i) a heavy chain comprising the amino acid sequence shown in SEQ ID NO:2010; and (ii) a light chain comprising the amino acid sequence shown in SEQ ID NO:2012.

[0203] In some cases, the antibody is the antibody described in International Patent Application Publication No. WO 2017 / 172260, which is incorporated herein by reference in its entirety. In other cases, the antibody is a humanized form of the antibody described in International Patent Application Publication No. WO2017 / 172260, which is incorporated herein by reference in its entirety.

[0204] In some cases, the antibody specifically binds to the same epitope as that described in International Patent Application Publication No. WO 2017 / 172260, which is incorporated herein by reference in its entirety.

[0205] In some cases, antibodies compete with those described in International Patent Application Publication No. WO 2017 / 172260 for binding to human GFRAL, which is incorporated herein by reference in its entirety.

[0206] In some cases, the antibody specifically binds to the same epitope as antibodies with VH and VL as those in any of the tables in Tables 1-24. In some cases, the antibody specifically binds to the same epitope as antibody 3P10 (see Table 1). In some cases, the antibody specifically binds to the same epitope as antibody Hz3P10 (see Table 1A). In some cases, the antibody specifically binds to the same epitope as antibody 5F12 (see Table 2).

[0207] In some cases, the antibody competes with the antibody described in any of Tables 1-24 for binding to human GFRAL. In some cases, the antibody competes with antibodies containing both VH and VL of the antibody described in any of Tables 1-24 for binding to human GFRAL. In some cases, the antibody competes with antibody 3P10 (see Table 1) for binding to human GFRAL. In some cases, the antibody competes with antibody Hz3P10 (see Table 1A) for binding to human GFRAL. In some cases, the antibody competes with antibody 5F12 (see Table 2) for binding to human GFRAL.

[0208] In some cases, antibodies specifically bind to human GFRAL within amino acid residues 220-316 of the amino acid sequence shown in SEQ ID NO: 1797. Non-limiting examples of antibodies that bind to human GFRAL within amino acid residues 220-316 of the amino acid sequence shown in SEQ ID NO: 1797 include 5F12, 3P10, 6G9, 6N16, 2B11, and 1B3 (see working example in International Patent Application Publication No. WO 2017 / 172260, which is incorporated herein by reference in its entirety).

[0209] In some cases, antibodies specifically bind to one or more residues (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19) selected from the group consisting of the following amino acid sequences: Met214, Pro216, Pro217, Gln290, Cys291, Thr292, Cys293, Arg294, Thr295, Ile296, Thr297, Gln298, Ser299, Glu301, Lys305, Gln308, His309, His312, and Ser315. In some cases, the antibody specifically binds to human GFRAL at Thr297, Gln298, and Ser299 of the amino acid sequence shown in SEQ ID NO:1797.

[0210] In some cases, the antibody specifically binds to human GFRAL within amino acid residues 20-130 of the amino acid sequence shown in SEQ ID NO: 1797. In some cases, the antibody does not inhibit the binding of human GDF15 to human GFRAL. Non-limiting examples of antibodies that bind to human GFRAL within amino acid residues 20-130 of the amino acid sequence shown in SEQ ID NO: 1797 include 1A3, P1B6, P1H8, and P8G4 (see working example of International Patent Application Publication No. WO 2017 / 172260, which is incorporated herein by reference in its entirety).

[0211] In some cases, the antibody specifically binds to human GFRAL within amino acid residues 131-210 of the amino acid sequence shown in SEQ ID NO: 1797. In some cases, the antibody inhibits the binding of human GDF15 to human GFRAL. Non-limiting examples of antibodies that bind to human GFRAL within amino acid residues 131-210 of the amino acid sequence shown in SEQ ID NO: 1797 include 17J16, 8C10, 25M22, 12A3, 19K19, 1C1, 8D8, 22N5, 2A9, and 5A20 (see working example of International Patent Application Publication No. WO 2017 / 172260, which is incorporated herein by reference in its entirety).

[0212] In some cases, the antibody specifically binds to one or more residues selected from the group consisting of: GLY140, LEU148, ALA149, ALA146, VAL142, ASN145, VAL139, ALA135, GLU136, LEU152, LEU132, SER201, ALA204, LEU205, LYS153, ILE196, PRO197, and GLN200 of the GFRAL protein (SEQ ID NO: 1797). In some cases, the antibody inhibits the binding of human GFRAL to human GDF15.

[0213] In some cases, the antibody specifically binds to one or more residues selected from the group consisting of: SER156, GLN147, SER150, TYR151, ALA154, CYS155, PHE174, TYR175, ALA137, CYS138, ASP141, VAL143, CYS144, LEU186, CYS189, CYS191, ALA192, GLN193, SER194, ASP195, CYS198, GLN199, LYS202, GLU203, HIS206, SER207, SER130, CYS131, LEU132, GLU133, and VAL134 of the GFRAL protein (SEQ ID NO: 1797). In some cases, the antibody inhibits the binding of human GFRAL to human GDF15.

[0214] In some cases, antibodies specifically bind to one or more residues selected from the group consisting of: SER156, GLN147, LEU148, ALA149, SER150, TYR151, LEU152, LYS153, ALA154, CYS155, PHE174, TYR175, GLU136, ALA137, CYS138, VAL139, GLY140, ASP141, VAL142, VAL143, CYS144, ASN145, ALA146, LEU1 86, CYS189, CYS191, ALA192, GLN193, SER194, ASP195, ILE196, PRO197, CYS198, GLN199, GLN200, SER201, LYS202, GLU203, ALA204, LEU205, HIS206, SER207, SER130, CYS131, LEU132, GLU133, VAL134, and ALA135. In some cases, the antibodies inhibit the binding of human GFRAL to human GDF15.

[0215] In some cases, the antibody specifically binds to one or more residues selected from the group consisting of: GLU136, ALA137, VAL139, GLY140, ASP141, VAL142, VAL143, CYS144, ASN145, ALA146, GLN147, PHE173, ASN177, ILE178, PRO179, ASN181, ILE182, and MET185 of the GFRAL protein (SEQ ID NO: 1797). In some cases, the antibody inhibits the binding of human GFRAL to human GDF15.

[0216] In some cases, the antibody specifically binds to one or more residues selected from the group consisting of: LEU132, GLU133, VAL134, ALA135, CYS138, LEU148, ALA149, SER150, TYR151, PHE174, TYR175, ALA169, ALA170, ILE171, ARG172, GLN176, PHE180, ALA183, GLN184, LEU186, ALA187, PHE188, and CYS189 of the GFRAL protein (SEQ ID NO: 1797). In some cases, the antibody inhibits the binding of human GFRAL to human GDF15.

[0217] In some cases, antibodies specifically bind to one or more residues selected from the group consisting of: LEU132, GLU133, VAL134, ALA135, GLU136, ALA137, CYS138, VAL139, GLY140, ASP141, VAL142, VAL143, CYS144, ASN145, ALA146, GLN147, LEU148, ALA149, SER150, TYR151 of the GFRAL protein (SEQ ID NO: 1797). PHE174, TYR175, ALA169, ALA170, ILE171, ARG172, PHE173, GLN176, ASN177, ILE178, PRO179, PHE180, ASN181, ILE182, ALA183, GLN184, MET185, LEU186, ALA187, PHE188, and CYS189. In some cases, the antibodies inhibit the binding of human GFRAL to human GDF15.

[0218] In some cases, the antibody specifically binds to one or more residues selected from the group consisting of: MET214, PRO216, PRO217, GLN290, CYS291, THR292, CYS293, ARG294, THR295, ILE296, THR297, GLN298, SER299, GLU301, LYS305, GLN308, HIS309, HIS312, and SER315 of the GFRAL protein (SEQ ID NO: 1797). In some cases, the antibody inhibits the binding of human GFRAL to human RET.

[0219] In some cases, antibodies are humanized antibodies.

[0220] Various methods for generating humanized antibodies are known in the art. In some embodiments, the humanized antibody comprises one or more amino acid residues introduced therefrom from a non-human source. In some embodiments, humanization is performed by replacing the corresponding CDR sequence of a human antibody with one or more non-human CDR sequences. In some embodiments, the humanized antibody is constructed by replacing the corresponding CDR of a human antibody with all six CDRs of a non-human antibody (e.g., a mouse antibody).

[0221] The choice of which human heavy chain variable region and / or light chain variable region to use for generating humanized antibodies can be based on a variety of factors and through various methods known in the art. In some embodiments, a "best-fit" approach is used, where variable region sequences for non-human (e.g., rodent) antibodies are screened against an entire library of known human variable region sequences. This is similar to selecting the human sequence most similar to the non-human (e.g., rodent) sequence as the human variable region framework for the humanized antibody. In some embodiments, a specific variable region framework derived from a common sequence of all human antibodies from a particular light chain or heavy chain subgroup is selected as the variable region framework. In some embodiments, the variable region framework sequence is derived from a common sequence of the most abundant human subclass. In some embodiments, human germline genes are used as the source of the variable region framework sequence.

[0222] Other humanization methods include, but are not limited to: methods referred to as “hyperhumanization,” which are described as directly transferring CDRs to human germline architectures; methods referred to as Human String Content (HSC), which are based on “antibody humanity” measures; methods based on the generation of large humanized variant libraries (including phage, ribosome, and yeast display libraries); and methods based on architecture region shuffling.

[0223] In some cases, the antibody is a human IgG1 antibody. In some cases, the antibody is a human IgG2 antibody. In some cases, the antibody is a human IgG4 antibody. In some cases, the antibody contains the human κ light chain constant region. In some cases, the antibody contains the human λ light chain constant region.

[0224] In some cases, an antibody is an antibody fragment containing at least one antigen-binding site. In some embodiments, the antibody or antibody fragment is Fab, Fab′, F(ab′)2, Fv, scFv, (scFv)2, single-chain antibody, dual-variable-region antibody, single-variable-region antibody, linear antibody, double-chain antibody, nanobody, or V-region antibody.

[0225] In some cases, the antibody is a bispecific antibody. In some cases, a bispecific antibody comprises the first VH and first VL of a first antibody (e.g., 3P10, Hz3p10, 5F12, or humanized 5F12) and the second VH and second VL of a second antibody.

[0226] The antibodies described herein can be produced by any suitable method known in the art. Such methods range from direct protein synthesis methods to constructing DNA sequences encoding polypeptide sequences and expressing those sequences in a suitable host. For a description of the various methods for producing antibodies, see, for example, International Patent Application Publication No. WO 2017 / 172260, which is incorporated herein by reference in its entirety.

[0227] This document also provides pharmaceutical compositions comprising the antibodies described herein and pharmaceutically acceptable carriers. The pharmaceutical compositions described herein may be used in the methods described herein.

[0228] In some cases, the pharmaceutical composition comprises the antibody described herein and a pharmaceutically acceptable carrier. In some cases, the pharmaceutical composition comprises: an antibody comprising VH, said VH comprising VH CDR1, VHCDR2, and VH CDR3 of antibody 3P10 or Hz3P10 (see Tables 1 and 1A); and VL comprising VL CDR1, VL CDR2, and VL CDR3 of antibody 3P10 or Hz3P10 (see Tables 1 and 1A); and a pharmaceutically acceptable carrier. In some cases, the pharmaceutical composition comprises: an antibody comprising VH containing the amino acid sequence shown in SEQ ID NO:1982 and VL containing the amino acid sequence shown in SEQ ID NO:1997; and a pharmaceutically acceptable carrier. In some cases, the pharmaceutical composition comprises: an antibody comprising a heavy chain containing the amino acid sequence shown in SEQ ID NO:2010 and a light chain containing the amino acid sequence shown in SEQ ID NO:2012; and a pharmaceutically acceptable carrier.

[0229] This document also provides a kit containing the antibody or pharmaceutical composition described herein. In some cases, the kit is used in the methods described herein. In some cases, the kit provides instructions for using the antibody or pharmaceutical composition in the methods described herein.

[0230] C. Method GDF15 has been shown to induce nausea and vomiting. Furthermore, genome-wide association studies have identified GDF15 as associated with HG, and higher levels of circulating GDF15 have been associated with vomiting during pregnancy. Therefore, the antibodies described herein (or pharmaceutical compositions containing said antibodies) may be used to treat, reduce, or prevent nausea, vomiting, or a combination thereof in human subjects (e.g., human subjects with NVP or HG).

[0231] Nausea and vomiting during pregnancy (NVP) (also known as “morning sickness”) affects up to 70% of pregnant women. NVP usually subsides by week 14 of pregnancy. NVP is characterized by: weight loss, adequate food intake for most of the time, unpleasant nausea and vomiting but not limiting most basic activities, the ability to modify diet and lifestyle to make symptoms largely manageable, symptoms usually not significantly relieved until week 14 of pregnancy, and the ability to perform daily duties (such as household responsibilities and employment-related activities) for most of the time, especially after week 14 of pregnancy. NVP can be mild, moderate, or severe.

[0232] Hyperemesis gravidarum (HG) is generally considered a more severe form of non-pregnant vomiting (NVP). It is estimated that HG affects as many as approximately 3% to 11% of pregnant women. Hyperemesis gravidarum is characterized by weight loss of at least 5%, persistent inadequate food intake for weeks or months, distressing nausea and vomiting that often limits daily activities (including self-care), necessary medical treatment for nausea and vomiting (usually including intravenous rehydration and parenteral nutrition), symptoms that may subside or persist until delivery, and difficulty or inability to perform household responsibilities for weeks to months. The International Classification of Diseases (ICD) describes HG as mild or accompanied by metabolic disturbances. In some cases, mild HG is vomiting that occurs during pregnancy in response to dietary changes and antiemetic treatment. In other cases, HG with metabolic disturbances is vomiting that is unresponsive to dietary changes and antiemetic treatment and is associated with electrolyte disturbances and acid-base imbalances. HG typically appears between the 6th and 8th weeks of gestation and usually persists until the 16th to 20th weeks of gestation, but can continue until delivery.

[0233] This article provides a method for treating nausea, vomiting, or a combination thereof in a human subject in need, the method comprising administering to the human subject a therapeutically effective amount of an antibody that specifically binds to human GFRAL (e.g., the antibody described herein) or a pharmaceutical composition comprising said antibody (e.g., as described herein). In some cases, the human subject does not vomit for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 doses of antibody (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 days or more after administration of the antibody. In some cases, human subjects experienced fewer than 2, 3, 4, 5, 6, 7, 8, 9, or 10 doses of antibody, or more, vomiting fewer than 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 times within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 times within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days after antibody administration. In some cases, human subjects did not experience dry heaving within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days after antibody administration. In some cases, human subjects experienced fewer than 2, 3, 4, 5, 6, 7, 8, 9, or 10 days of dry heaving (e.g., at doses 1, 2, 3, 4, 5, 6, 7, 8, 9, 9, 10, 11, 12, 13, 14, or 15 times) within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days after antibody administration (e.g., at doses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10). In some cases, human subjects did not experience nausea within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days of dry heaving (e.g., at doses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10). In some cases, human subjects were pregnant (e.g., in the first, second, or third trimester of pregnancy). In some cases, human subjects have, are suspected of having hemorrhagic vomiting (HG) (e.g., having 1, 2, 3, 4, 5, 6, 7, 8 or more HG symptoms) or are at risk of developing HG (e.g., pregnancy). In some cases, human subjects have HG. In some cases, human subjects have, are suspected of having non-emetic vomiting (NVP) (e.g., having 1, 2, 3, 4, 5, 6, 7, 8 or more NVP symptoms) or are at risk of developing NVP (e.g., pregnancy). In some cases, human subjects experience nausea, vomiting or a combination thereof that is unresponsive to antiemetic treatment (e.g., nausea, vomiting or a combination thereof persists for 1, 2, 3, 4, 5, 6, 7 days after antiemetic treatment). In some cases, the antibody is Hz3P10.In some cases, the antibody comprises the CDR or VH and VL of antibody Hz3P10 (see Table 1 for CDR and Table 1A for VH and VL). In some cases, the antibody is 3P10 or a humanized variant thereof (see, for example). Figure 5A and Figure 5B In some cases, the antibody is 5F12 or its humanized variant (see, for example...). Figure 4A and Figure 4B In some cases, the antibody contains the CDR or VH and VL of antibody Hz3P10 (see Table 2).

[0234] This document provides a method for preventing nausea, vomiting, or a combination thereof in human subjects in need, the method comprising administering to the human subject a therapeutically effective amount of an antibody that specifically binds to human GFRAL (e.g., the antibody described herein) or a pharmaceutical composition containing said antibody (e.g., as described herein). In some cases, the human subject does not vomit for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 doses of the antibody (e.g., doses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), for 11, 12, 13, 14 days or more after administration of the antibody. In some cases, the human subject does not dry heave for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 doses of the antibody (e.g., doses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), for 11, 12, 13, 14 days or more after administration of the antibody. In some cases, human subjects did not experience nausea for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days after antibody administration (e.g., doses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or more days after administration of the antibody. In some cases, human subjects were pregnant (e.g., in the first, second, or third trimester of pregnancy). In some cases, human subjects had, were suspected of having hepatitis G (e.g., having 1, 2, 3, 4, 5, 6, 7, 8, or more hepatitis G symptoms), or were at risk of developing hepatitis G (e.g., pregnancy). In some cases, human subjects had hepatitis G. In some cases, human subjects had, were suspected of having non-performing pneumonia (e.g., having 1, 2, 3, 4, 5, 6, 7, 8, or more non-performing pneumonia symptoms), or were at risk of developing non-performing pneumonia (e.g., pregnancy). In some cases, human subjects experienced nausea, vomiting, or a combination thereof that was unresponsive to treatment with antiemetics (e.g., nausea, vomiting, or a combination thereof persisted for 1, 2, 3, 4, 5, 6, or 7 days after treatment with antiemetics). In some cases, the antibody was Hz3P10. In some cases, the antibody contained the CDR or VH and VL of antibody Hz3P10 (see Table 1 for CDR and Table 1A for VH and VL). In some cases, the antibody was 3P10 or a humanized variant thereof (see, for example...). Figure 5A and Figure 5BIn some cases, the antibody is 5F12 or its humanized variant (see, for example...). Figure 4A and Figure 4B In some cases, the antibody contains the CDR or VH and VL of antibody Hz3P10 (see Table 2).

[0235] This article provides a method for treating hemorrhagic encephalopathy (HG), such as mild HG or HG with metabolic disturbances, in human subjects in need. The method comprises administering to the human subject a therapeutically effective amount of an antibody that specifically binds to human GFRAL (e.g., the antibody described herein) or a pharmaceutical composition containing said antibody (e.g., as described herein). In some cases, the HG is mild HG. In some cases, the HG is HG with metabolic disturbances. In some cases, the human subject does not vomit for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 doses of the antibody (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 doses of the antibody) for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 days or more after administration of the antibody. In some cases, human subjects experienced fewer than 2, 3, 4, 5, 6, 7, 8, 9, or 10 doses of antibody, or more, vomiting fewer than 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 times within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 times within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days after antibody administration. In some cases, human subjects did not experience dry heaving within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days after antibody administration. In some cases, human subjects experienced fewer than 2, 3, 4, 5, 6, 7, 8, 9, or 10 days of dry heaving (e.g., at doses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) or more days after antibody administration (days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10). In some cases, human subjects did not experience nausea (nausea) at any of these times within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days after antibody administration (days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10). In some cases, human subjects were in their first pregnancy. In some cases, human subjects were in their second pregnancy. In some cases, the human subjects were in the third trimester of pregnancy. In some cases, the human subjects experienced nausea, vomiting, or a combination thereof that was unresponsive to treatment with antiemetics (e.g., nausea, vomiting, or a combination thereof persisted for 1, 2, 3, 4, 5, 6, or 7 days after treatment with antiemetics). In some cases, the antibody was Hz3P10. In some cases, the antibody contained the CDR or VH and VL of antibody Hz3P10 (see Table 1 for CDR and Table 1A for VH and VL). In some cases, the antibody was 3P10 or a humanized variant thereof (see, for example...). Figure 5A and Figure 5B In some cases, the antibody is 5F12 or its humanized variant (see, for example...). Figure 4A and Figure 4B In some cases, the antibody contains the CDR or VH and VL of antibody Hz3P10 (see Table 2).

[0236] This document also provides a method for treating NVP (e.g., mild, moderate, or severe NVP) in human subjects in need, the method comprising administering to the human subject a therapeutically effective amount of an antibody that specifically binds to human GFRAL (e.g., the antibody described herein) or a pharmaceutical composition comprising said antibody (e.g., as described herein). In some cases, the human subject does not vomit for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 doses of antibody (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 days or more after administration of the antibody. In some cases, human subjects experienced fewer than 2, 3, 4, 5, 6, 7, 8, 9, or 10 doses of antibody, or more, vomiting fewer than 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 times within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 times within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days after antibody administration. In some cases, human subjects did not experience dry heaving within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days after antibody administration. In some cases, human subjects experienced fewer than 2, 3, 4, 5, 6, 7, 8, 9, or 10 days of dry heaving (e.g., at doses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) or more days after antibody administration (days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10). In some cases, human subjects did not experience nausea (nausea) at any of these times within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days after antibody administration (days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10). In some cases, human subjects were in their first pregnancy. In some cases, human subjects were in their second pregnancy. In some cases, the human subjects were in the third trimester of pregnancy. In some cases, the human subjects experienced nausea, vomiting, or a combination thereof that was unresponsive to treatment with antiemetics (e.g., nausea, vomiting, or a combination thereof persisted for 1, 2, 3, 4, 5, 6, or 7 days after treatment with antiemetics). In some cases, the antibody was Hz3P10. In some cases, the antibody contained the CDR or VH and VL of antibody Hz3P10 (see Table 1 for CDR and Table 1A for VH and VL). In some cases, the antibody was 3P10 or a humanized variant thereof (see, for example...). Figure 5A and Figure 5BIn some cases, the antibody is 5F12 or its humanized variant (see, for example...). Figure 4A and Figure 4B In some cases, the antibody contains the CDR or VH and VL of antibody Hz3P10 (see Table 2).

[0237] This document also provides a method for treating nausea, vomiting, or a combination thereof in a human subject in need, the method comprising administering to the human subject a therapeutically effective amount of an antibody that specifically binds to human GFRAL (e.g., the antibody described herein) or a pharmaceutical composition containing said antibody (e.g., as described herein), wherein the human subject has unresolved nausea, vomiting, or a combination thereof following treatment with an antiemetic. In some cases, the human subject does not vomit for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 doses of antibody (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 doses of antibody) for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 days or more after administration of the antibody. In some cases, human subjects experienced fewer than 2, 3, 4, 5, 6, 7, 8, 9, or 10 doses of antibody, or more, vomiting fewer than 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 times within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 times within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days after antibody administration. In some cases, human subjects did not experience dry heaving within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days after antibody administration. In some cases, human subjects experienced fewer than 2, 3, 4, 5, 6, 7, 8, 9, or 10 days of dry heaving (e.g., at doses 1, 2, 3, 4, 5, 6, 7, 8, 9, 9, 10, 11, 12, 13, 14, or 15 times) within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days after antibody administration (e.g., at doses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10). In some cases, human subjects did not experience nausea within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days of dry heaving (e.g., at doses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10). In some cases, human subjects were pregnant (e.g., in the first, second, or third trimester of pregnancy). In some cases, human subjects have, are suspected of having hepatitis G (e.g., having 1, 2, 3, 4, 5, 6, 7, 8 or more hepatitis G symptoms), or are at risk of developing hepatitis G (e.g., pregnancy). In some cases, human subjects have hepatitis G. In some cases, human subjects have, are suspected of having non-viral phlegm-phlegm (e.g., having 1, 2, 3, 4, 5, 6, 7, 8 or more non-viral phlegm-phlegm symptoms), or are at risk of developing non-viral phlegm-phlegm (e.g., pregnancy).In some cases, human subjects experienced nausea, vomiting, or a combination thereof that did not respond to treatment with antiemetics (e.g., nausea, vomiting, or a combination thereof persisted for 1, 2, 3, 4, 5, 6, or 7 days after treatment with antiemetics). In some cases, unresolved vomiting included 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 doses of antiemetics for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days after treatment with antiemetics, or 15 or more vomiting episodes. In some cases, unresolved vomiting includes 1 to 4, 2 to 6, 3 to 7, 4 to 8, 5 to 9, 6 to 10, 7 to 11, 8 to 12, 9 to 13, 10 to 14, or 11 to 15 vomiting episodes following treatment with antiemetics (e.g., within 1 to 10 days of antiemetics). In some cases, vomiting episodes occur daily. In some cases, vomiting episodes are the average number of vomiting episodes over a period of several days (e.g., days 1, 2, 3, 4, 5, 6, 9, 10). In some cases, unresolved vomiting includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 doses of antiemetics for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days, 11, 12, 13, 14 or more dry heaving episodes per day after treatment with antiemetics. In some cases, unresolved vomiting includes 1 to 4, 2 to 6, 3 to 7, 4 to 8, 5 to 9, 6 to 10, 7 to 11, 8 to 12, 9 to 13, 10 to 14, or 11 to 15 dry heaving episodes per day after treatment with antiemetics (e.g., within 1 to 21 days of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 days of antiemetic treatment). In some cases, dry heaving episodes occur daily. In some cases, dry heaving episodes are the average number of episodes over a period of several days (e.g., days 1, 2, 3, 4, 5, 6, 7). In some cases, the antibody is Hz3P10. In some cases, the antibody comprises the CDR or VH and VL of antibody Hz3P10 (see Table 1 for CDR and Table 1A for VH and VL). In some cases, the antibody is 3P10 or a humanized variant thereof (see, for example). Figure 5A and Figure 5B In some cases, the antibody is 5F12 or its humanized variant (see, for example...). Figure 4A and Figure 4B In some cases, the antibody contains the CDR or VH and VL of antibody Hz3P10 (see Table 2).

[0238] Antiemetics are medications that relieve nausea or vomiting. Antiemetics are known in the art. Non-limiting examples of antiemetics include aprepitant, dexamethasone, dimenhydrinate, diphenhydramine, dolasetron, dolasetron, fluphenazine, granisetron, meclizine, metoclopramide, ondansetron, palonosetron, prochlorperazine, promethazine, rolapitant, and vitamin B6 (pyridoxine). Additional treatments for nausea, vomiting, or combinations thereof include ginger, acupuncture, acupressure, acupoint stimulation, peppermint oil, lavender oil, and lemon oil.

[0239] Nausea, vomiting, or combinations thereof (e.g., in NVP or HG) are also associated with a number of sequelae, including hyponatremia, hypovolemia, ketonuria, electrolyte abnormalities, vitamin deficiencies, and weight loss. Therefore, the antibodies described herein may also be used to treat sequelae of nausea, vomiting, or combinations thereof in human subjects (e.g., human subjects with NVP or HG), such as hyponatremia, hypovolemia, ketonuria, electrolyte abnormalities, vitamin deficiencies, and weight loss.

[0240] Therefore, this document also provides a method for treating hypovolemia in human subjects in need, the method comprising administering to the human subject a therapeutically effective amount of an antibody specifically binding to human GFRAL (e.g., the antibody described herein) or a pharmaceutical composition containing said antibody (e.g., as described herein), wherein the human subject suffers from nausea, vomiting, or a combination thereof. This document also provides a method for treating weight loss in human subjects in need, the method comprising administering to the human subject a therapeutically effective amount of an antibody specifically binding to human GFRAL (e.g., the antibody described herein) or a pharmaceutical composition containing said antibody (e.g., as described herein), wherein the human subject is pregnant, and wherein the human subject suffers from nausea, vomiting, or a combination thereof (e.g., HG or NVP). This document also provides a method for treating electrolyte abnormalities in human subjects in need, the method comprising administering to the human subject a therapeutically effective amount of an antibody specifically binding to human GFRAL (e.g., the antibody described herein) or a pharmaceutical composition containing said antibody (e.g., as described herein), wherein the human subject suffers from nausea, vomiting, or a combination thereof (e.g., HG or NVP). This article also provides a method for treating ketonuria in human subjects in need, the method comprising administering to a human subject a therapeutically effective amount of an antibody that specifically binds to human GFRAL (e.g., the antibody described herein) or a pharmaceutical composition containing said antibody (e.g., as described herein), wherein the human subject suffers from nausea, vomiting, or a combination thereof (e.g., HG or NVP).

[0241] In some cases of the methods described herein, the human subject has been diagnosed with HG. In some cases of the methods described herein, the human subject is at risk of developing HG. In some cases of the methods described herein, the human subject has one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8) HG symptoms.

[0242] In some cases of the methods described herein, the human subject has been diagnosed with NVP. In some cases of the methods described herein, the human subject is at risk of developing NVP. In some cases of the methods described herein, the human subject has one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8) NVP symptoms.

[0243] In some cases, the human subjects were in the first trimester of pregnancy. In some cases, they were in the second trimester. In some cases, they were in the third trimester. In some cases, they were 1 to 12 weeks pregnant. In some cases, they were 12 to 24 weeks pregnant. In some cases, they were 24 to 40 weeks pregnant. In some cases, human subjects were in the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, 30th, 31st, 32nd, 33rd, 34th, 35th, 36th, 37th, 38th, 39th, or 40th week of pregnancy.

[0244] In some cases, biological samples obtained from human subjects have elevated levels of GDF15. In some cases, biological samples are obtained from human subjects at baseline (i.e., prior to antibody administration, e.g., within 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days prior to antibody administration). In some cases, the biological samples are blood, plasma, or serum samples. In some cases, GDF15 levels are elevated compared to control levels in humans who did not have NVP, HG, nausea or vomiting, or were not pregnant, or in a group of humans (e.g., 2, 3, 4, 5, 10, 15, 20, 25, or more humans). In some cases, the GDF15 level is the mRNA level of GDF15. In some cases, the GDF15 level is the protein level of GDF15. In some cases, biological samples (e.g., serum) obtained from human subjects have a concentration of at least 500 pg / mL (e.g., at least 500 pg / mL, at least 750 pg / mL, at least 1,000 pg / mL, at least 1,500 pg / mL, at least 2,000 pg / mL, at least 3,000 pg / mL, at least 4,000 pg / mL, at least 5,000 pg / mL, at least 6,000 pg / mL, at least 7,000 pg / mL, at least 8,000 pg / mL, at least 9,000 pg / mL, at least 10,000 pg / mL, at least 15,000 pg / mL, at least 20,000 pg / mL, at least 25,000 pg / mL, at least 30,000 pg / mL, at least 35,000 pg / mL, at least 40,000 pg / mL, at least 45,000 pg / mL). GDF15 levels are typically between 1,000 pg / mL and 60,000 pg / mL (or at least 50,000 pg / mL). In some cases, biological samples (e.g., serum) obtained from human subjects have GDF15 levels between 2,000 pg / mL and 60,000 pg / mL (inclusive). In some cases, biological samples (e.g., serum) obtained from human subjects have GDF15 levels between 5,000 pg / mL and 60,000 pg / mL (inclusive). In some cases, biological samples (e.g., serum) obtained from human subjects have GDF15 levels between 8,000 pg / mL and 15,000 pg / mL (inclusive).

[0245] In some cases, human subjects did not respond to the antiemetic. In some cases, the antiemetic was promethazine or ondansetron. In some cases, human subjects were given one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) doses of the antiemetic, but still experienced nausea, vomiting, or a combination thereof.

[0246] In some cases, human subjects did not respond to conservative treatments for nausea and vomiting during pregnancy. Conservative treatments included dietary adjustments, emotional support, ginger, acupressure, or combinations thereof. In some cases, human subjects did not respond to intravenous fluid replacement, antiemetics, corticosteroids, or parenteral nutrition, or combinations thereof.

[0247] The Pregnancy-Unique Quantification of Emesis (PUQE) questionnaire can be used to measure the severity of NVP or HG (see Koren et al., 2002, Am. J. Obstet Gynecol., 186(5: Suppl Understanding): S228-31, which is incorporated herein by reference in its entirety). It is based on the number of vomiting episodes per day, the duration of nausea per day (in hours), and the number of dry heaving episodes. In some cases, human subjects had a PUQE score of 4 to 6 at baseline (i.e., prior to antibody administration, e.g., within 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 days prior to antibody administration). In some cases, human subjects had a PUQE score of 7 to 12 at baseline. In some cases, human subjects had a PUQE score of 13 or higher at baseline.

[0248] In some cases, human subjects vomited 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days prior to antibody administration, at baseline. In some cases, human subjects vomited 1-2 times per day at baseline. In some cases, human subjects vomited 3-5 times per day at baseline. In some cases, human subjects vomited 6-8 times per day at baseline. In some cases, human subjects vomited 9-12 times per day at baseline. In some cases, human subjects vomited 13 times or more per day at baseline. In some cases, human subjects dry heaved 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days prior to antibody administration, at baseline.

[0249] In some cases, human subjects experienced dry heaving 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days prior to antibody administration (i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 times or more per day at baseline. In some cases, human subjects experienced dry heaving 1-2 times per day at baseline. In some cases, human subjects experienced dry heaving 3-5 times per day at baseline. In some cases, human subjects experienced dry heaving 6-8 times per day at baseline. In some cases, human subjects experienced dry heaving 9-12 times per day at baseline. In some cases, human subjects experienced dry heaving 13 times or more per day at baseline.

[0250] In some cases, human subjects experienced a weight loss of at least 1%, at least 2%, at least 3%, at least 4%, or at least 5% within a timeframe (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10) prior to antibody administration (e.g., within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days prior to antibody administration). In other cases, human subjects experienced a weight loss of 1%-10%, 1%-7%, 1%-5%, 3%-10%, 3%-7%, 3%-5%, or 5%-10% within a timeframe (e.g., within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days prior to antibody administration).

[0251] In some cases, the method includes administering a single dose of a therapeutically effective amount of the antibody to a human subject. In some cases, the single dose is administered during the first trimester of pregnancy. In some cases, the single dose is administered during the second trimester of pregnancy. In some cases, the single dose is administered during the third trimester of pregnancy. In some cases, the single dose is administered during either the first or second trimester of pregnancy. In some cases, the single dose is administered during either the second or third trimester of pregnancy. In some cases, a single dose is administered during the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, eleventh, thirteenth, eleventh, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, or thirteenth week of pregnancy.

[0252] In some cases, the method includes administering a therapeutically effective amount of the antibody to a human subject at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 doses, or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more doses. In some cases, the dosage is administered once every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, every 8 weeks, every 9 weeks, or every 10 weeks. In some cases, the dosage is administered once every approximately 4 weeks. In some cases, the dosage is administered once every approximately 4 weeks. In some cases, the dosage is administered once every approximately 3 weeks. In some cases, the dosage is administered every 3 weeks. In some cases, the first dose is administered during the first trimester of pregnancy. In some cases, the first dose is administered during the second trimester of pregnancy. In some cases, the first dose is administered during the third trimester of pregnancy. In some cases, the first dose is administered during either the first or second trimester of pregnancy. In some cases, the first dose is administered during either the second or third trimester of pregnancy. In some cases, the first dose is administered during weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 of pregnancy. In some cases, the last dose is administered during the first trimester. In some cases, the last dose is administered during the second trimester. In some cases, the last dose is administered during the third trimester. In some cases, the final dose is administered during the first or second trimester of pregnancy. In other cases, the final dose is administered during the second or third trimester of pregnancy.In some cases, the dosage is administered during the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, eleventh, thirteenth, eleventh, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, thirteenth, or thirteenth week of pregnancy.

[0253] In some cases, the therapeutically effective dose of the antibody is 1 mg to 150 mg, 10 mg to 150 mg, 25 mg to 150 mg, 50 mg to 150 mg, 75 mg to 125 mg, 90 mg to 110 mg, 95 mg to 105 mg, 10 mg to 50 mg, 20 mg to 40 mg, and 25 mg to 35 mg. In some cases, the therapeutically effective dose is about 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, or more. In some cases, the therapeutically effective dose is about 100 mg. In some cases, the therapeutically effective dose is about 75 mg. In some cases, the therapeutically effective dose is about 30 mg. In some cases, the therapeutically effective dose is 100 mg. In some cases, the therapeutically effective dose is 75 mg. In some cases, the effective therapeutic dose is 30 mg.

[0254] In some cases, therapeutically effective amounts of antibodies are administered subcutaneously to human subjects.

[0255] In some cases, therapeutically effective doses of antibodies are administered intravenously to human subjects.

[0256] In some cases, human subjects did not lose more than 1%, 2%, 3%, 4%, or 5% of their body weight within a certain timeframe (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10) following antibody administration (e.g., within 1, 2, 3, 4, 4, 5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 days after administration of 1, 2, 3, 4, 5, or more doses of antibody). In some cases, no weight loss was observed until the third trimester. In some cases, no weight loss was observed until the end of pregnancy. In some cases, no weight loss is relative to the subject's weight before treatment. In other cases, given that subjects typically gain weight gradually during pregnancy, no weight loss is relative to the subject's expected weight and / or weight gain during the stated gestational stage. In other cases, no weight loss was defined as no change in the rate of weight gain after treatment relative to a normal subject who had not yet received therapy.

[0257] In some cases, the methods described herein reduce the PUQE score of human subjects by at least 0.5, at least 0.75, at least 1.0, at least 1.25, at least 1.5, at least 1.75, at least 2, at least 2.25, at least 2.5, at least 2.75, at least 3, at least 3.25, at least 3.5, at least 3.75, at least 4, at least 4.25, at least 4.5, at least 4.75, at least 5, at least 5.25, at least 5.5, at least 5.75, at least 6, at least 6.25, at least 6.5, at least 6.75, at least 7, at least 7.25, at least 7.5, at least 7.75, or at least 8 compared to baseline (i.e., before antibody administration, for example, within 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days before antibody administration). In some cases, the methods described herein reduced PUQE scores in human subjects to less than 10, less than 9, less than 8, less than 7, less than 6, or less than 5 (e.g., within 1, 2, 3, 4, 5, or 21 days after administration of 1, 2, 3, 4, 5, or 21 doses of the antibody). In some cases, a reduction in PUQE scores in human subjects was observed up to the third trimester. In some cases, a reduction in PUQE scores in human subjects was observed up to the end of pregnancy.

[0258] In some cases, the methods described herein reduce the number of daily vomiting episodes by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days prior to antibody administration by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 or more times compared to baseline (i.e., before antibody administration, for example, within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 days prior to antibody administration). In some cases, the methods described herein reduce the number of daily vomiting episodes to less than 13, less than 12, less than 11, less than 10, less than 9, less than 8, less than 7, less than 6, less than 5, less than 4, less than 3, less than 2, 1, or 0 times (e.g., within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days after administration of 1, 2, 3, 4, 5, or 21 doses of antibody). In some cases, the reduction in the frequency of vomiting is the average number of vomiting episodes over 2, 3, 4, 5, 6, 7, 8, 9, or 10 days. In some cases, the reduction in the frequency of vomiting is observed to last for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, or at least 15 weeks. In some cases, the reduction in the frequency of vomiting is observed until the third trimester. In some cases, the reduction in the frequency of vomiting is observed until the end of pregnancy.

[0259] In some cases, the methods described herein reduce the number of daily nausea episodes by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days prior to antibody administration by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 or more times compared to baseline (i.e., before antibody administration, for example, within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 times). In some cases, the methods described herein reduce the number of daily nausea episodes to less than 13, less than 12, less than 11, less than 10, less than 9, less than 8, less than 7, less than 6, less than 5, less than 4, less than 3, less than 2, 1, or 0 times (e.g., within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days after administration of 1, 2, 3, 4, 5, or 21 doses of antibody). In some cases, the reduction in the frequency of nausea is the average number of nausea episodes over 2, 3, 4, 5, 6, 7, 8, 9, or 10 days. In some cases, the reduction in the frequency of nausea is observed to last for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, or 15 weeks. In some cases, the reduction in the frequency of nausea is observed until the third trimester. In some cases, the reduction in the frequency of nausea is observed until the end of pregnancy.

[0260] In some cases, the methods described herein reduce the severity of nausea to moderate, mild, or no nausea. Methods for scoring nausea are known in the art. For example, nausea can be scored on a scale of 0 to 5, where 0 is no nausea, 1 to 2 are mild nausea, 3-4 are moderate nausea, and 5 is severe nausea. In some cases, reduction in nausea severity occurs within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days after administration of 1, 2, 3, 4, 5, or more doses of the antibody. In some cases, reduction in nausea severity is observed until the third trimester. In some cases, reduction in nausea severity is observed until the end of pregnancy.

[0261] In some cases, the methods described herein further include administering an antiemetic to the subject, or another therapy for nausea, vomiting, or a combination thereof. Non-limiting examples of antiemetics include aprepitant, dexamethasone, dimenhydrinate, diphenhydramine, dolasetron, dolacemin (e.g., dolacemin succinate), droperidol, granisetron, meclopramide, ondansetron, palonosetron, prochlorperazine, chlorpromazine, promethazine, lorapidan, and vitamin B6 (pyridoxine, such as pyridoxine hydrochloride). Additional treatments for nausea, vomiting, or a combination thereof include ginger, acupuncture, acupressure, acupoint electrostimulation, and essential oils (e.g., peppermint oil, lavender oil, and lemon oil). In some cases, the additional treatment is a dual-release formulation of dolacemin and pyridoxine.

[0262] In some cases, the antibody comprises (i) VH, which comprises VH CDR1, VH CDR2, and VH CDR3 of the amino acid sequence shown in SEQ ID NO:3 or 1982; and (ii) VL, which comprises VL CDR1, VL CDR2, and VL CDR3 of the amino acid sequence shown in SEQ ID NO:4 or 1997. In some cases, the antibody comprises: (i) VH, which comprises VH CDR1 of the amino acid sequence shown in SEQ ID NO:46, VH CDR2 of the amino acid sequence shown in SEQ ID NO:137, and VH CDR3 of the amino acid sequence shown in SEQ ID NO:225; and (ii) VL, which comprises VL CDR1 of the amino acid sequence shown in SEQ ID NO:301, VL CDR2 of the amino acid sequence shown in SEQ ID NO:376, and VL CDR3 of the amino acid sequence shown in SEQ ID NO:426. In some cases, the antibody comprises: (i) VH, which comprises VH CDR1 comprising the amino acid sequence shown in SEQ ID NO:48, VH CDR2 comprising the amino acid sequence shown in SEQ ID NO:137, and VH CDR3 comprising the amino acid sequence shown in SEQ ID NO:225; and (ii) VL, which comprises VL CDR1 comprising the amino acid sequence shown in SEQ ID NO:301, VL CDR2 comprising the amino acid sequence shown in SEQ ID NO:376, and VL CDR3 comprising the amino acid sequence shown in SEQ ID NO:426. In some cases, the antibody comprises: (i) a VH containing an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the amino acid sequence shown in SEQ ID NO:1982; and (ii) a VL containing an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the amino acid sequence shown in SEQ ID NO:1997. In some cases, the antibody comprises a VH containing the amino acid sequence shown in SEQ ID NO:1982. In some cases, the antibody comprises a VL containing the amino acid sequence shown in SEQ ID NO:1997. In some cases, the antibody comprises: (i) a VH containing the amino acid sequence shown in SEQ ID NO:1982; and (ii) a VL containing the amino acid sequence shown in SEQ ID NO:1997.In some cases, the antibody comprises a heavy chain having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the amino acid sequence shown in SEQ ID NO:2010. In some cases, the antibody comprises a light chain having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the amino acid sequence shown in SEQ ID NO:2012. In some cases, the antibody comprises: (i) a heavy chain comprising an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the amino acid sequence shown in SEQ ID NO:2010; and (ii) a light chain comprising an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the amino acid sequence shown in SEQ ID NO:2012. In some cases, the antibody comprises a heavy chain comprising the amino acid sequence shown in SEQ ID NO:2010. In some cases, the antibody comprises a heavy chain consisting of the amino acid sequence shown in SEQ ID NO:2010. In some cases, the antibody comprises a light chain comprising the amino acid sequence shown in SEQ ID NO:2012. In some cases, the antibody comprises a light chain consisting of the amino acid sequence shown in SEQ ID NO:2012. In some cases, the antibody comprises: (i) a heavy chain comprising the amino acid sequence shown in SEQ ID NO:2010; and (ii) a light chain comprising the amino acid sequence shown in SEQ ID NO:2012. In some cases, the antibody comprises: (i) a heavy chain consisting of the amino acid sequence shown in SEQ ID NO:2010; and (ii) a light chain consisting of the amino acid sequence shown in SEQ ID NO:2012. In some cases, the therapeutically effective amount of the antibody is about 30 mg. In some cases, the therapeutically effective amount of the antibody is 30 mg. In some cases, the therapeutically effective amount of the antibody is about 100 mg. In some cases, the therapeutically effective amount of the antibody is 100 mg. In some cases, the antibody is administered approximately every 2, 3, 4, 5, 6, 7, or 8 weeks, or even only once, twice, or three times during pregnancy. In some cases, the antibody is administered every 3 or 4 weeks. In some cases, the therapeutically effective amount is about 30 mg, administered approximately every 3 or 4 weeks.In some cases, the effective therapeutic dose of the antibody is 30 mg, administered every 3 or 4 weeks. In some cases, the effective therapeutic dose of the antibody is approximately 100 mg, administered approximately every 3 or 4 weeks. In some cases, the effective therapeutic dose of the antibody is 100 mg, administered every 3 or 4 weeks. In some cases, the antibody is administered subcutaneously. In some cases, the antibody is administered subcutaneously at a dose of 30 mg every 3 or 4 weeks. In some cases, the antibody is administered subcutaneously at a dose of 100 mg every 3 or 4 weeks. In some cases, the effective therapeutic dose is 30 mg or 100 mg and is administered once, twice, or three times throughout the pregnancy. In some cases, the antibody is administered as needed to control symptoms.

[0263] In some cases, the antibody comprises the CDR, VH, and VL of antibody Hz3P10, or the heavy and light chains (see Table 1A). In some cases, the method involves administering a single dose of the antibody. In some cases, the single dose is administered during the first trimester. In some cases, the single dose is administered during the second trimester. In some cases, the single dose is administered during the third trimester. In some cases, the single dose is about 30 mg. In some cases, the single dose is about 100 mg. In some cases, the single dose is 30 mg. In some cases, the single dose is 100 mg. In some cases, it is administered subcutaneously.

[0264] In some cases, the antibody comprises the CDR, VH, and VL of antibody Hz3P10, or the heavy and light chains (see Table 1A). In some cases, the method involves administering more than one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more) dose of the antibody. In some cases, the first dose is administered during the first trimester. In some cases, the first dose is administered during the second trimester. In some cases, the first dose is administered during the third trimester. In some cases, the single dose is 30 mg. In some cases, the single dose is 100 mg. In some cases, the single dose is about 30 mg. In some cases, the single dose is about 100 mg. In some cases, it is administered subcutaneously.

[0265] In some cases, the antibody contains CDR or VH and VL antibody 5F12 (see Table 1A) or its humanized form (see example). Figure 4A and Figure 4BIn some cases, the method involves administering a single dose of the antibody. In some cases, the single dose is administered during the first trimester. In some cases, the single dose is administered during the second trimester. In some cases, the single dose is administered during the third trimester. In some cases, the single dose is about 30 mg. In some cases, the single dose is about 100 mg. In some cases, the single dose is 30 mg. In some cases, the single dose is 100 mg. In some cases, it is administered subcutaneously.

[0266] In some cases, the antibody contains CDR or VH and VL antibody 5F12 (see Table 1A) or its humanized form (see example). Figure 4A and Figure 4B In some cases, the method involves administering more than one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) doses of the antibody. In some cases, the first dose is administered during the first trimester. In some cases, the first dose is administered during the second trimester. In some cases, the first dose is administered during the third trimester. In some cases, the dose is about 30 mg. In some cases, the dose is about 75 mg. In some cases, the single dose is about 100 mg. In some cases, the single dose is 30 mg. In some cases, the single dose is 75 mg. In some cases, the single dose is 100 mg. In some cases, it is administered subcutaneously. In some cases, it is administered intravenously.

[0267] VI. Examples Multiple studies in mice and rats have confirmed that the anti-GFRAL antibody hz3P10 can ameliorate GDF15-induced weight loss. Weight loss in rodents is used as a surrogate indicator of nausea and vomiting in humans because rodents are unable to vomit. Serum levels of GDF15 have been increased by direct administration of the GDF15-Fc fusion protein, by using tumor models secreting GDF15, by using adeno-associated virus, or by chemotherapy that increases stress induction of GDF15. In all models, doses of hz3P10 ≥1 mg / kg ameliorated GDF15-induced weight loss.

[0268] Example 1: Weight changes in mice subcutaneously administered Hz3P10 after GDF15-Fc fusion protein-induced weight loss. This study evaluated the efficacy of subcutaneous (SC) 3P10 in blocking GDF15-induced weight loss in obese male mice (n=8 / dose group, approximately 19 weeks old at the start of the study) and identified its no-effect dose and saturable dose. A single dose of the GDF15-Fc fusion protein was administered to mice via SC at 0 (phosphate-buffered saline [PBS] control) or 0.1 mg / kg to induce weight loss. Two days later, mice receiving the GDF15-Fc fusion protein were randomly assigned to receive a single SC injection of hz3P10 at 0 (PBS control), 0.1, 0.3, 1, 3, or 10 mg / kg. Body weight was assessed daily for one week following hz3P10 injection. Figure 6 As shown, mice receiving PBS instead of GDF15-Fc fusion protein throughout the study showed a steady increase in body weight, as did mice receiving 0.1 mg / kg GDF15-Fc fusion protein followed by 1, 3, or 10 mg / kg hz3P10 two days later. In contrast, mice receiving GDF15-Fc fusion protein followed by 0, 0.1, or 0.3 mg / kg 3P10 showed either a decrease or no increase in body weight. In summary, a single SC dose of ≥1 mg / kg hz3P10 prevented GDF15-induced weight loss in obese mice.

[0269] Example 2: Hz3P10 reverses dose-response in GDF15-induced weight loss in mice within 28 days This study evaluated the activity of a single SC dose of hz3P10 in a GDF15-induced lean mouse weight loss model over a 28-day period to identify ineffective and maximum effective doses. C57BL / 6J mice (male, n=8 / dose group, approximately 18 weeks old at the start of the study) were administered placebo (PBS) or adeno-associated virus (AAV) carrying GDF15 DNA (AAV-GDF15) to induce weight loss through sustained high levels of GDF15. Serum GDF15 and body weight were measured throughout the study. Two weeks after AAV-GDF15 induction, mice with GDF15 levels greater than 1 ng / mL were selected and randomly assigned to receive a single SC dose of hz3P10 at 0 (isotype control antibody), 0.3, 1, 3, 6, or 12 mg / kg. Following hz3P10 administration, mice in the control group and the 0.3 mg / kg 3P10 group continued to lose weight. Figure 7By the end of the study, doses of 1 and 3 mg / kg resulted in similar weight gain to the non-transgenic control group, while doses of 6 and 12 mg / kg resulted in significantly greater weight gain than the non-transgenic control group. Mice receiving ≥3 mg / kg hz3P10 also exhibited increased food consumption compared to the AAV-GDF15 control group. In summary, a single SC dose of hz3P10 reversed GDF15-induced weight loss in lean mice within 28 days. In mice, the no-effect dose of hz3P10 blocking GDF15-induced weight loss was 0.3 mg / kg, while 6 mg / kg was fully effective.

[0270] Example 3: Dose-response of Hz3P10 in reversing HT1080 tumor-induced weight loss in SCID mice This study evaluated the efficacy and potency of a single SC dose of hz3P10 in inhibiting GDF15-induced weight loss in severely combined immunodeficient (SCID) HT1080 xenograft mice, and identified ineffective and maximum effective doses. Institute of Cancer Research (ICR) SCID mice (female, n=7 / dose group, approximately 7 weeks old at the start of the study) were implanted with hGDF15-producing HT1080 tumor cells, and tumors were allowed to grow for 2 weeks; the control group remained uninoculated. Mice were then randomly assigned to 0 (anti-keyhole limpethemocyanin (KLH) control), 0.3, 1, 3, 6, and 13 mg / kg 3P10 SC dose groups based on weight loss. Mice were assessed for an additional 11 days after single-dose administration, with body weight and food consumption measured throughout. Serum GDF15 levels were measured at the end of the study. Non-tumor-bearing controls had unmeasurable hGDF15 levels, while a single group of tumor-bearing mice had hGDF15 levels ranging from 740 to 18,180 pg / mL. Figure 8 ).

[0271] Example 4: The efficacy of 3P10 and Hz3P10 in inhibiting tumor-induced weight loss in PDX and syngeneic mouse tumor models This study evaluated the efficacy of hz3P10 or 3P10 (hz3P10 parental antibody) in inhibiting tumor-derived GDF15-induced weight loss in various mouse tumor models (both syngeneic and patient-derived xenograft [PDX]). For syngeneic models (KLN2015, B16b, or Renca), male mice (DBA / 2, BL / 6, and BALB / c, respectively) were used, with n=10 mice per dose group (hIgG1 control or hz3P10, 3 mg / kg). For PDX models (GA0037 stomach, OV0276 ovary, and LI1098 liver), female BALB / c nude mice were used, ranging from 9 to 20 mice per dose group (mIgG1 control or 3P10, 3 mg / kg). Dosage administration was as follows: gastric PDX was administered on days 0 and 7 of the study; ovarian PDX was administered on days 0, 7, 22, 28, 35, 49, and 63 of the study; liver PDX was administered every 2 weeks for 2 months; and syngeneic tumor models were administered weekly for up to 1 month. In all models, GDF15 was increased due to tumors. Figure 9 A and Figure 9 B), and weight loss due to the use of 3P10 ( Figure 10 A- Figure 10 C) or hz3P10 ( Figure 11 A- Figure 11 C) Improved through treatment.

[0272] Example 5: Effect of 3P10 on cisplatin-induced cachexia in mice This study evaluated the effect of 3P10 on the development of cisplatin-induced weight loss in cisplatin-treated mice when administered weekly via SC for 4 weeks. C57BL / 6J mice (male, n=10 / dose group, approximately 17 weeks old at the start of the study) were randomly assigned to either untreated control, cisplatin plus a control antibody, or cisplatin plus 3P10. The control antibody and 3P10 were administered weekly via SC at 1 mg / kg for 4 weeks, while cisplatin was administered intraperitoneally at 5 mg / kg one day after each dose. Body weight, food consumption, and serum GDF15 levels were measured throughout the study. At 1 month post-study, serum GDF15 levels were 100 (±16), 1606 (±903), and 1905 (±899) pg / mL in the untreated control, cisplatin plus control antibody, and cisplatin plus 3P10 dose groups, respectively. By the end of the study, the cisplatin plus control antibody group had lost approximately 20% of their initial body weight, while the cisplatin plus 3P10 group had lost approximately 5%. The untreated controls gained approximately 2%. Food intake was similarly affected, with the 3P10 group showing increased food consumption compared to the control antibody group. Figure 12 A- Figure 12 C).

[0273] Example 6: Identifying the no-effect and saturable doses of Hz3P10 in inhibiting GDF15-induced weight loss in rats In this study, human GDF15-Fc fusion protein was used to induce weight loss in rats, followed by administration of hz3P10 to evaluate its efficacy in improving weight loss. Male Sprague Dawley rats (n=6 / dose group, approximately 6 weeks old at the start of the study) were administered placebo (PBS) or GDF15-Fc fusion protein at a dose that reduced food intake and resulted in weight loss. Two days later, hz3P10 was administered at a single SC dose of 0 (PBS), 0.3, 1, 3, or 10 mg / kg.

[0274] Animals administered GDF15-Fc fusion protein and PBS showed significantly reduced weight gain compared to controls over the following week. Similarly, groups receiving GDF15-Fc fusion protein followed by 0.3 mg / kg hz3P10 showed reduced weight gain. However, there was no difference in weight gain between the groups receiving placebo (PBS / PBS) or GDF15-Fc fusion protein followed by 1, 3, or 10 mg / kg hz3P10; all groups gained weight at similar rates over the following week. At the end of week 1, the mean weight of the groups receiving GDF15-Fc fusion protein alone or with 0.3 mg / kg hz3P10 was significantly lower, while the placebo control group was indistinguishable from the groups receiving GDF15-Fc fusion protein followed by 1, 3, or 10 mg / kg hz3P10. Figure 13 Food consumption was similarly affected, with doses of NGM120 of 1, 3, or 10 mg / kg preventing the reduced intake observed in the case of the GDF15-FC fusion protein.

[0275] Example 7: Identifying the no-effect dose and maximum effective dose of Hz3P10 in inhibiting cisplatin-induced weight loss in rats To evaluate the efficacy of weekly subcutaneous doses of hz3P10 in blocking the weight loss effects of cisplatin on food intake and body weight in lean rats, Sprague Dawley rats (male, n=8 / dose group, approximately 6 weeks old at the start of the study) were administered 0, 0.3, 1, 3, or 10 mg / kg hz3P10 (PBS), followed by administration of 4 mg / kg PBS or cisplatin one day later. This was continued weekly for four doses per group. Food intake and body weight were measured to assess the effects of cisplatin and the efficacy of hz3P10 in mitigating these effects. Additionally, serum GDF15 was measured 24 hours after each cisplatin dose.

[0276] Although all animals receiving cisplatin experienced less weight gain than the placebo control, 1, 3, and 10 mg / kg doses of hz3P10 resulted in significant weight gain compared to the cisplatin:PBS group. Figure 14 There was no significant difference between the 0.3 mg / kg hz3P10 group and the cisplatin:PBS group. In all animals receiving cisplatin, serum GDF15 levels were significantly increased compared to the placebo control.

[0277] Example 8: Predicted effective human dose The rodent preclinical pharmacology studies described in the foregoing examples were used to predict effective human doses. The minimum effective dose level in these studies was the same across weight-induction methods and species, and was determined to be 1 mg / kg. Higher doses did not provide additional benefit. A dose of 0.3 mg / kg was consistently ineffective. Based on the assumption that weight loss in rodent models is driven by the same mechanisms as nausea and vomiting in humans, a minimum effective exposure of 1 mg / kg was used to guide human dose selection in humans.

[0278] Mean serum C of hz3P10 at a dose of 1 mg / kg max It was comparable between mice (9.11 µg / mL) and rats (10.8 µg / mL), and 9.96 µg / mL (the average C value from those two species) was also comparable. max The effective exposure (taking the average value) is used as the target concentration threshold in the exposure criticality calculation. Assuming an average body weight of 75 kg, an effective exposure of 75 mg hz3P10 (equivalent to 1 mg / kg) is expected to be achieved within 4 days. Figure 15 A) and maintain exposure within the effective range until approximately 3 weeks after administration. Figure 15 (B) It should be understood that the absolute dose may be increased or decreased based on the subject's weight to achieve a target dose of approximately 1 mg / kg.

[0279] Example 9: Pharmacokinetics and Drug Metabolism in Humans A single escalation dose (SAD) study was conducted in which a total of 48 healthy adult human volunteers received a single subcutaneous dose of humanized anti-GFRAL antibody 3P10 (containing the heavy chain of SEQ ID NO:2010 and the light chain of SEQ ID NO:2012) of 10 mg, 30 mg, 100 mg, 200 mg, or 400 mg. A multiple escalation dose (MAD) study was conducted in which a total of 44 healthy adult human volunteers were administered 10 mg, 30 mg, 100 mg, or 200 mg subcutaneously every four weeks (Q4W) for a total of three doses.

[0280] In the SAD portion of the study, the median Tmax Within 4 to 15 days after a single SC dose of hz3P10. Mean C max and AUC 0-56d Values ​​increased approximately dose-proportional between the 10 mg, 30 mg, 100 mg, 200 mg, and 400 mg dose levels. Within each dose group, the mean apparent oral clearance (CL / F) ranged from 87.9 to 118 mL / day and t 1 / 2 The (geometric mean) ranges from 28.3 to 40.0 days.

[0281] In the MAD portion of the study, the median T for the first and third doses (i.e., day 1 and day 57, respectively) was... max For approximately 7 days. Exposure after the third dose following administration of 10 mg, 30 mg, 100 mg, or 200 mg hz3P10 at Q4W (based on C). max and AUC 0-28d The exposure was approximately twice that after the first dose. The average cumulative effect after the fourth dose for C... max In terms of AUC, it is in the range of 1.6 to 2.0. 0-28d The value is in the range of 1.7 to 2.2.

[0282] All publications, patents, patent applications, websites, and accession / database sequences (including both polynucleotide and polypeptide sequences cited herein) are hereby incorporated in their entirety by reference for all purposes, as if each individual publication, patent, patent application, website, or accession / database sequence were expressly and individually incorporated by reference.

Claims

1. An antibody that specifically binds to human GDNF family receptor α-like (GFRAL) for the treatment of hyperemesis gravidarum in human subjects in need.

2. An antibody that specifically binds to human GFRAL for the treatment of nausea and vomiting (NVP) during pregnancy in human subjects in need, optionally wherein the NVP is mild, moderate or severe.

3. An antibody that specifically binds to human GFRAL for the treatment of nausea and / or vomiting in human subjects in need.

4. An antibody that specifically binds to human GFRAL for reducing nausea and / or vomiting in human subjects in need.

5. The antibody used in any one of claims 1 to 4, wherein the administration is performed subcutaneously.

6. The antibody used in any one of claims 1 to 4, wherein the administration is performed intravenously.

7. The antibody used in any one of claims 1 to 6, wherein the therapeutically effective amount of said antibody is about 100 mg, optionally wherein the therapeutically effective amount of said antibody is 100 mg.

8. The antibody used in any one of claims 1 to 6, wherein the therapeutically effective amount of the antibody is about 75 mg, optionally wherein the therapeutically effective amount of the antibody is 75 mg.

9. The antibody used in any one of claims 1 to 6, wherein the therapeutically effective amount of the antibody is about 30 mg, optionally wherein the therapeutically effective amount of the antibody is 30 mg.

10. The antibody used in any one of claims 1 to 9, wherein the method comprises administering only a single dose of the therapeutically effective amount of the antibody to the human subject.

11. The antibody used in any one of claims 1 to 9, wherein the method comprises administering to the human subject more than one dose of the therapeutically effective amount of the antibody, optionally wherein each dose is administered once every approximately four weeks.

12. The antibody used in any one of claims 1 to 11, wherein the biological sample obtained from the human subject has an elevated level of GDF15 compared to the control level of GDF15 in a control biological sample obtained from one or more humans who have not suffered from nausea and vomiting during pregnancy, hyperemesis gravidarum, nausea or vomiting, or other illnesses, optionally wherein the biological sample is serum, plasma or blood.

13. The antibody used in any one of claims 1 to 12, wherein the antibody inhibits the binding of human GFRAL to human RET.

14. The antibody used in any one of claims 1 to 13, wherein the antibody does not inhibit the binding of human GDF15 to human GFRAL.

15. The antibody used in any one of claims 1 to 12, wherein the antibody inhibits the binding of human GDF15 to human GFRAL.

16. The antibody used in any one of claims 1 to 12, wherein the antibody specifically binds to amino acid residues 220-316 of the amino acid sequence shown in SEQ ID NO:1797, optionally wherein the antibody inhibits the binding of human RET to human GFRAL, and optionally wherein the antibody does not inhibit the binding of human GDF15 to human GFRAL.

17. The antibody used in any one of claims 1 to 12, wherein the antibody specifically binds to one or more residues selected from the group consisting of: Met214, Pro216, Pro217, Gln290, Cys291, Thr292, Cys293, Arg294, Thr295, Ile296, Thr297, Gln298, Ser299, Glu301, Lys305, Gln308, His309, His312, and Ser315 of the amino acid sequence shown in SEQ ID NO: 1797, optionally wherein the antibody inhibits the binding of human RET to human GFRAL, and optionally wherein the antibody does not inhibit the binding of human GDF15 to human GFRAL.

18. The antibody used in any one of claims 1 to 14, wherein the antibody specifically binds to Thr297, Gln298 and Ser299 of the amino acid sequence shown in SEQ ID NO:1797.

19. The antibody used in any one of claims 1 to 14 and 16 to 18, wherein the antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), and wherein the VH comprises VH complementarity-determining regions (CDRs) 1, VH CDR2, and VH CDR3 from the amino acid sequence shown in SEQ ID NO:1982, and the VL comprises VL CDR1, VL CDR2, and VL CDR3 from the amino acid sequence shown in SEQ ID NO:1997.

20. The antibody used as claimed in claim 19, wherein: (a) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 respectively contain the amino acid sequences shown in SEQ ID NO:46, SEQ ID NO:137, SEQ ID NO:225, SEQ ID NO:301, SEQ ID NO:376 and SEQ ID NO:426; (b) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 respectively contain the amino acid sequences shown in SEQ ID NO:47, SEQ ID NO:138, SEQ ID NO:226, SEQ ID NO:302, SEQ ID NO:377 and SEQ ID NO:426; (c) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 respectively contain the amino acid sequences shown in SEQ ID NO:48, SEQ ID NO:137, SEQ ID NO:225, SEQ ID NO:301, SEQ ID NO:376 and SEQ ID NO:426; (d) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 respectively contain the amino acid sequences shown in SEQ ID NO:49, SEQ ID NO:139, SEQ ID NO:227, SEQ ID NO:303, SEQ ID NO:377 and SEQ ID NO:427; (e) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 respectively contain the amino acid sequences shown in SEQ ID NO:50, SEQ ID NO:140, SEQ ID NO:228, SEQ ID NO:304, SEQ ID NO:378, and SEQ ID NO:428; or (f) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 respectively contain the amino acid sequences shown in SEQ ID NO:46, SEQ ID NO:141, SEQ ID NO:225, SEQ ID NO:301, SEQ ID NO:376 and SEQ ID NO:

426.

21. The antibody used as claimed in claim 19 or 20, wherein: (a) The VH comprises an amino acid sequence having at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence shown in any of SEQ ID NO:1978-1988; (b) The VL comprises an amino acid sequence having at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence shown in any of SEQ ID NO:1990-2000; (c) The VH comprises an amino acid sequence having at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence shown in any one of SEQ ID NO:1978-1988, and the VL comprises an amino acid sequence having at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence shown in any one of SEQ ID NO:1990-2000; (d) The VH contains the amino acid sequence shown in any one of SEQ ID NO: 1978-1988; (e) The VL contains the amino acid sequence shown in any one of SEQ ID NO:1990-2000; (f) The VH contains the amino acid sequence shown in SEQ ID NO:1982; (g) The VL contains the amino acid sequence shown in SEQ ID NO:1997; (h) The VH comprises an amino acid sequence having at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence shown in SEQ ID NO:3; (i) The VL comprises an amino acid sequence having at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence shown in SEQ ID NO:4; (j) The VH comprises an amino acid sequence having at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence shown in SEQ ID NO:3, and the VL comprises an amino acid sequence having at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence shown in SEQ ID NO:4; (k) The VH contains the amino acid sequence shown in SEQ ID NO:3; (l) The VL contains the amino acid sequence shown in SEQ ID NO:4; or (m) The VH contains the amino acid sequence shown in SEQ ID NO:3 and the VL contains the amino acid sequence shown in SEQ ID NO:

4.

22. The antibody used in any one of claims 1 to 15, wherein the VH comprises the amino acid sequence shown in SEQ ID NO:1982 and the VL comprises the amino acid sequence shown in SEQ ID NO:1997.

23. The antibody used in any one of claims 1 to 14, wherein the antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), and wherein: (a) The VH comprises VH complementarity-determining regions (CDRs) 1, VH CDR 2, and VH CDR 3 of the amino acid sequences shown in any one of SEQ ID NO:7 and 1957-1965, and the VL comprises VL CDR 1, VL CDR 2, and VL CDR 3 of the amino acid sequences shown in any one of SEQ ID NO:8 and 1967-1976; (b) The VH comprises VH CDR1, VH CDR2 and VHCDR3 from the amino acid sequence shown in SEQ ID NO:21, and the VL comprises VL CDR1, VL CDR2 and VLCDR3 from the amino acid sequence shown in SEQ ID NO:22; (c) The VH comprises VH CDR1, VH CDR2 and VHCDR3 from the amino acid sequence shown in SEQ ID NO:23, and the VL comprises VL CDR1, VL CDR2 and VLCDR3 from the amino acid sequence shown in SEQ ID NO:24; (d) The VH comprises VH CDR1, VH CDR2 and VHCDR3 from the amino acid sequence shown in SEQ ID NO:25, and the VL comprises VL CDR1, VL CDR2 and VLCDR3 from the amino acid sequence shown in SEQ ID NO:26; (e) The VH comprises VH CDR1, VH CDR2, and VHCDR3 from the amino acid sequence shown in SEQ ID NO:37, and the VL comprises VL CDR1, VL CDR2, and VLCDR3 from the amino acid sequence shown in SEQ ID NO:38; or (f) The VH comprises VH CDR1, VH CDR2 and VHCDR3 from the amino acid sequence shown in SEQ ID NO:39, and the VL comprises VL CDR1, VL CDR2 and VLCDR3 from the amino acid sequence shown in SEQ ID NO:

40.

24. The antibody used as claimed in claim 23, wherein: (a) (i) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 respectively contain the amino acid sequences shown in SEQ ID NO: 56, SEQ ID NO: 147, SEQ ID NO: 233, SEQ ID NO: 309, SEQ ID NO: 382 and SEQ ID NO: 432; (ii) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VLCDR3 respectively contain the amino acid sequences shown in SEQ ID NO: 57, SEQ ID NO: 148, SEQ ID NO: 234, SEQ ID NO: 310, SEQ ID NO: 383 and SEQ ID NO: 432; (iii) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VLCDR3 respectively contain the amino acid sequences shown in SEQ ID NO: 58, SEQ ID NO: 147, SEQ ID NO: 233, SEQ ID NO: 309, SEQ ID NO: 382 and SEQ ID NO: 432; (iv) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VLCDR3 respectively contain the amino acid sequences shown in SEQ ID NO: 49, SEQ ID NO: 149, SEQ ID NO: 235, SEQ ID NO: 311, SEQ ID NO: 383 and SEQ ID NO: 433; (v) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VLCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO: 59, SEQ ID NO: 150, SEQ ID NO: 236, SEQ ID NO: 312, SEQ ID NO: 384, and SEQ ID NO: 434; or (vi) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VLCDR3 respectively contain the amino acid sequences shown in SEQ ID NO: 56, SEQ ID NO: 151, SEQ ID NO: 233, SEQ ID NO: 309, SEQ ID NO: 382 and SEQ ID NO: 432; (b) (i) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 respectively contain the amino acid sequences shown in SEQ ID NO: 86, SEQ ID NO: 177, SEQ ID NO: 261, SEQ ID NO: 337, SEQ ID NO: 401 and SEQ ID NO: 453; (ii) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VLCDR3 respectively contain the amino acid sequences shown in SEQ ID NO: 87, SEQ ID NO: 178, SEQ ID NO: 262, SEQ ID NO: 338, SEQ ID NO: 386 and SEQ ID NO: 453; (iii) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VLCDR3 respectively contain the amino acid sequences shown in SEQ ID NO: 88, SEQ ID NO: 179, SEQ ID NO: 261, SEQ ID NO: 337, SEQ ID NO: 401 and SEQ ID NO: 453; (iv) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VLCDR3 respectively contain the amino acid sequences shown in SEQ ID NO: 89, SEQ ID NO: 168, SEQ ID NO: 263, SEQ ID NO: 339, SEQ ID NO: 386 and SEQ ID NO: 454; (v) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VLCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO: 90, SEQ ID NO: 180, SEQ ID NO: 264, SEQ ID NO: 340, SEQ ID NO: 402, and SEQ ID NO: 455; or (vi) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VLCDR3 respectively contain the amino acid sequences shown in SEQ ID NO: 86, SEQ ID NO: 181, SEQ ID NO: 261, SEQ ID NO: 337, SEQ ID NO: 401 and SEQ ID NO: 453; (c) (i) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 respectively contain the amino acid sequences shown in SEQ ID NO: 91, SEQ ID NO: 182, SEQ ID NO: 265, SEQ ID NO: 341, SEQ ID NO: 385 and SEQ ID NO: 456; (ii) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VLCDR3 respectively contain the amino acid sequences shown in SEQ ID NO: 92, SEQ ID NO: 183, SEQ ID NO: 266, SEQ ID NO: 342, SEQ ID NO: 386 and SEQ ID NO: 456; (iii) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VLCDR3 respectively contain the amino acid sequences shown in SEQ ID NO: 93, SEQ ID NO: 182, SEQ ID NO: 265, SEQ ID NO: 341, SEQ ID NO: 385 and SEQ ID NO: 456; (iv) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VLCDR3 respectively contain the amino acid sequences shown in SEQ ID NO: 75, SEQ ID NO: 184, SEQ ID NO: 267, SEQ ID NO: 343, SEQ ID NO: 386 and SEQ ID NO: 457; (v) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VLCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO: 94, SEQ ID NO: 185, SEQ ID NO: 268, SEQ ID NO: 344, SEQ ID NO: 403, and SEQ ID NO: 458; or (vi) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VLCDR3 respectively contain the amino acid sequences shown in SEQ ID NO: 91, SEQ ID NO: 186, SEQ ID NO: 265, SEQ ID NO: 341, SEQ ID NO: 385 and SEQ ID NO: 456; (d) (i) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 respectively contain the amino acid sequences shown in SEQ ID NO: 95, SEQ ID NO: 187, SEQ ID NO: 269, SEQ ID NO: 345, SEQ ID NO: 404 and SEQ ID NO: 459; (ii) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VLCDR3 respectively contain the amino acid sequences shown in SEQ ID NO: 96, SEQ ID NO: 188, SEQ ID NO: 270, SEQ ID NO: 346, SEQ ID NO: 405 and SEQ ID NO: 459; (iii) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VLCDR3 respectively contain the amino acid sequences shown in SEQ ID NO: 97, SEQ ID NO: 187, SEQ ID NO: 269, SEQ ID NO: 345, SEQ ID NO: 404 and SEQ ID NO: 459; (iv) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VLCDR3 respectively contain the amino acid sequences shown in SEQ ID NO: 98, SEQ ID NO: 184, SEQ ID NO: 271, SEQ ID NO: 347, SEQ ID NO: 405 and SEQ ID NO: 460; (v) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VLCDR3 respectively contain the amino acid sequences shown in SEQ ID NO: 99, SEQ ID NO: 189, SEQ ID NO: 272, SEQ ID NO: 348, SEQ ID NO: 406, and SEQ ID NO: 461; or (vi) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VLCDR3 respectively contain the amino acid sequences shown in SEQ ID NO: 95, SEQ ID NO: 190, SEQ ID NO: 269, SEQ ID NO: 345, SEQ ID NO: 404 and SEQ ID NO: 459; (e) (i) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 respectively contain the amino acid sequences shown in SEQ ID NO: 124, SEQ ID NO: 210, SEQ ID NO: 289, SEQ ID NO: 365, SEQ ID NO: 418 and SEQ ID NO: 474; (ii) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VLCDR3 respectively contain the amino acid sequences shown in SEQ ID NO: 73, SEQ ID NO: 211, SEQ ID NO: 290, SEQ ID NO: 366, SEQ ID NO: 419 and SEQ ID NO: 474; (iii) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VLCDR3 respectively contain the amino acid sequences shown in SEQ ID NO: 125, SEQ ID NO: 210, SEQ ID NO: 289, SEQ ID NO: 365, SEQ ID NO: 418 and SEQ ID NO: 474; (iv) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VLCDR3 respectively contain the amino acid sequences shown in SEQ ID NO: 75, SEQ ID NO: 212, SEQ ID NO: 291, SEQ ID NO: 367, SEQ ID NO: 419 and SEQ ID NO: 475; (v) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VLCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO: 126, SEQ ID NO: 213, SEQ ID NO: 292, SEQ ID NO: 368, SEQ ID NO: 420, and SEQ ID NO: 476; or (vi) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VLCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO: 124, SEQ ID NO: 214, SEQ ID NO: 289, SEQ ID NO: 365, SEQ ID NO: 418, and SEQ ID NO: 474; or (f) (i) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 respectively contain the amino acid sequences shown in SEQ ID NO: 127, SEQ ID NO: 215, SEQ ID NO: 293, SEQ ID NO: 369, SEQ ID NO: 421 and SEQ ID NO: 477; (ii) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VLCDR3 respectively contain the amino acid sequences shown in SEQ ID NO: 128, SEQ ID NO: 216, SEQ ID NO: 294, SEQ ID NO: 370, SEQ ID NO: 405 and SEQ ID NO: 477; (iii) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VLCDR3 respectively contain the amino acid sequences shown in SEQ ID NO: 129, SEQ ID NO: 215, SEQ ID NO: 293, SEQ ID NO: 369, SEQ ID NO: 421 and SEQ ID NO: 477; (iv) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VLCDR3 respectively contain the amino acid sequences shown in SEQ ID NO: 130, SEQ ID NO: 217, SEQ ID NO: 295, SEQ ID NO: 371, SEQ ID NO: 405 and SEQ ID NO: 478; (v) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VLCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO: 131, SEQ ID NO: 218, SEQ ID NO: 296, SEQ ID NO: 372, SEQ ID NO: 422, and SEQ ID NO: 479; or (vi) The VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VLCDR3 respectively contain the amino acid sequences shown in SEQ ID NO: 127, SEQ ID NO: 219, SEQ ID NO: 293, SEQ ID NO: 369, SEQ ID NO: 421 and SEQ ID NO:

477.

25. The antibody used as claimed in claim 23 or 24, wherein: (1) The VH comprises an amino acid sequence having at least 80%, at least 90%, or at least 95% sequence identity with the amino acid sequence shown in any one of SEQ ID NO:7 and 1957-1965, and the VL comprises an amino acid sequence having at least 80%, at least 90%, or at least 95% sequence identity with the amino acid sequence shown in any one of SEQ ID NO:8 and 1967-1976; (2) The VH contains an amino acid sequence having at least 80%, at least 90%, or at least 95% sequence identity with the amino acid sequence shown in SEQ ID NO:21, and the VL contains an amino acid sequence having at least 80%, at least 90%, or at least 95% sequence identity with the amino acid sequence shown in SEQ ID NO:

22. (3) The VH contains an amino acid sequence having at least 80%, at least 90%, or at least 95% sequence identity with the amino acid sequence shown in SEQ ID NO:23, and the VL contains an amino acid sequence having at least 80%, at least 90%, or at least 95% sequence identity with the amino acid sequence shown in SEQ ID NO:

24. (4) The VH contains an amino acid sequence having at least 80%, at least 90%, or at least 95% sequence identity with the amino acid sequence shown in SEQ ID NO:25, and the VL contains an amino acid sequence having at least 80%, at least 90%, or at least 95% sequence identity with the amino acid sequence shown in SEQ ID NO:

26. (5) The VH contains an amino acid sequence having at least 80%, at least 90%, or at least 95% sequence identity with the amino acid sequence shown in SEQ ID NO:37, and the VL contains an amino acid sequence having at least 80%, at least 90%, or at least 95% sequence identity with the amino acid sequence shown in SEQ ID NO:

38. (6) The VH contains an amino acid sequence having at least 80%, at least 90%, or at least 95% sequence identity with the amino acid sequence shown in SEQ ID NO:39, and the VL contains an amino acid sequence having at least 80%, at least 90%, or at least 95% sequence identity with the amino acid sequence shown in SEQ ID NO:

40. (7) The VH contains the amino acid sequence of any one of SEQ ID NO:7 and 1957-1965, and the VL contains the amino acid sequence of any one of SEQ ID NO:8 and 1967-1976; (8) The VH contains the amino acid sequence of SEQ ID NO:21, and the VL contains the amino acid sequence of SEQ ID NO:22; (9) The VH contains the amino acid sequence of SEQ ID NO:23, and the VL contains the amino acid sequence of SEQ ID NO:24; (10) The VH contains the amino acid sequence of SEQ ID NO:25, and the VL contains the amino acid sequence of SEQ ID NO:26; (11) The VH contains the amino acid sequence of SEQ ID NO:37, and the VL contains the amino acid sequence of SEQ ID NO:38; or (12) The VH contains the amino acid sequence of SEQ ID NO:39 and the VL contains the amino acid sequence of SEQ ID NO:

40.

26. The antibody used in any one of claims 1 to 12, wherein the antibody specifically binds to amino acid residues 20-130 of the amino acid sequence shown in SEQ ID NO:1797, optionally wherein the antibody does not inhibit the binding of human GDF15 to human GFRAL.

27. The antibody used in any one of claims 1 to 12, wherein the antibody specifically binds to amino acid residues 131-210 of the amino acid sequence shown in SEQ ID NO:1797, optionally wherein the antibody inhibits the binding of human GDF15 to human GFRAL.

28. The antibody used in any one of claims 1 to 12, wherein the antibody specifically binds to: (a) One or more residues selected from the group consisting of GLY140, LEU148, ALA149, ALA146, VAL142, ASN145, VAL139, ALA135, GLU136, LEU152, LEU132, SER201, ALA204, LEU205, LYS153, ILE196, PRO197 and GLN200 of the GFRAL protein (SEQ ID NO: 1797), and optionally wherein the antibody inhibits the binding of the GFRAL protein to the GDF15 protein; (b) One or more residues selected from the group consisting of: SER156, GLN147, SER150, TYR151, ALA154, CYS155, PHE174, TYR175, ALA137, CYS138, ASP141, VAL143, CYS144, LEU186, CYS189, CYS191, ALA192, GLN193, SER194, ASP195, CYS198, GLN199, LYS202, GLU203, HIS206, SER207, SER130, CYS131, LEU132, GLU133 and VAL134 of the GFRAL protein (SEQ ID NO: 1797), and optionally wherein the antibody inhibits the binding of the GFRAL protein to the GDF15 protein; (c) One or more residues selected from the group consisting of: SER156, GLN147, LEU148, ALA149, SER150, TYR151, LEU152, LYS153, ALA154, CYS155, PHE174, TYR175, GLU136, ALA137, CYS138, VAL139, GLY140, ASP141, VAL142, VAL143, CYS144, ASN145, ALA146, LEU186, CYS189, CYS191 of the GFRAL protein (SEQ ID NO: 1797). ALA192, GLN193, SER194, ASP195, ILE196, PRO197, CYS198, GLN199, GLN200, SER201, LYS202, GLU203, ALA204, LEU205, HIS206, SER207, SER130, CYS131, LEU132, GLU133, VAL134, and ALA135, and optionally wherein said antibody inhibits the binding of said GFRAL protein to GDF15 protein; (d) One or more residues selected from the group consisting of GLU136, ALA137, VAL139, GLY140, ASP141, VAL142, VAL143, CYS144, ASN145, ALA146, GLN147, PHE173, ASN177, ILE178, PRO179, ASN181, ILE182 and MET185 of the GFRAL protein (SEQ ID NO: 1797), and optionally wherein the antibody inhibits the binding of the GFRAL protein to the GDF15 protein; (e) One or more residues selected from the group consisting of: LEU132, GLU133, VAL134, ALA135, CYS138, LEU148, ALA149, SER150, TYR151, PHE174, TYR175, ALA169, ALA170, ILE171, ARG172, GLN176, PHE180, ALA183, GLN184, LEU186, ALA187, PHE188 and CYS189 of the GFRAL protein (SEQ ID NO: 1797), and optionally wherein the antibody inhibits the binding of the GFRAL protein to the GDF15 protein; (f) One or more residues selected from the group consisting of: LEU132, GLU133, VAL134, ALA135, GLU136, ALA137, CYS138, VAL139, GLY140, ASP141, VAL142, VAL143, CYS144, ASN145, ALA146, GLN147, LEU148, ALA149, SER150, TYR151, PHE174, TYR175, ALA1 of the GFRAL protein (SEQ ID NO: 1797). 69, ALA170, ILE171, ARG172, PHE173, GLN176, ASN177, ILE178, PRO179, PHE180, ASN181, ILE182, ALA183, GLN184, MET185, LEU186, ALA187, PHE188, and CYS189, and optionally wherein said antibody inhibits the binding of said GFRAL protein to GDF15 protein; or (g) One or more residues selected from the group consisting of: MET214, PRO216, PRO217, GLN290, CYS291, THR292, CYS293, ARG294, THR295, ILE296, THR297, GLN298, SER299, GLU301, LYS305, GLN308, HIS309, HIS312 and SER315 of the GFRAL protein (SEQ ID NO: 1797), and optionally wherein the antibody inhibits the binding of the GFRAL protein to the RET protein.

29. The antibody used in any one of claims 1 to 12, wherein the antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), and wherein: (a) The VH comprises VHCDR1, VH CDR2 and VH CDR3 of the amino acid sequences shown in any one of SEQ ID NO:15 and 1936-1941, and the VL comprises VL CDR1, VL CDR2 and VL CDR3 of the amino acid sequences shown in any one of SEQ ID NO:16 and 1943-1947; (b) The VH comprises VHCDR1, VH CDR2, and VH CDR3 of the amino acid sequences shown in any one of SEQ ID NO:1 and 1918-1927, and the VL comprises VL CDR1, VL CDR2, and VL CDR3 of the amino acid sequences shown in any one of SEQ ID NO:2 and 1929-1934; or (c) The VH comprises VH CDR1, VH CDR2 and VHCDR3 from the amino acid sequence shown in SEQ ID NO:11, and the VL comprises VL CDR1, VL CDR2 and VLCDR3 from the amino acid sequence shown in SEQ ID NO:12; (d) The VH comprises VH CDR1, VH CDR2 and VHCDR3 from the amino acid sequence shown in SEQ ID NO:5, and the VL comprises VL CDR1, VL CDR2 and VLCDR3 from the amino acid sequence shown in SEQ ID NO:6; (e) The VH comprises VH CDR1, VH CDR2 and VHCDR3 from the amino acid sequence shown in SEQ ID NO:9, and the VL comprises VL CDR1, VL CDR2 and VLCDR3 from the amino acid sequence shown in SEQ ID NO:10; (f) The VH comprises VH CDR1, VH CDR2 and VHCDR3 from the amino acid sequence shown in SEQ ID NO:13, and the VL comprises VL CDR1, VL CDR2 and VLCDR3 from the amino acid sequence shown in SEQ ID NO:14; (g) The VH comprises VH CDR1, VH CDR2 and VHCDR3 from the amino acid sequence shown in SEQ ID NO:17, and the VL comprises VL CDR1, VL CDR2 and VLCDR3 from the amino acid sequence shown in SEQ ID NO:18; (h) The VH comprises VH CDR1, VH CDR2 and VHCDR3 from the amino acid sequence shown in SEQ ID NO:19, and the VL comprises VL CDR1, VL CDR2 and VLCDR3 from the amino acid sequence shown in SEQ ID NO:20; (i) The VH comprises VH CDR1, VH CDR2 and VHCDR3 from the amino acid sequence shown in SEQ ID NO:27, and the VL comprises VL CDR1, VL CDR2 and VLCDR3 from the amino acid sequence shown in SEQ ID NO:28; (j) The VH comprises VH CDR1, VH CDR2 and VHCDR3 from the amino acid sequence shown in SEQ ID NO:29, and the VL comprises VL CDR1, VL CDR2 and VLCDR3 from the amino acid sequence shown in SEQ ID NO:30; (k) The VH comprises VH CDR1, VH CDR2 and VHCDR3 from the amino acid sequence shown in SEQ ID NO:31, and the VL comprises VL CDR1, VL CDR2 and VLCDR3 from the amino acid sequence shown in SEQ ID NO:32; (l) The VH comprises VH CDR1, VH CDR2 and VHCDR3 from the amino acid sequence shown in SEQ ID NO:33, and the VL comprises VL CDR1, VL CDR2 and VLCDR3 from the amino acid sequence shown in SEQ ID NO:34; (m) The VH comprises VH CDR1, VH CDR2 and VHCDR3 from the amino acid sequence shown in SEQ ID NO:35, and the VL comprises VL CDR1, VL CDR2 and VLCDR3 from the amino acid sequence shown in SEQ ID NO:36; (n) The VH comprises VH CDR1, VH CDR2 and VHCDR3 from the amino acid sequence shown in SEQ ID NO:480, and the VL comprises VL CDR1, VL CDR2 and VLCDR3 from the amino acid sequence shown in SEQ ID NO:481; (o) The VH comprises VH CDR1, VH CDR2 and VHCDR3 from the amino acid sequence shown in SEQ ID NO:482, and the VL comprises VL CDR1, VL CDR2 and VLCDR3 from the amino acid sequence shown in SEQ ID NO:483; (p) The VH comprises VH CDR1, VH CDR2, and VHCDR3 from the amino acid sequence shown in SEQ ID NO:484, and the VL comprises VL CDR1, VL CDR2, and VLCDR3 from the amino acid sequence shown in SEQ ID NO:485; or (q) The VH comprises VH CDR1, VH CDR2 and VHCDR3 from the amino acid sequence shown in SEQ ID NO:486, and the VL comprises VL CDR1, VL CDR2 and VLCDR3 from the amino acid sequence shown in SEQ ID NO:

487.

30. The antibody used in any one of claims 1 to 18, wherein the antibody is an antibody that competes with the antibodies in any one of the tables 1 to 24 for binding to human GFRAL.

31. The antibody used in any one of claims 1 to 30, wherein the antibody comprises two heavy chains and two light chains.

32. The antibody used in any one of claims 1 to 30, wherein the antibody is a human IgG1, human IgG2, or human IgG4 antibody.

33. The antibody used in any one of claims 1 to 30, wherein the antibody is a human IgG1 antibody.

34. The antibody used in any one of claims 1 to 33, wherein the antibody comprises a constant region of the human κ light chain.

35. The antibody used in any one of claims 1 to 33, wherein the antibody comprises a constant region of the human λ light chain.

36. The antibody used in any one of claims 1 to 30, wherein the antibody is Fab, Fab′, F(ab′)2, Fv, scFv, (scFv)2, single-chain antibody, dual variable region antibody, single variable region antibody, linear antibody, double-chain antibody, nanobody or V-region antibody.

37. The antibody used in any one of claims 20 to 23, wherein the antibody comprises a heavy chain having an amino acid sequence having at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence shown in SEQ ID NO:2010; and a light chain having an amino acid sequence having at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence shown in SEQ ID NO:2012.

38. The antibody used in any one of claims 20 to 23, wherein the antibody comprises a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 2010 and a light chain comprising the amino acid sequence shown in SEQ ID NO: 2012.

39. The antibody used in any one of claims 20 to 23, wherein the antibody comprises a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 2010 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 2012.

40. The antibody used in any one of claims 1 to 37, wherein the antibody is humanized.

41. The antibody used in any one of claims 1 to 40, wherein the human subject (a) is unresponsive to prior administration of an antiemetic or (b) has unresolved nausea, vomiting, or a combination thereof following prior administration of an antiemetic.

42. The antibody used in any one of claims 1 to 41, further comprising administration of one or more of the following: dralazine, pyridoxine, a dual-release formulation of dralazine and pyridoxine, ondansetron, dopamine antagonist, diphenhydramine, fluphenazine, methylprednisolone, mirtazapine, dimenhydrinate, chlorpromazine, prochlorperazine, steroid therapy, antiemetic, vitamin B1, vitamin B6, folic acid, vitamin K, vitamin D, magnesium, and ginger.

43. A composition comprising an anti-GFRAL antibody and a combination of one or more of the following: dralazine, pyridoxine, a dual-release formulation of dralazine and pyridoxine, ondansetron, a dopamine antagonist, diphenhydramine, fluphenazine, methylprednisolone, mirtazapine, dimenhydrinate, chlorpromazine, prochlorperazine, steroid therapy, an antiemetic, vitamin B1, vitamin B6, folic acid, vitamin K, vitamin D, magnesium, and ginger, optionally wherein the anti-GFRAL antibody comprises VH and VL, wherein the VH comprises the amino acid sequence shown in SEQ ID NO:1982, and the VL comprises the amino acid sequence shown in SEQ ID NO:1997.

Images