Antibody capable of specifically recognizing GDF15 and application thereof

Abstract

The invention relates to an antibody or an antigen binding fragment capable of specifically recognizing a growth differentiation factor-15 (GDF15), and a preparation method and application of the antibody or the antigen binding fragment.

Description

Antibodies specifically recognizing GDF15 and their applications

[0001] Submit sequence listing as XML text file

[0002] This application claims priority to Chinese patent application number 202210497637.0, application date 2022.05.09, and invention name “Antibodies specifically recognizing GDF15 and their applications”, and the entire contents of that application are incorporated herein by reference.

[0003] Submit sequence listing as XML file

[0004] The contents of the electronic sequence listing are incorporated herein by reference in their entirety: (text name: GDF15-seq.xml, recording date: 2023.03.16, size: 87KB). Technical Field

[0005] The present invention relates to antibodies that specifically recognize GDF15, as well as preparation methods and uses thereof, including methods for treating cancer, cachexia and / or metabolic diseases using the antibodies. Background Art

[0006] Growth differentiation factor-15 (GDF15), also known as macrophage inhibitory cytokine 1 (MIC-1), is an atypical member of the transforming growth factor β (TGF-β) superfamily. The maturation of human GDF15 undergoes a series of post-translational modifications. The unprocessed GDF15 protein (pre-pro-GDF15) consists of 308 amino acids, including a signal peptide sequence (29 aa), a propeptide (167 aa), and a mature protein (112 aa). The synthesized precursor form of pro-GDF15 protein forms a pro-GDF15 homodimer through cysteine ​​residues; it is then cleaved at the RXXR site, releasing the mature dimeric GDF15 protein and a propeptide at the C-terminus (Wang X et al., Biochem Pharmacol, 2013).

[0007] Mature dimeric GDF15 protein is secreted into the extracellular matrix, with normal circulating concentrations in healthy individuals ranging from approximately 0.15 to 1.15 ng / ml. GDF15 concentrations increase with age, but there are no sex differences in healthy elderly individuals. GDF15 concentrations correlate with cystatin C and C-reactive protein levels (Brown, DA et al. Lancet, 2002; Kempf, T. et al. Clin. Chem, 2007). Circulating GDF15 increases in humans during exercise and post-exercise recovery. GDF15 is expressed in most tissues, including skeletal muscle. Studies have shown that GDF15 is secreted from muscle in response to cellular stress or injury, acting locally in an autocrine or paracrine manner (Kleinert, M. et al. Mol. Metab., 2018). GDF15 is not normally expressed in adult myocardium, but is significantly induced in damaged or failing hearts. During myocardial injury, GDF15 is expressed in cardiomyocytes, adipocytes, macrophages, endothelial cells, and vascular smooth muscle cells (Wollert, KC et al. Clin Chem. 2017; Planavila, A et al. Adv. Protein Chem. 2017). In summary, under physiological conditions, GDF15 production in most tissues is weak, but it is strongly induced during inflammation and tissue injury.

[0008] Although GDF15 is classified as a member of the TGFβ family, current research has not identified a TGFβ receptor that GDF15 directly binds to. Four different research groups have simultaneously identified GFRAL as a GDF15 receptor (Hsu et al., Nature, 2017; Yang, L. et al., Nat Med, 2017; Mullican, SE et al., Nat Med, 2017; Emmerson, PJ et al., Nat Med, 2017). Hsu et al.'s research found that GDF15 does not bind to any known TGFβ receptor. Crystal structure analysis of the GDF15 protein revealed an additional disulfide bond distinct from that found in TGFβ family members. Furthermore, GFRAL, a glial cell-derived neurotrophic factor (GDNF) receptor α-like protein, was identified as the brainstem-restricted receptor for GDF15 (Hsu et al., Nature, 2017). This receptor mediates downstream signaling through the tyrosine kinase co-receptor RET. In the GDF15-GFRAL signaling pathway, GDF15 dimers bind to the GFRAL receptor. The GDF15-GFRAL complex recruits the co-receptor RET, leading to RET dimerization and phosphorylation, as well as phosphorylation of intracellular signaling proteins AKT, ERK1 / 2, and phospholipase C (PLCγ) (Shannon E. Mullican & Rangwala, 2018; L. Yang et al., 2017). Although the GDF15 / GFRAL signaling pathway remains incompletely understood and more research is needed to link the GDF15 receptor to the biological activity of mature GDF15, it is clear that the molecular basis of GDF15 activity is through GFRAL / RET, rather than TGFβ signaling (Hsu et al., Nature, 2017).

[0009] The GDF15 protein is associated with various diseases, such as obesity and insulin resistance (SNBreit et al., Growth Factors, 2011). GDF15 knockout in genetically engineered mice results in weight gain, while GDF15 overexpression leads to reduced body weight and fat mass, and altered metabolic parameters (L. Maccia et al., PLOS ONE, 2012; VWTsai et al., PLOS ONE, 2013). Subsequent studies in transgenic mice further confirmed the weight loss and these phenotypes, including: ubiquitous expression of hGDF15 in mice did not reduce food intake but improved glucose tolerance and insulin sensitivity, as well as reduced body weight, insulin, glucose, serum IGF-1 levels, leptin levels, and adipose tissue (Chrysovergis et al., 2014). These findings suggest that GDF15 is an important regulator of body weight and energy balance.

[0010] GDF15 plays a crucial role in the development of cancer cachexia. Cachexia is a medical symptom caused by cancer, typically involving weight loss, muscle atrophy, fatigue, weakness, and severe loss of appetite in those who are not actively trying to lose weight. It is a leading cause of morbidity and mortality in the late stages of chronic diseases such as AIDS, chronic obstructive pulmonary disease (COPD), congestive heart failure, multiple sclerosis, tuberculosis, and cancer. Malignant tumors are a major cause of refractory cachexia. Conservative estimates suggest that the number of new cases of cancer cachexia in my country exceeds 1.5 million annually (accounting for approximately 36.4% of new cancer patients), and approximately 20% of cancer patients die from cachexia itself (Murphy KT. et al., Expert Opin Emerg Drugs. 2009). GDF15 levels are significantly elevated in tumors and serum of patients with many malignant cancers, particularly aggressive brain cancer, melanoma, lung cancer, gastrointestinal cancer, colon cancer, pancreatic cancer, prostate cancer, and breast cancer (Huang CY et al., Clin Cancer Res. 2009). A study by L. Lerner et al. showed that circulating levels of GDF15 were significantly increased in cancer patients who lost weight compared to non-cancer controls and cancer patients who did not lose weight (Lerner L et al., J Cachexia Sarcopenia Muscle. 2015.). Furthermore, GDF15 levels were associated with weight loss, decreased fat mass, muscle mass, strength, physical performance scores, and survival in cancer patients, while decreased lean body mass (LBM) was a negative and independent prognostic factor in cancer patients (Reuben DB et al., Arch Intern Med, 1988.), and decreased grip strength was associated with decreased survival in this population (Gale CR et al., Int J Epidemiol. 2007).

[0011] Patent application WO2014100689A1 discloses monoclonal antibodies that bind to and inhibit the activity of human GDF15, and discloses that these antibodies can be used to treat weight loss associated with human GDF15 overexpression, including cachexia. WO2015144855A1 relates to a monoclonal antibody against human GDF15 and an antigen-binding portion thereof, which can inhibit cancer cachexia and / or cancer growth, and is used to treat cancer-induced weight loss and / or cancer cachexia, as well as cancer.

[0012] Therefore, there remains a need in the art for therapeutic antibodies that effectively inhibit or otherwise antagonize GDF15, as well as related methods for treating diseases or conditions mediated by GDF15, such as cancer, cancer cachexia, cancer-induced weight loss, and the like.

[0013] The disclosures of all publications, patents, patent applications, and published patent applications mentioned herein are incorporated by reference in their entirety.

[0014] Application Overview

[0015] In some embodiments, an isolated anti-GDF15 antibody is provided, comprising a heavy chain variable domain (V H ), the V H The invention comprises: a heavy chain complementary determining region (HC-CDR) 1 comprising X1YYMX2 (SEQ ID NO: 35), wherein X1 is D or N, and X2 is S or T; HC-CDR2 comprising MISFSGTTX1ATWAKG (SEQ ID NO: 36), wherein X1 is H or Y; and HC-CDR3 comprising VVYAGWTYPLGI (SEQ ID NO: 13); and a light chain variable domain (V L ), the V L It comprises: a light chain complementarity determining region (LC-CDR) 1 comprising QASQSISSVLS (SEQ ID NO: 18); a LC-CDR2 comprising EASX1X2AS (SEQ ID NO: 37), wherein X1 is I or T, and X2 is L or Q; and a LC-CDR3 comprising QANYDVYNYGNP (SEQ ID NO: 30).

[0016] In some embodiments, an isolated anti-GDF15 antibody is provided, comprising V H , the V Hcomprising: an HC-CDR1 comprising an amino acid sequence as shown in any one of SEQ ID NOs: 1-2 or a variant thereof, wherein the variant comprises a substitution of at most about 3 amino acids; an HC-CDR2 comprising an amino acid sequence as shown in any one of SEQ ID NOs: 7-8 or a variant thereof, wherein the variant comprises a substitution of at most about 3 amino acids; and an HC-CDR3 comprising an amino acid sequence as shown in SEQ ID NO: 13 or a variant thereof, wherein the variant comprises a substitution of at most about 3 amino acids; and V L , the V L Comprising: LC-CDR1, which comprises the amino acid sequence shown in SEQ ID NO: 18 or a variant thereof, wherein the variant comprises substitutions of up to about 3 amino acids; LC-CDR2, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 23-25 ​​or a variant thereof, wherein the variant comprises substitutions of up to about 3 amino acids; and LC-CDR3, which comprises the amino acid sequence shown in SEQ ID NO: 30 or a variant thereof, wherein the variant comprises substitutions of up to about 3 amino acids.

[0017] In some embodiments, an isolated anti-GDF15 antibody is provided, comprising: V H , the V H Comprising V as shown in any one of the amino acid sequences of SEQ ID NOs: 38-47 H Contains HC-CDR1, HC-CDR2 and HC-CDR3, as well as V L , the V L Comprising V as shown in any one of the amino acid sequences of SEQ ID NOs: 52-59 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0018] In some embodiments, an isolated anti-GDF15 antibody is provided, comprising: (i) V H , which comprises V as shown in the amino acid sequence SEQ ID NO: 38 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:52 L Containing LC-CDR1, LC-CDR2 and LC-CDR3; (ii) V H , which comprises V as shown in the amino acid sequence SEQ ID NO: 39 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:53 LContaining LC-CDR1, LC-CDR2 and LC-CDR3; (iii) V H , which comprises V as shown in the amino acid sequence SEQ ID NO:40 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:53 L Containing LC-CDR1, LC-CDR2 and LC-CDR3; (iv) V H , which comprises V as shown in the amino acid sequence SEQ ID NO:41 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:53 L Containing LC-CDR1, LC-CDR2 and LC-CDR3; (v) V H , which comprises V as shown in the amino acid sequence SEQ ID NO:42 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:53 L Containing LC-CDR1, LC-CDR2 and LC-CDR3; (vi) V H , which comprises V as shown in the amino acid sequence SEQ ID NO:43 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:53 L Containing LC-CDR1, LC-CDR2 and LC-CDR3; (vii) V H , which comprises V as shown in the amino acid sequence SEQ ID NO:44 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:53 L Containing LC-CDR1, LC-CDR2 and LC-CDR3; (viii) V H , which comprises V as shown in the amino acid sequence SEQ ID NO: 39 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:54 LContaining LC-CDR1, LC-CDR2 and LC-CDR3; (ix) V H , which comprises V as shown in the amino acid sequence SEQ ID NO:40 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:54 L Contains LC-CDR1, LC-CDR2 and LC-CDR3; (x) V H , which comprises V as shown in the amino acid sequence SEQ ID NO:41 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:54 L Containing LC-CDR1, LC-CDR2 and LC-CDR3; (xi) V H , which comprises V as shown in the amino acid sequence SEQ ID NO:42 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:54 L LC-CDR1, LC-CDR2 and LC-CDR3 included; (xii) V H , which comprises V as shown in the amino acid sequence SEQ ID NO:43 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:54 L LC-CDR1, LC-CDR2 and LC-CDR3 included; (xiii) V H , which comprises V as shown in the amino acid sequence SEQ ID NO:44 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:54 L Containing LC-CDR1, LC-CDR2 and LC-CDR3; (xiv) V H , which comprises V as shown in the amino acid sequence SEQ ID NO: 39 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:55 LContains LC-CDR1, LC-CDR2 and LC-CDR3; (xv) V H , which comprises V as shown in the amino acid sequence SEQ ID NO:40 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:55 L Containing LC-CDR1, LC-CDR2 and LC-CDR3; (xvi) V H , which comprises V as shown in the amino acid sequence SEQ ID NO:41 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:55 L Containing LC-CDR1, LC-CDR2 and LC-CDR3; (xvii) V H , which comprises V as shown in the amino acid sequence SEQ ID NO:42 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:55 L LC-CDR1, LC-CDR2 and LC-CDR3 included; (xviii) V H , which comprises V as shown in the amino acid sequence SEQ ID NO:43 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:55 L Containing LC-CDR1, LC-CDR2 and LC-CDR3; (xix) V H , which comprises V as shown in the amino acid sequence SEQ ID NO:44 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:55 L Contains LC-CDR1, LC-CDR2 and LC-CDR3; (xx) V H , which comprises V as shown in the amino acid sequence SEQ ID NO:45 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:56L Containing LC-CDR1, LC-CDR2 and LC-CDR3; (xxi) V H , which comprises V as shown in the amino acid sequence SEQ ID NO:45 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO: 57 L Containing LC-CDR1, LC-CDR2 and LC-CDR3; (xxii) V H , which comprises V as shown in the amino acid sequence SEQ ID NO:46 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO: 58 L Containing LC-CDR1, LC-CDR2 and LC-CDR3; (xxiii) V H , which comprises V as shown in the amino acid sequence SEQ ID NO:47 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO: 59 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0019] In some embodiments, an isolated anti-GDF15 antibody is provided, comprising: (i) V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 13, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30, or the V L A variant comprising up to about 5 amino acid substitutions in its LC-CDRs; (ii) V H , the V Hcomprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 13, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 24, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30, or the V L A variant comprising up to about 5 amino acid substitutions in its LC-CDRs; (iii) V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 13, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30, or the V L A variant comprising up to about 5 amino acid substitutions in its LC-CDRs; (iv) V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 2, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 13, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30, or the V L A variant comprising up to about 5 amino acid substitutions in its LC-CDRs; (v) V H, the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 13, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30, or the V L A variant comprising up to about 5 amino acid substitutions in its LC-CDRs.

[0020] In some embodiments, any of the isolated anti-GDF15 antibodies described above comprises: V H , comprising an amino acid sequence as shown in any one of SEQ ID NOs: 38-47 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence as shown in any one of SEQ ID NOs: 38-47; and V L , which comprises the amino acid sequence shown in any one of SEQ ID NOs: 52-59 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence shown in any one of SEQ ID NOs: 52-59.

[0021] In some embodiments, an isolated anti-GDF15 antibody is provided comprising: (i) V H , comprising the amino acid sequence of SEQ ID NO: 38 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 38; and V L , comprising the amino acid sequence of SEQ ID NO: 52 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 52; (ii) V H , comprising the amino acid sequence of SEQ ID NO: 39 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 39; and V L , comprising the amino acid sequence of SEQ ID NO: 53 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 53; (iii) V H, comprising the amino acid sequence of SEQ ID NO: 40 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 40; and V L , comprising the amino acid sequence of SEQ ID NO: 53 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 53; (iv) V H , comprising the amino acid sequence of SEQ ID NO: 41 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 41; and V L , comprising the amino acid sequence of SEQ ID NO: 53 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 53; (v) V H , comprising the amino acid sequence of SEQ ID NO: 42 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 42; and V L , comprising the amino acid sequence of SEQ ID NO: 53 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 53; (vi) V H , comprising the amino acid sequence of SEQ ID NO: 43 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 43; and V L , comprising the amino acid sequence of SEQ ID NO: 53 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 53; (vii) V H , comprising the amino acid sequence of SEQ ID NO: 44 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 44; and V L , comprising the amino acid sequence of SEQ ID NO: 53 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 53; (viii) V H , comprising the amino acid sequence of SEQ ID NO: 39 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 39; and V L , comprising the amino acid sequence of SEQ ID NO: 54 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 54; (ix) V H, comprising the amino acid sequence of SEQ ID NO: 40 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 40; and V L , comprising the amino acid sequence of SEQ ID NO: 54 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 54; (x) V H , comprising the amino acid sequence of SEQ ID NO: 41 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 41; and V L , comprising the amino acid sequence of SEQ ID NO: 54 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 54; (xi) V H , comprising the amino acid sequence of SEQ ID NO: 42 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 42; and V L , comprising the amino acid sequence of SEQ ID NO: 54 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 54; (xii) V H , comprising the amino acid sequence of SEQ ID NO: 43 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 43; and V L , comprising the amino acid sequence of SEQ ID NO: 54 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 54; (xiii) V H , comprising the amino acid sequence of SEQ ID NO: 44 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 44; and V L , comprising the amino acid sequence of SEQ ID NO: 54 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 54; (xiv) V H , comprising the amino acid sequence of SEQ ID NO: 39 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 39; and V L , comprising the amino acid sequence of SEQ ID NO: 55 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 55; (xv) V H, comprising the amino acid sequence of SEQ ID NO: 40 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 40; and V L , comprising the amino acid sequence of SEQ ID NO: 55 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 55; (xvi) V H , comprising the amino acid sequence of SEQ ID NO: 41 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 41; and V L , comprising the amino acid sequence of SEQ ID NO: 55 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 55; (xvii) V H , comprising the amino acid sequence of SEQ ID NO: 42 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 42; and V L , comprising the amino acid sequence of SEQ ID NO: 55 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 55; (xviii) V H , comprising the amino acid sequence of SEQ ID NO: 43 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 43; and V L , comprising the amino acid sequence of SEQ ID NO: 55 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 55; (xix) V H , comprising the amino acid sequence of SEQ ID NO: 44 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 44; and V L , comprising the amino acid sequence of SEQ ID NO: 55 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 55; (xx) V H , comprising the amino acid sequence of SEQ ID NO: 45 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 45; and V L , comprising the amino acid sequence of SEQ ID NO: 56 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 56; (xxi) V H, comprising the amino acid sequence of SEQ ID NO: 45 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 45; and V L , comprising the amino acid sequence of SEQ ID NO: 57 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 57; (xxii) V H , comprising the amino acid sequence of SEQ ID NO: 46 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 46; and V L , comprising the amino acid sequence of SEQ ID NO: 58 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 58; (xxiii) V H , comprising the amino acid sequence of SEQ ID NO: 47 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 47; and V L , comprising the amino acid sequence of SEQ ID NO: 59 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 59.

[0022] In some embodiments, an isolated anti-GDF15 antibody is provided, comprising: (i) V H , which comprises V as shown in the amino acid sequence SEQ ID NO:48 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO: 60 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0023] In some embodiments, an isolated anti-GDF15 antibody is provided, comprising: (i) V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 14, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V Lcomprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 19, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 31, or the V L A variant comprising up to about 5 amino acid substitutions in its LC-CDRs.

[0024] In some embodiments, any of the isolated anti-GDF15 antibodies described above comprises: V H , comprising the amino acid sequence shown in SEQ ID NO: 48 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 48; and V L , which comprises the amino acid sequence shown in SEQ ID NO: 60 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 60.

[0025] In some embodiments, an isolated anti-GDF15 antibody is provided, comprising: (i) V H , which comprises V as shown in the amino acid sequence SEQ ID NO:49 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:61 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0026] In some embodiments, an isolated anti-GDF15 antibody is provided, comprising: (i) V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 15, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 20, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 27, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 32, or the V L A variant comprising up to about 5 amino acid substitutions in its LC-CDRs.

[0027] In some embodiments, any of the isolated anti-GDF15 antibodies described above comprises: V H , comprising the amino acid sequence shown in SEQ ID NO: 49 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 49; and V L , which comprises the amino acid sequence shown in SEQ ID NO: 61 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 61.

[0028] In some embodiments, an isolated anti-GDF15 antibody is provided, comprising: (i) V H , which comprises V as shown in the amino acid sequence SEQ ID NO: 50 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO: 62 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0029] In some embodiments, an isolated anti-GDF15 antibody is provided, comprising: (i) V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 5, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 16, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 28, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 33, or the V L A variant comprising up to about 5 amino acid substitutions in its LC-CDRs.

[0030] In some embodiments, any of the isolated anti-GDF15 antibodies described above comprises: V H , comprising the amino acid sequence shown in SEQ ID NO: 50 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 50; and V L, which comprises the amino acid sequence shown in SEQ ID NO: 62 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 62.

[0031] In some embodiments, an isolated anti-GDF15 antibody is provided, comprising a heavy chain variable domain (V H ), the V H The invention comprises: a heavy chain complementarity determining region (HC-CDR) 1 comprising SYDMT (SEQ ID NO: 6); HC-CDR2 comprising IIX1X2SGX3TYYASWAKG (SEQ ID NO: 79), wherein X1 is N or S, X2 is G, N or S, and X3 is N or S; and HC-CDR3 comprising GILVYADYGDHNL (SEQ ID NO: 17); and a light chain variable domain (V L ), the V L Comprising: a light chain complementarity determining region (LC-CDR) 1 comprising QASEDIYTNLA (SEQ ID NO: 22); a LC-CDR2 comprising AASTLAS (SEQ ID NO: 29); and a LC-CDR3 comprising LGVYTYISAX1GA (SEQ ID NO: 81), wherein X1 is D or E.

[0032] In some embodiments, an isolated anti-GDF15 antibody is provided, comprising V H , the V H comprising: an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6 or a variant thereof, wherein the variant comprises at most about 3 amino acid substitutions; an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 12, 75-78 or a variant thereof, wherein the variant comprises at most about 3 amino acid substitutions; and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 17 or a variant thereof, wherein the variant comprises at most about 3 amino acid substitutions; and V L , the V L Comprising: LC-CDR1, which comprises the amino acid sequence shown in SEQ ID NO:22 or a variant thereof, wherein the variant comprises substitutions of up to about 3 amino acids; LC-CDR2, which comprises the amino acid sequence shown in SEQ ID NO:29 or a variant thereof, wherein the variant comprises substitutions of up to about 3 amino acids; and LC-CDR3, which comprises the amino acid sequence shown in any one of SEQ ID NOs:34, 80 or a variant thereof, wherein the variant comprises substitutions of up to about 3 amino acids.

[0033] In some embodiments, an isolated anti-GDF15 antibody is provided, comprising: V H , the V H Comprising V as shown in any one of the amino acid sequences of SEQ ID NOs: 51, 82-89 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , the V L Comprising V as shown in any one of the amino acid sequences of SEQ ID NOs: 63, 90-91 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0034] In some embodiments, an isolated anti-GDF15 antibody is provided, comprising: (i) V H , which comprises V as shown in the amino acid sequence SEQ ID NO:51 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO: 63 L Containing LC-CDR1, LC-CDR2 and LC-CDR3; (ii) V H , which comprises V as shown in the amino acid sequence SEQ ID NO: 82 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:90 L Containing LC-CDR1, LC-CDR2 and LC-CDR3; (iii) V H , which comprises V as shown in the amino acid sequence SEQ ID NO: 83 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:90 L Containing LC-CDR1, LC-CDR2 and LC-CDR3; (iv) V H , which comprises V as shown in the amino acid sequence SEQ ID NO: 84 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:90 L Containing LC-CDR1, LC-CDR2 and LC-CDR3; (v) V H , which comprises V as shown in the amino acid sequence SEQ ID NO: 85H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:90 L Containing LC-CDR1, LC-CDR2 and LC-CDR3; (vi) V H , which comprises V as shown in the amino acid sequence SEQ ID NO: 86 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:91 L Containing LC-CDR1, LC-CDR2 and LC-CDR3; (vii) V H , which comprises V as shown in the amino acid sequence SEQ ID NO: 87 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:91 L Containing LC-CDR1, LC-CDR2 and LC-CDR3; (viii) V H , which comprises V as shown in the amino acid sequence SEQ ID NO: 88 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:91 L Containing LC-CDR1, LC-CDR2 and LC-CDR3; (ix) V H , which comprises V as shown in the amino acid sequence SEQ ID NO: 89 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:91 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0035] In some embodiments, an isolated anti-GDF15 antibody is provided, comprising: (i) V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 12, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 17, or the V HA variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 34, or the V L A variant comprising up to about 5 amino acid substitutions in its LC-CDRs; (ii) V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 75, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 17, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 80, or the V L A variant comprising up to about 5 amino acid substitutions in its LC-CDRs; (iii) V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 76, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 17, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 80, or the V L A variant comprising up to about 5 amino acid substitutions in its LC-CDRs; (iv) V H , the V Hcomprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 77, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 17, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 80, or the V L A variant comprising up to about 5 amino acid substitutions in its LC-CDRs; (v) V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 78, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 17, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 80, or the V L A variant comprising up to about 5 amino acid substitutions in its LC-CDRs.

[0036] In some embodiments, any of the isolated anti-GDF15 antibodies described above comprises: V H , comprising an amino acid sequence as shown in any one of SEQ ID NOs: 51, 82-89 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence as shown in any one of SEQ ID NOs: 51, 82-89; and V L , which comprises the amino acid sequence shown in any one of SEQ ID NOs: 63, 90-91 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence shown in any one of SEQ ID NOs: 63, 90-91.

[0037] In some embodiments, any of the isolated anti-GDF15 antibodies described above comprises: (i) V H, comprising the amino acid sequence shown in SEQ ID NO: 51 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 51; and V L , which comprises the amino acid sequence shown in SEQ ID NO: 63 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 63; (ii) V H , comprising the amino acid sequence of SEQ ID NO: 82 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 82; and V L , comprising the amino acid sequence of SEQ ID NO: 90 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 90; (iii) V H , comprising the amino acid sequence of SEQ ID NO: 83 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 83; and V L , comprising the amino acid sequence of SEQ ID NO: 90 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 90. (iv) V H , comprising the amino acid sequence of SEQ ID NO: 84 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 84; and V L , comprising the amino acid sequence of SEQ ID NO: 90 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 90; (v) V H , comprising the amino acid sequence of SEQ ID NO: 85 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 85; and V L , comprising the amino acid sequence of SEQ ID NO: 90 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 90; (vi) V H , comprising the amino acid sequence of SEQ ID NO: 86 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 86; and V L , comprising the amino acid sequence of SEQ ID NO: 91 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 91; (vii) V H, comprising the amino acid sequence of SEQ ID NO: 87 or a variant thereof having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 87; and V L , comprising the amino acid sequence of SEQ ID NO: 91 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 91; (viii) V H , comprising the amino acid sequence of SEQ ID NO: 88 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 88; and V L , comprising the amino acid sequence of SEQ ID NO: 91 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 91; (ix) V H , comprising the amino acid sequence of SEQ ID NO: 89 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 89; and V L , comprising the amino acid sequence of SEQ ID NO: 91 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 91.

[0038] In some embodiments, the isolated anti-GDF15 antibody binds to human GDF15 with a Kd value of 0.1 pM to about 10 nM.

[0039] In some embodiments, an isolated anti-GDF15 antibody is provided that competes with any of the above isolated anti-GDF15 antibodies for specific binding to GDF15. In some embodiments, an isolated anti-GDF15 antibody is provided that specifically binds to the same epitope as any of the above isolated anti-GDF15 antibodies.

[0040] In some embodiments, any of the isolated anti-GDF15 antibodies described above comprises an Fc fragment. In some embodiments, the isolated anti-GDF15 antibody is a full-length IgG antibody. In some embodiments, the isolated anti-GDF15 antibody is a full-length IgG1, IgG2, IgG3, or IgG4 antibody. In some embodiments, the isolated anti-GDF15 antibody is a chimeric, fully human, or humanized antibody. In some embodiments, the isolated anti-GDF15 antibody is an antigen-binding fragment selected from the group consisting of Fab, Fab', F(ab)'2, Fab'-SH, single-chain Fv (scFv), Fv fragment, dAb, Fd, nanobody, diabody, and linear antibody.

[0041] In some embodiments, an isolated nucleic acid molecule is provided, encoding any of the anti-GDF15 antibodies described above. In some embodiments, a vector is provided, comprising any of the nucleic acid molecules described above. In some embodiments, a host cell is provided, comprising any of the anti-GDF15 antibodies described above, any of the nucleic acid molecules described above, or any of the vectors described above. In some embodiments, a method for preparing an anti-GDF15 antibody is provided, comprising: a) culturing any of the host cells described above under conditions effective for expressing the anti-GDF15 antibody; and b) obtaining the expressed anti-GDF15 antibody from the host cell.

[0042] In some embodiments, a method of treating a disease or condition in a desired individual is provided, comprising administering to the individual an effective amount of any of the anti-GDF15 antibodies described above. In some embodiments, use of any of the anti-GDF15 antibodies described above in the preparation of a pharmaceutical composition for treating a disease or condition in a desired individual is provided. In some embodiments, use of any of the anti-GDF15 antibodies described above or a pharmaceutical composition comprising an anti-GDF15 antibody in the preparation of a medicament for treating a disease or condition is provided. In some embodiments, the disease or condition is related to the GDF15 signaling pathway, including cancer, cachexia, and metabolic diseases or conditions. In some embodiments, the disease or condition is selected from, for example, cancer (such as brain cancer, melanoma, lung cancer, gastrointestinal tumors, colon cancer, pancreatic cancer, prostate cancer, breast cancer, oral cancer, liver cancer, leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, bladder cancer, cervical cancer, uterine body cancer, testicular cancer, thyroid cancer, kidney cancer, gallbladder cancer, multiple myeloma, nasopharyngeal cancer, laryngeal cancer, pharyngeal cancer, esophageal cancer, etc.), cachexia, cachexia-related weight loss, anorexia nervosa, metabolic diseases (such as fat and energy metabolism imbalance, appetite regulation, weight regulation).

[0043] Also provided are pharmaceutical compositions, kits, and manufactured products comprising any of the anti-GDF15 antibodies described above. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] FIG1 shows the effect of an exemplary lead anti-GDF15 antibody GDF-R37-rabIg1 on body weight changes in mice in the tumor cachexia animal model HT1080.

[0045] Figures 2A-2C show the binding affinity of humanized anti-GDF15 antibodies derived from the lead antibody GDF-R37-rabIg1 to human GDF15 as analyzed by ELISA.

[0046] Figures 3A-3C show the neutralization effect of humanized anti-GDF15 antibodies derived from the lead antibody GDF-R37-rabIg1 on the binding of GDF15 to GFRAL as analyzed by ELISA.

[0047] Figures 4A-4D show the in vitro biological activity of humanized anti-GDF15 antibodies derived from the lead antibody GDF-R37-rabIg1 in inhibiting GFRAL and RET downstream signaling activation as analyzed in reporter cells.

[0048] FIG5 shows the effects of exemplary anti-GDF15 antibodies Hum-R37-2, Hum-R37-5, and Hum-R37-8 on the changes in mouse body weight in a mouse rapid weight loss model.

[0049] Detailed description of this application

[0050] In one aspect, the present application provides anti-GDF15 antibody molecules. Through a combination of screening using a constructed 293T cell display library, antibody humanization, affinity maturation, and appropriately designed biochemical and biological experiments, a highly potent antibody molecule capable of binding to human GDF15 and inhibiting the interaction between human GDF15 and its receptor GFRAL has been identified. The results presented herein demonstrate that, compared to the known anti-GDF15 antibody Hu01G06-127 (AVEO), the antibodies described in the present application are even more potent than or comparable to Hu01G06-127 in various biological experiments.

[0051] The anti-GDF15 antibodies provided herein include, for example, full-length anti-GDF15 antibodies, anti-GDF15 single-chain antibodies (scFvs), anti-GDF15 Fc fusion proteins, multispecific (eg, bispecific) anti-GDF15 antibodies, anti-GDF15 immunoconjugates, and the like.

[0052] On the other hand, the present application provides an anti-GDF15 antibody, wherein the anti-GDF15 antibody comprises: a heavy chain variable domain (V H ), the V H The invention comprises: a heavy chain complementary determining region (HC-CDR) 1 comprising X1YYMX2 (SEQ ID NO: 35), wherein X1 is D or N, and X2 is S or T; HC-CDR2 comprising MISFSGTTX1ATWAKG (SEQ ID NO: 36), wherein X1 is H or Y; and HC-CDR3 comprising VVYAGWTYPLGI (SEQ ID NO: 13); and a light chain variable domain (V L ), the V LIt comprises: a light chain complementarity determining region (LC-CDR) 1 comprising QASQSISSVLS (SEQ ID NO: 18); a LC-CDR2 comprising EASX1X2AS (SEQ ID NO: 37), wherein X1 is I or T, and X2 is L or Q; and a LC-CDR3 comprising QANYDVYNYGNP (SEQ ID NO: 30).

[0053] On the other hand, the present application provides an anti-GDF15 antibody, wherein the anti-GDF15 antibody comprises: a heavy chain variable domain (V H ), the V H comprising: a heavy chain complementarity determining region (HC-CDR) 1 comprising DYYMS (SEQ ID NO: 3); HC-CDR2 comprising DIYGGSGTTDYASWVKG (SEQ ID NO: 9); and HC-CDR3 comprising GITADI (SEQ ID NO: 14); and a light chain variable domain (V L ), the V L It comprises: a light chain complementarity determining region (LC-CDR) 1 comprising QASQSISSYLA (SEQ ID NO: 19); a LC-CDR2 comprising KASTLAS (SEQ ID NO: 26); and a LC-CDR3 comprising RCIYGDSYGAA (SEQ ID NO: 31).

[0054] On the other hand, the present application provides an anti-GDF15 antibody, wherein the anti-GDF15 antibody comprises: a heavy chain variable domain (V H ), the V H The heavy chain complementarity determining region (HC-CDR) 1 comprises SHWMS (SEQ ID NO: 4); HC-CDR2 comprises FVSPSGRAYYTSWVNG (SEQ ID NO: 10); and HC-CDR3 comprises GYTSGLDI (SEQ ID NO: 15); and a light chain variable domain (V L ), the V L It comprises: a light chain complementarity determining region (LC-CDR) 1 comprising QSSKSVVNGDWLA (SEQ ID NO: 20); a LC-CDR2 comprising DAATLAS (SEQ ID NO: 27); and a LC-CDR3 comprising AGVYNNDSDNG (SEQ ID NO: 32).

[0055] On the other hand, the present application provides an anti-GDF15 antibody, wherein the anti-GDF15 antibody comprises: a heavy chain variable domain (V H ), the V HThe heavy chain complementarity determining region (HC-CDR) 1 comprises TYWMS (SEQ ID NO: 5); HC-CDR2 comprises TIYAGSGGTWYASWVKG (SEQ ID NO: 11); and HC-CDR3 comprises GPNYSDAI (SEQ ID NO: 16); and a light chain variable domain (V L ), the V L It comprises: a light chain complementarity determining region (LC-CDR) 1 comprising QASEYIYSSLA (SEQ ID NO:21); a LC-CDR2 comprising DASDLAS (SEQ ID NO:28); and a LC-CDR3 comprising QCTDLSSSAGNT (SEQ ID NO:33).

[0056] On the other hand, the present application provides an anti-GDF15 antibody, wherein the anti-GDF15 antibody comprises: a heavy chain variable domain (V H ), the V H The invention comprises: a heavy chain complementarity determining region (HC-CDR) 1 comprising SYDMT (SEQ ID NO: 6); HC-CDR2 comprising IIX1X2SGX3TYYASWAKG (SEQ ID NO: 79), wherein X1 is N or S, X2 is G, N or S, and X3 is N or S; and HC-CDR3 comprising GILVYADYGDHNL (SEQ ID NO: 17); and a light chain variable domain (V L ), the V L Comprising: a light chain complementarity determining region (LC-CDR) 1 comprising QASEDIYTNLA (SEQ ID NO: 22); a LC-CDR2 comprising AASTLAS (SEQ ID NO: 29); and a LC-CDR3 comprising LGVYTYISAX1GA (SEQ ID NO: 81), wherein X1 is D or E.

[0057] Also provided are nucleic acids encoding anti-GDF15 antibodies, compositions comprising anti-GDF15 antibodies, and methods of making and using anti-GDF15 antibodies.

[0058] definition

[0059] As used herein, "treatment" or "treating" is a method of obtaining beneficial or desired results, including clinical results. For the purposes of this application, the beneficial or desired clinical results include, but are not limited to, one or more of the following: alleviating one or more symptoms caused by the disease, reducing the extent of the disease, stabilizing the disease (e.g., preventing or delaying the worsening of the disease), preventing or delaying the spread of the disease (e.g., metastasis), preventing or delaying the recurrence of the disease, delaying or slowing the progression of the disease, improving the disease state, alleviating the disease (partially or completely), reducing the dose of one or more other drugs required to treat the disease, delaying the progression of the disease, improving or enhancing the quality of life, increasing body weight, and / or prolonging survival. At the same time, "treatment" also includes the reduction of pathological results of the disease

[0060] (For example, for cancer, tumor volume.) The methods of the present application contemplate any one or more aspects of these treatments.

[0061] The term "antibody" includes full-length antibodies and antigen-binding fragments thereof. Full-length antibodies include two heavy chains and two light chains. The variable regions of the light and heavy chains are responsible for antigen binding. The variable regions in both chains typically include three hypervariable loops, known as complementarity determining regions (CDRs) (light chain (LC) CDRs include LC-CDR1, LC-CDR2, and LC-CDR3, and heavy chain (HC) CDRs include HC-CDR1, HC-CDR2, and HC-CDR3). The CDR boundaries of the antibodies or antigen-binding fragments disclosed herein can be defined or identified by the Kabat, Chothia, or Al-Lazikani conventions (Al-Lazikani 1997; Chothia 1985; Chothia 1987; Chothia 1989; Kabat 1987; Kabat 1991). The three CDR regions of the heavy or light chain are inserted between flanking segments called framework regions (FRs), which are more highly conserved than the CDR regions and form a scaffold that supports the hypervariable loops. The constant regions of the heavy and light chains are not involved in antigen binding but exhibit various effector functions. Antibodies are classified based on the amino acid sequence of their heavy chain constant regions. The five major classes or isotypes of antibodies are IgA, IgD, IgE, IgG, and IgM, which are characterized by having heavy chains of type α, δ, ε, γ, and μ, respectively. Several major antibody classes are divided into subclasses, such as IgG1 (γ1 heavy chain), IgG2 (γ2 heavy chain), IgG3 (γ3 heavy chain), IgG4 (γ4 heavy chain), IgA1 (α1 heavy chain), or IgA2 (α2 heavy chain).

[0062] As used herein, the term "antigen-binding fragment" includes antibody fragments, such as diabodies, Fab, Fab', F(ab')2, Fv fragments, disulfide-stabilized Fv fragments (dsFv), (dsFv)2, bispecific dsFv (dsFv-dsFv'), disulfide-stabilized diabodies (dsdiabodies), single-chain Fv (scFv), scFv dimers (divalent diabodies), multispecific antibodies composed of antibody fragments comprising one or more CDRs, single-domain antibodies, nanobodies, domain antibodies, bivalent domain antibodies, or any other antibody fragment that can bind to an antigen but does not contain a complete antibody structure. Antigen-binding fragments can bind to the same antigen as a parent antibody or parent antibody fragment (such as a parent scFv). Antigen-binding fragments also include fusion proteins comprising the above-mentioned antibody fragments. In some embodiments, an antigen-binding fragment may include one or more CDRs from a specific human antibody that are transplanted to a framework region from one or more different human antibodies.

[0063] As used herein, the term "epitope" refers to a specific group of atoms or amino acids on an antigen to which an antibody or antibody portion binds. If two antibodies or antibody portions exhibit competitive binding to an antigen, they likely bind to the same epitope on the antigen.

[0064] As used herein, a first antibody "competes" for binding to a GDF15 target with a second antibody when the first antibody, at equimolar concentrations, inhibits binding of the second antibody to the GDF15 target by at least 50% (e.g., at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%), and vice versa. PCT Publication WO 03 / 48731 describes a high-throughput antibody "epitope binning" method based on cross-competition.

[0065] As used herein, the terms "specifically bind," "specifically recognize," or "specific for" refer to a measurable and reproducible interaction, e.g., binding of an antibody to a target that can confirm the presence of the target in a heterogeneous population of molecules, including biomolecules. For example, an antibody that specifically recognizes a target (which may be an epitope) means that the antibody binds to the target with greater affinity, avidity, more readily, and / or more persistently than it binds to other targets. In some embodiments, an antibody that specifically recognizes an antigen reacts with one or more antigenic determinants of the antigen with an affinity that is at least 10 times greater than its binding affinity to other targets.

[0066] As used herein, an "isolated" anti-GDF15 antibody refers to an anti-GDF15 antibody that (1) is not related to a naturally occurring protein, (2) does not contain other proteins from the same source, (3) is expressed by cells of a different species, or (4) does not occur in nature.

[0067] As used herein, the term "isolated nucleic acid" refers to a nucleic acid of genomic, cDNA, or synthetic origin, or a combination thereof. Depending on its origin, the "isolated nucleic acid" is (1) unrelated to all or part of the polynucleotide sequence found in nature, (2) operably linked to a polynucleotide sequence with which it is not naturally associated, or (3) not found in nature as part of a longer sequence.

[0068] As used herein, the term "CDR" or "complementarity determining region" refers to the non-contiguous antigen binding sites found within the variable domains of heavy and light chain polypeptides. In the literature Kabat et al., J. Biol. Chem. 252: 6609-6616 (1977); Kabat et al., USDept. of Health and Human Services, "Sequences of proteins of immunological interest" (1991); Chothia et al., J. Mol. Biol. 196: 901-917 (1987); Al-Lazikani B. et al. al., J. Mol. Biol., 273: 927-948 (1997); MacCallum et al., J. Mol. Biol. 262: 732-745 (1996); Abhinandan and Martin, Mol. Immunol., 45: 3832-3839 (2008); Lefranc MPet These specific regions are described in, for example, Desmond et al., Dev. Comp. Immunol., 27:55-77 (2003); and Honegger and Plückthun, J. Mol. Biol., 309:657-670 (2001), where these definitions include overlap or subsets of amino acid residues when compared to one another. However, any definition used to designate a CDR of an antibody, grafted antibody, or variant thereof is included within the scope of the term as defined and used herein. Table 1 lists the positions of the amino acid residues included in the CDRs defined by the various references cited above for comparison. Algorithms and binding interfaces for CDR prediction are known in the art, including, for example, Abhinandan and Martin, Mol. Immunol., 45: 3832-3839 (2008); Ehrenmann F. et al., Nucleic Acids Res., 38: D301-D307 (2010); and Adolf-Bryfogle J. et al., Nucleic Acids Res., 43: D432-D438 (2015). The contents of the references cited in this paragraph are incorporated herein by reference in their entirety for use in this application and in one or more claims that may be included in this article.

[0069] Table 1: CDR definitions

[0070] 1The amino acid residue numbers refer to the nomenclature of Kabat et al.

[0071] 2 The amino acid residue numbers refer to the nomenclature of Chothia et al.

[0072] 3 The amino acid residue numbers refer to the nomenclature of MacCallum et al.

[0073] 4 The amino acid residue numbers refer to the nomenclature of Lefranc et al.

[0074] 5 The amino acid residue numbers refer to the nomenclature of Honegger and Plückthun.

[0075] The term "chimeric antibody" refers to an antibody in which a portion of the heavy chain and / or light chain is identical or homologous to the corresponding sequence in an antibody from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical or homologous to the corresponding sequence in an antibody from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, as long as they have the biological activity described in the present application (see US Patent No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81: 6851-6855 (1984)).

[0076] "Fv" is the smallest antibody fragment that contains a complete antigen recognition and binding site. This fragment is a dimer formed by a heavy chain variable domain and a light chain variable domain tightly non-covalently linked. Six hypervariable loops (3 loops each in the light chain and heavy chain) are derived from the folding of these two domains. The hypervariable loops provide the antibody with amino acid residues for binding to the antigen and confer specificity for binding to the antibody. However, even a single variable domain (or half of an Fv fragment, which only contains 3 CDRs specific for the antigen) has the ability to recognize and bind to the antigen, although its affinity is lower than that of the complete binding site.

[0077] "Single-chain Fv", also abbreviated as "sFv" or "scFv", is a Fv that contains V molecules linked into a single polypeptide chain. H and V L In some embodiments, the scFv polypeptide further comprises a V H and V LThe linker polypeptide between the domains allows the scFv to form an ideal structure for antigen binding. For an overview of scFv, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994).

[0078] The term "diabody" is used in V H and V L A small antibody fragment is prepared by constructing scFv fragments (see above) using short linkers (e.g., 5-10 residues) between the domains. This allows the variable domains to pair between chains rather than within the chain, resulting in a bivalent fragment, that is, a fragment with two antigen-binding sites. Bispecific diabodies are heterodimers of two "crossover" scFv fragments, in which the V domains of the two antibodies are H and V L The domains are located on different polypeptide chains. Diabodies are fully described in EP 404,097; WO 93 / 11161; Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993).

[0079] The "humanized" form of a non-human (such as a rodent) antibody is a chimeric antibody that includes minimal sequences from a non-human antibody. In most cases, a humanized antibody is a human immunoglobulin (recipient antibody) in which the hypervariable region (HVR) residues of the recipient antibody are replaced by hypervariable region residues from a non-human species such as a mouse, rat, rabbit or non-human mammal with ideal antibody specificity, affinity and performance (donor antibody). In some cases, residues in the human immunoglobulin framework region are replaced by corresponding non-human residues. In addition, a humanized antibody may include residues that are not present in either the recipient antibody or the donor antibody. These modifications can further improve the performance of the antibody. Typically, a humanized antibody will comprise substantially all, at least one, and usually two variable domains, wherein all or substantially all of the hypervariable loops correspond to the hypervariable loops of a non-human immunoglobulin, and all or substantially all of the framework regions are human immunoglobulin sequences. The human antibody optionally also comprises at least a portion of an immunoglobulin constant region (Fc), typically a constant region of a human immunoglobulin. For details, see Jones et al., Nature 321: 522-525 (1986); Riechmann et al., Nature 332: 323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2: 593-596 (1992).

[0080] The "percent (%) amino acid sequence identity" or "homology" of the polypeptide and antibody sequences identified herein is defined as the percentage of identical amino acid residues in a candidate sequence and the polypeptide sequence being compared, when the sequences are aligned, considering conservative substitutions as part of the sequence identity. Percent amino acid sequence identity can be determined by various alignment methods within the skill in the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, Megalign (DNASTAR), or MUSCLE software. One skilled in the art can determine appropriate parameters for measuring alignment, including any algorithm needed to maximize alignment over the full length of the sequences being compared. However, for the purposes of this article, percent amino acid sequence identity values ​​are generated using the sequence alignment computer program MUSCLE (Edgar, RC, Nucleic Acids Research 32(5):1792-1797, 2004; Edgar, RC, BMC Bioinformatics 5(1):113, 2004).

[0081] The term "Fc receptor" or "FcR" is used to describe a receptor that binds to the Fc region of an antibody. In some embodiments, the FcR described herein is an FcR that binds to an IgG antibody (a gamma receptor), including receptors of the FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants and alternatively spliced ​​forms of these receptors. FcγRII receptors include FcγRIIA ("activating receptor") and FcγRIIB ("inhibiting receptor"), which have similar amino acid sequences and differ primarily in the cytoplasmic domain. The cytoplasmic domain of the activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM). The cytoplasmic domain of the inhibitory receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) (see M.in Annu. Rev. Immunol. 15:203-234 (1997). The term also includes allotypes, such as the FcγRIIIA allotypes: FcγRIIIA-Phe158, FcγRIIIA-Val158, FcγRIIA-R131, and / or FcγRIIA-H131. FcRs are described in Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991) and Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995). The term FcR in this application encompasses other types of FcRs, including those identified in the future. The term FcR also includes the neonatal receptor FcRn, which is responsible for the transfer of maternal IgGs to the newborn (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)).

[0082] The term "FcRn" refers to the neonatal Fc receptor (FcRn). FcRn is structurally similar to the major histocompatibility complex (MHC) and consists of an α chain non-covalently bound to β2 microglobulin. The various functions of the neonatal Fc receptor FcRn are reviewed in Ghetie and Ward (2000) Annu. Rev. Immunol. 18, 739-766. FcRn plays an important role in the passive transport of immunoglobulins (IgGs) from mother to newborn and in regulating serum IgG levels. As a salvage receptor, FcRn can bind and transport endocytosed IgGs in their intact form within and between cells, protecting them from the default degradation pathway.

[0083] The "CH1 domain" of a human IgG heavy chain constant region typically stretches from amino acid 118 to amino acid 215 (EU numbering system).

[0084] The "hinge region" is generally defined as stretching from Glu 216 to Pro 230 of human IgG1 (Burton, Molec. Immunol. 22: 161-206 (1985)). By placing the first and last cysteine ​​residues that form inter-heavy chain disulfide bonds in the same positions as in IgG1, the hinge regions of other IgG isotypes can be aligned with the IgG1 sequence.

[0085] The "CH2 domain" of the human IgG Fc region typically extends from amino acids 231 to 340. The CH2 domain is unique in that it does not closely pair with another domain. Instead, two N-terminally linked branched sugar chains are inserted between the two CH2 domains of the intact native IgG molecule. It is hypothesized that carbohydrates may serve as a substitute for domain-to-domain pairing, helping to maintain CH2 domain stability. Burton, Molec. Immunol. 22:161-206 (1985).

[0086] The "CH3" domain includes the CH2 domain extending from the C-terminal residue within the Fc region (from amino acid 341 to the C-terminus of the antibody sequence, usually amino acid residue 446 or 447 in IgG).

[0087] A "functional Fc fragment" possesses the "effector functions" of a native Fc region sequence. Exemplary "effector functions" include C1q binding; complement-dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; and downregulation of cell surface receptors (e.g., B cell receptor; BCR). These effector functions typically require the Fc region to be bound to a binding domain (e.g., an antibody variable region) and can be assessed using a variety of experimental methods known in the art.

[0088] IgG Fc variant antibodies with "altered" FcR binding affinity or ADCC activity have increased or decreased FcR binding activity and / or ADCC activity compared to the parent polypeptide or a polypeptide comprising a native Fc sequence. Fc variants that exhibit "enhanced binding" to FcRs have a higher binding affinity (e.g., lower apparent Kd or IC) to at least one FcR compared to the parent polypeptide or a polypeptide comprising a native IgG Fc sequence. 50In some embodiments, the binding capacity is enhanced by 3-fold, e.g., 5-, 10-, 25-, 50-, 60-, 100-, 150-, 200-, or even up to 500-fold, or the binding capacity is increased by 25% to 1000%, compared to the parent polypeptide. An Fc variant that exhibits "reduced binding" to an FcR has a lower affinity for at least one FcR (e.g., a higher apparent Kd or IC) than the parent polypeptide. 50 Compared with the parent polypeptide, its binding capacity is reduced by 40% or more.

[0089] "Antibody-dependent cell-mediated cytotoxicity" or "ADCC" is a form of cytotoxicity that refers to the binding of secreted Ig to Fc receptors (FcRs) present on certain cytotoxic cells (e.g., natural killer (NK) cells, neutrophils, and macrophages), enabling these cytotoxic effector cells to specifically bind to target cells bearing antigen and subsequently kill the target cells using cytotoxins. Antibodies "arm" the cytotoxic cells and are required for this killing. Of the major cell types that mediate ADCC, NK cells express only FcγRIII, while monocytes express FcγRI, FcγRII, and FcγRIII. The expression of FcRs on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991). To assess the ADCC activity of a target molecule, an in vitro ADCC assay can be performed, as described in U.S. Patent Nos. 5,500,362 or 5,821,337. Effector cells suitable for such experiments include peripheral blood mononuclear cells (PBMC) and natural killer cells (NK). Alternatively, or in addition, the ADCC activity of the target molecule can also be assessed in vivo, for example, as described in the animal model disclosed in Clynes et al. PNAS (USA) 95: 652-656 (1998).

[0090] Polypeptides comprising Fc region variants exhibit "enhanced ADCC activity" or are capable of more effectively mediating ADCC in the presence of human effector cells, compared to polypeptides comprising wild-type IgG Fc polypeptides or parent polypeptides. When tested in substantially the same quantity as polypeptides comprising wild-type IgG Fc polypeptides (or parent polypeptides), such polypeptides comprising Fc region variants are capable of more effectively mediating ADCC, both in vitro and in vivo. Such variants are generally identified using any in vitro ADCC assay known in the art, such as assays or methods for identifying ADCC activity, such as in animal models. In some embodiments, such variants mediate ADCC 5- to 100-fold more efficiently, such as 25- to 50-fold more efficiently, than wild-type Fc (or parent polypeptide).

[0091] "Complement-dependent cytotoxicity" or "CDC" refers to the lysis of target cells in the presence of complement. Activation of the classical complement pathway is initiated by the binding of the first component of the complement system (Clq) to an antibody (of the appropriate structural subclass) that binds to the cognate antigen. To assess complement activation, a CDC assay, such as that described in Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996), can be performed. Polypeptide variants with altered Fc region amino acid sequences and increased or decreased Clq binding capacity are described in U.S. Patent No. 6,194,551 Bl and WO99 / 51642. The contents of these patent publications are expressly incorporated herein by reference. See also Idusogie et al. J. Immunol. 164:4178-4184 (2000).

[0092] Unless otherwise indicated, a "nucleotide sequence encoding an amino acid sequence" includes all nucleotide sequences that are degenerate versions of each other and encode the same amino acid sequence. A nucleotide sequence encoding a protein or RNA may also include introns, for example, a nucleotide sequence encoding a protein may contain introns in some forms.

[0093] The term "operably linked" refers to a functional connection between a regulatory sequence and a heterologous nucleotide sequence, thereby enabling expression of the latter. For example, a first nucleotide sequence is operably linked to a second nucleotide sequence when the first nucleotide sequence is in a functional relationship with the second nucleotide sequence. For example, a promoter is operably linked to a coding sequence if the promoter affects the transcription or expression of the coding sequence. Generally, operably linked DNA sequences are contiguous and, if necessary, can link two protein coding regions in the same reading frame.

[0094] "Homologous" refers to the sequence similarity or sequence identity between two polypeptides or between two nucleic acid molecules. If the same base or amino acid monomer subunit is present at the same position in two compared sequences, for example, adenine is present at the same position in two DNA molecules, then the two DNA molecules are homologous at that position. The percentage homology between two sequences refers to the ratio of the number of matching or homologous positions shared by the two sequences to the total number of positions multiplied by 100. For example, if 6 out of 10 positions in two sequences are matched or homologous, then the homology between the two sequences is 60%. For example, the DNA sequences ATTGCC and TATGGC have 50% homology. Generally speaking, when aligning two sequences, the comparison is performed with the goal of obtaining maximum homology.

[0095] An "effective amount" of an anti-GDF15 antibody or composition disclosed herein is an amount sufficient to achieve a specific purpose. An "effective amount" can be determined empirically and by known methods relevant to the stated purpose.

[0096] The term "therapeutically effective amount" refers to an amount of an anti-GDF15 antibody or composition disclosed herein that is effective in treating a disease or symptom in an individual. For example, in the case of cancer, a therapeutically effective amount of an anti-GDF15 antibody or composition thereof means an amount that can reduce the number of cancer cells; reduce the size or weight of a tumor; inhibit (i.e., slow down or preferably stop to some extent) the infiltration of tumor cells into surrounding organs; inhibit (i.e., slow down or preferably stop to some extent) tumor metastasis; inhibit tumor growth to some extent, and / or alleviate to some extent one or more symptoms associated with cancer. For example, in the case of cancer-related cachexia, a therapeutically effective amount of an anti-GDF15 antibody or composition thereof means an amount that can inhibit (i.e., slow down or preferably stop to some extent) the loss of muscle mass; inhibit (i.e., slow down or preferably stop to some extent) the loss of fat mass; restore to some extent involuntary weight loss, inhibit organ mass loss to some extent, and / or alleviate to some extent one or more symptoms of the underlying disease associated with cachexia. The anti-GDF15 antibodies or compositions disclosed herein are capable of inhibiting and / or killing existing tumor cells to some extent, which can be cytostatic or cytotoxic. In some embodiments, a therapeutically effective amount means an amount that can prolong the patient's survival. In some embodiments, a therapeutically effective amount is an amount that can improve the patient's progression-free survival.

[0097] As used herein, "pharmaceutically acceptable" or "pharmacologically compatible" refers to a material that is free of biological activity or other undesirable properties, e.g., a material that can be added to a pharmaceutical composition administered to a patient without causing a significant adverse biological reaction, or that does not interact in a deleterious manner with any other component contained in the composition. Pharmaceutically acceptable carriers or excipients preferably meet the required standards for toxicology or manufacturing testing and / or are included in the inactive ingredient guide compiled by the U.S. Food and Drug Administration.

[0098]

[0066] The embodiments of the present application described herein should be understood to include "consisting of" and / or "consisting essentially of" embodiments.

[0099] Reference herein to "about" for a value or parameter includes (and describes) variations of the value or parameter itself. For example, a description involving "about X" includes a description of "X".

[0100] As used herein, reference to "not" a value or parameter generally indicates and describes "other than" a value or parameter. For example, "the method cannot be used to treat type X cancer" means that the method is generally used to treat other types of cancer besides type X cancer.

[0101] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0102] Anti-GDF15 antibody

[0103] In one aspect, the present application provides anti-human, rhesus monkey and / or mouse GDF15 antibodies that specifically bind to GDF15. The anti-GDF15 antibodies include, but are not limited to, humanized antibodies, chimeric antibodies, mouse antibodies, human antibodies, and antibody molecules comprising heavy chain and / or light chain CDRs as described herein. In one aspect, the present application provides isolated antibodies that bind to GDF15. Contemplated anti-GDF15 antibodies include, for example, full-length anti-GDF15 antibodies (such as full-length IgG1 or IgG4), anti-GDF15 single-chain antibodies, anti-GDF15 Fc fusion proteins, multispecific (such as bispecific) anti-GDF15 antibodies, anti-GDF15 immunoconjugates, and the like. In some embodiments, the anti-GDF15 antibody is a full-length antibody (such as full-length IgG1 or IgG4) or an antigen-binding fragment thereof that specifically binds to GDF15. In some embodiments, the anti-GDF15 antibody is a Fab, Fab', F(ab)'2, Fab'-SH, single-chain Fv (scFv), Fv fragment, dAb, Fd, nanobody, diabody or linear antibody. In some embodiments, an antibody that specifically binds to GDF15 means that the antibody binds to GDF15 with an affinity that is at least 10 times greater than the affinity for binding to a non-target (including, for example, 10 ... 2 , 10 3 , 10 4 , 10 5 , 10 6 , or 10 7 In some embodiments, a non-target antigen is an antigen that is not GDF15. Binding affinity can be determined by methods known in the art, such as ELISA, fluorescence-activated cell sorting (FACS) analysis, or radioimmunoprecipitation assay (RIA). Kd values ​​can be determined by methods known in the art, such as surface plasmon resonance (SPR) or biolayer interferometry (BLI).

[0104] Although anti-GDF15 antibodies comprising human sequences (e.g., human heavy and light chain variable domains comprising human CDR sequences) are generally discussed herein, non-human anti-GDF15 antibodies are also contemplated. In some embodiments, non-human anti-GDF15 antibodies comprise the human CDR sequences of the anti-GDF15 antibodies described herein and non-human framework region sequences. In some embodiments, the non-human framework region sequences include any sequence used to generate heavy and / or light chain variable domains using one or more human CDR sequences as described herein, including, for example, mammals such as mice, rats, rabbits, pigs, cattle (e.g., cows, bulls, buffaloes), deer, sheep, goats, chickens, cats, dogs, ferrets, primates (e.g., small apes, macaques), etc. In some embodiments, non-human anti-GDF15 antibodies include anti-GDF15 antibodies generated by grafting one or more human CDR sequences described herein into non-human framework regions (e.g., mouse or chicken framework region sequences).

[0105] The complete amino acid sequence of an exemplary human GDF15 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 68. The mature amino acid sequence of an exemplary human GDF15 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 69.

[0106] In some embodiments, the anti-GDF15 antibodies described herein specifically recognize an epitope in human GDF15. In some embodiments, the anti-GDF15 antibodies cross-react with GDF15 from species other than human. In some embodiments, the anti-GDF15 antibodies are completely specific for human GDF15 and do not cross-react with other non-human species.

[0107] In some embodiments, the anti-GDF15 antibody cross-reacts with at least one allelic variant of a GDF15 protein (or a fragment thereof). In some embodiments, the allelic variant has up to 30 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or 30) amino acid substitutions (e.g., conservative substitutions) compared to a naturally occurring GDF15 protein (or a fragment thereof). In some embodiments, the anti-GDF15 antibody does not cross-react with any allelic variant of a GDF15 protein (or a fragment thereof).

[0108] In some embodiments, the anti-GDF15 antibody cross-reacts with at least one interspecies variant of the GDF15 protein. In some embodiments, for example, the GDF15 protein (or fragment thereof) is human GDF15, and the interspecies variant of the GDF15 protein (or fragment thereof) is a variant in rhesus macaques. In some embodiments, the anti-GDF15 antibody does not cross-react with any interspecies variant of the GDF15 protein.

[0109] In some embodiments, as described herein, any anti-GDF15 antibody comprises an antibody heavy chain constant region and an antibody light chain constant region. In some embodiments, the anti-GDF15 antibody comprises an IgG1 heavy chain constant region. In some embodiments, the anti-GDF15 antibody comprises an IgG2 heavy chain constant region. In some embodiments, the anti-GDF15 antibody comprises an IgG3 heavy chain constant region. In some embodiments, the anti-GDF15 antibody comprises an IgG4 heavy chain constant region. In some embodiments, the heavy chain constant region comprises (consists of, or consists essentially of) the amino acid sequence of SEQ ID NO: 64. In some embodiments, the heavy chain constant region comprises (consists of, or consists essentially of) the amino acid sequence of SEQ ID NO: 65. In some embodiments, the anti-GDF15 antibody comprises a kappa light chain constant region. In some embodiments, the light chain constant region comprises (consists of, or consists essentially of) the amino acid sequence of SEQ ID NO: 66. In some embodiments, the anti-GDF15 antibody comprises a lambda light chain constant region. In some embodiments, the light chain constant region comprises (consists of, or consists essentially of) the amino acid sequence of SEQ ID NO: 67. In some embodiments, the anti-GDF15 antibody comprises an antibody heavy chain variable domain and an antibody light chain variable domain.

[0110] In some embodiments, the anti-GDF15 antibody comprises a heavy chain variable domain (V H ), the V H The invention comprises: a heavy chain complementary determining region (HC-CDR) 1 comprising X1YYMX2 (SEQ ID NO: 35), wherein X1 is D or N, and X2 is S or T; HC-CDR2 comprising MISFSGTTX1ATWAKG (SEQ ID NO: 36), wherein X1 is H or Y; and HC-CDR3 comprising VVYAGWTYPLGI (SEQ ID NO: 13); and a light chain variable domain (V L ), the V LIt comprises: a light chain complementarity determining region (LC-CDR) 1 comprising QASQSISSVLS (SEQ ID NO: 18); a LC-CDR2 comprising EASX1X2AS (SEQ ID NO: 37), wherein X1 is I or T, and X2 is L or Q; and a LC-CDR3 comprising QANYDVYNYGNP (SEQ ID NO: 30).

[0111] In some embodiments, the anti-GDF15 antibody comprises V H , the V H comprising: an HC-CDR1 comprising the amino acid sequence shown in any one of SEQ ID NOs: 1-2 or a variant thereof, wherein the variant comprises a substitution of up to about 3 (e.g., 1, 2, or 3) amino acids; an HC-CDR2 comprising the amino acid sequence shown in any one of SEQ ID NOs: 7-8 or a variant thereof, wherein the variant comprises a substitution of up to about 3 (e.g., 1, 2, or 3) amino acids; and an HC-CDR3 comprising the amino acid sequence shown in SEQ ID NO: 13 or a variant thereof, wherein the variant comprises a substitution of up to about 3 (e.g., 1, 2, or 3) amino acids.

[0112] In some embodiments, the anti-GDF15 antibody comprises V H , the V H It comprises: HC-CDR1, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 1-2, HC-CDR2, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 7-8, and HC-CDR3, which comprises the amino acid sequence shown in SEQ ID NO: 13.

[0113] In some embodiments, the anti-GDF15 antibody comprises V L , the V L Comprising: LC-CDR1, which comprises the amino acid sequence shown in SEQ ID NO: 18 or a variant thereof, wherein the variant comprises substitutions of up to about 3 (e.g., 1, 2 or 3) amino acids; LC-CDR2, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 23-25 ​​or a variant thereof, wherein the variant comprises substitutions of up to about 3 (e.g., 1, 2 or 3) amino acids; and LC-CDR3, which comprises the amino acid sequence shown in SEQ ID NO: 30 or a variant thereof, wherein the variant comprises substitutions of up to about 3 (e.g., 1, 2 or 3) amino acids.

[0114] In some embodiments, the anti-GDF15 antibody comprises V L , the V LIt comprises: LC-CDR1, which comprises the amino acid sequence shown in SEQ ID NO: 18, LC-CDR2, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 23-25, and LC-CDR3, which comprises the amino acid sequence shown in SEQ ID NO: 30.

[0115] In some embodiments, the anti-GDF15 antibody comprises V H , the V H comprising: an HC-CDR1 comprising an amino acid sequence as shown in any one of SEQ ID NOs: 1-2 or a variant thereof, wherein the variant comprises a substitution of up to about 3 (e.g., 1, 2, or 3) amino acids; an HC-CDR2 comprising an amino acid sequence as shown in any one of SEQ ID NOs: 7-8 or a variant thereof, wherein the variant comprises a substitution of up to about 3 (e.g., 1, 2, or 3) amino acids; and an HC-CDR3 comprising an amino acid sequence as shown in SEQ ID NO: 13 or a variant thereof, wherein the variant comprises a substitution of up to about 3 (e.g., 1, 2, or 3) amino acids; and V L , the V L Comprising: LC-CDR1, which comprises the amino acid sequence shown in SEQ ID NO: 18 or a variant thereof, wherein the variant comprises substitutions of up to about 3 (e.g., 1, 2 or 3) amino acids; LC-CDR2, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 23-25 ​​or a variant thereof, wherein the variant comprises substitutions of up to about 3 (e.g., 1, 2 or 3) amino acids; and LC-CDR3, which comprises the amino acid sequence shown in SEQ ID NO: 30 or a variant thereof, wherein the variant comprises substitutions of up to about 3 (e.g., 1, 2 or 3) amino acids.

[0116] In some embodiments, the anti-GDF15 antibody comprises V H , the V H comprising: an HC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 1-2, an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 7-8, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 13; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence shown in SEQ ID NO: 18, LC-CDR2, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 23-25, and LC-CDR3, which comprises the amino acid sequence shown in SEQ ID NO: 30.

[0117] In some embodiments, the anti-GDF15 antibody comprises VH , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 13, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 23, LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30, or the V L A variant comprising up to about 5 amino acid substitutions in its LC-CDRs.

[0118] In some embodiments, the anti-GDF15 antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 13; and V L , the V L It comprises: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30.

[0119] In some embodiments, the anti-GDF15 antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 13, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 24, LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30, or the V L A variant comprising up to about 5 amino acid substitutions in its LC-CDRs.

[0120] In some embodiments, the anti-GDF15 antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 13; and V L , the V L It comprises: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 24, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30.

[0121] In some embodiments, the anti-GDF15 antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 13, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30, or the V L A variant comprising up to about 5 amino acid substitutions in its LC-CDRs.

[0122] In some embodiments, the anti-GDF15 antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 13; and V L , the V L It comprises: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30.

[0123] In some embodiments, the anti-GDF15 antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 2, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 13, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30, or the V L A variant comprising up to about 5 amino acid substitutions in its LC-CDRs.

[0124] In some embodiments, the anti-GDF15 antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 2, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 13; and V L , the V L It comprises: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30.

[0125] In some embodiments, the anti-GDF15 antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 13, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30, or the V LA variant comprising up to about 5 amino acid substitutions in its LC-CDRs.

[0126] In some embodiments, the anti-GDF15 antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 13; and V L , the V L It comprises: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30.

[0127] In some embodiments, the anti-GDF15 antibody comprises V H , the V H Comprising V as shown in any one of the amino acid sequences of SEQ ID NOs: 38-47 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , the V L Comprising V as shown in any one of the amino acid sequences of SEQ ID NOs: 52-59 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0128] In some embodiments, the anti-GDF15 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO: 38 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:52 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0129] In some embodiments, the anti-GDF15 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO: 39 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:53 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0130] In some embodiments, the anti-GDF15 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:40 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:53 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0131] In some embodiments, the anti-GDF15 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:41 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:53 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0132] In some embodiments, the anti-GDF15 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:42 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:53 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0133] In some embodiments, the anti-GDF15 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:43 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:53 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0134] In some embodiments, the anti-GDF15 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:44 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:53 LContains LC-CDR1, LC-CDR2 and LC-CDR3.

[0135] In some embodiments, the anti-GDF15 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO: 39 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:54 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0136] In some embodiments, the anti-GDF15 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:40 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:54 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0137] In some embodiments, the anti-GDF15 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:41 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:54 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0138] In some embodiments, the anti-GDF15 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:42 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:54 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0139] In some embodiments, the anti-GDF15 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:43 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L, which comprises V as shown in the amino acid sequence SEQ ID NO:54 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0140] In some embodiments, the anti-GDF15 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:44 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:54 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0141] In some embodiments, the anti-GDF15 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO: 39 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:55 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0142] In some embodiments, the anti-GDF15 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:40 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:55 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0143] In some embodiments, the anti-GDF15 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:41 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:55 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0144] In some embodiments, the anti-GDF15 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:42 HHC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:55 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0145] In some embodiments, the anti-GDF15 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:43 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:55 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0146] In some embodiments, the anti-GDF15 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:44 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:55 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0147] In some embodiments, the anti-GDF15 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:45 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:56 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0148] In some embodiments, the anti-GDF15 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:45 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO: 57 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0149] In some embodiments, the anti-GDF15 antibody comprises V H, which comprises V as shown in the amino acid sequence SEQ ID NO:46 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO: 58 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0150] In some embodiments, the anti-GDF15 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:47 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO: 59 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0151] In some embodiments, the anti-GDF15 antibody comprises: V H , the V H comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 38-47 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence as set forth in any one of SEQ ID NOs: 38-47; and V L , the V L comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 52-59 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence as set forth in any one of SEQ ID NOs: 52-59. In some embodiments, the anti-GDF15 antibody comprises V H , the V H comprising the amino acid sequence shown in any one of SEQ ID NOs: 38-47, and V L , the V L Comprising the amino acid sequence shown in any one of SEQ ID NOs: 52-59.

[0152] In some embodiments, the anti-GDF15 antibody comprises: V H , the V Hcomprising the amino acid sequence of SEQ ID NO: 38 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 38; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 52 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 52. In some embodiments, the anti-GDF15 antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO: 38, and V L , the V L Comprising the amino acid sequence SEQ ID NO:52.

[0153] In some embodiments, the anti-GDF15 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 39 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 39; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 53 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 53. In some embodiments, the anti-GDF15 antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO: 39, and V L , the V L Comprising the amino acid sequence SEQ ID NO:53.

[0154] In some embodiments, the anti-GDF15 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 40 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 40; and V L , the V Lcomprising the amino acid sequence of SEQ ID NO: 53 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 53. In some embodiments, the anti-GDF15 antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO: 40, and V L , the V L Comprising the amino acid sequence SEQ ID NO:53.

[0155] In some embodiments, the anti-GDF15 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 41 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 41; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 53 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 53. In some embodiments, the anti-GDF15 antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO: 41, and V L , the V L Comprising the amino acid sequence SEQ ID NO:53.

[0156] In some embodiments, the anti-GDF15 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 42 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 42; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 53 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 53. In some embodiments, the anti-GDF15 antibody comprises V H , the VH Comprising the amino acid sequence SEQ ID NO: 42, and V L , the V L Comprising the amino acid sequence SEQ ID NO:53.

[0157] In some embodiments, the anti-GDF15 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 43 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 43; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 53 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 53. In some embodiments, the anti-GDF15 antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO: 43, and V L , the V L Comprising the amino acid sequence SEQ ID NO:53.

[0158] In some embodiments, the anti-GDF15 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 44 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 44; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 53 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 53. In some embodiments, the anti-GDF15 antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO: 44, and V L , the V L Comprising the amino acid sequence SEQ ID NO:53.

[0159] In some embodiments, the anti-GDF15 antibody comprises: V H, the V H comprising the amino acid sequence of SEQ ID NO: 39 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 39; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 54 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 54. In some embodiments, the anti-GDF15 antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO: 39, and V L , the V L Comprising the amino acid sequence SEQ ID NO:54.

[0160] In some embodiments, the anti-GDF15 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 40 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 40; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 54 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 54. In some embodiments, the anti-GDF15 antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO: 40, and V L , the V L Comprising the amino acid sequence SEQ ID NO:54.

[0161] In some embodiments, the anti-GDF15 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 41 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 41; and V L , the VL comprising the amino acid sequence of SEQ ID NO: 54 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 54. In some embodiments, the anti-GDF15 antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO: 41, and V L , the V L Comprising the amino acid sequence SEQ ID NO:54.

[0162] In some embodiments, the anti-GDF15 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 42 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 42; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 54 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 54. In some embodiments, the anti-GDF15 antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO: 42, and V L , the V L Comprising the amino acid sequence SEQ ID NO:54.

[0163] In some embodiments, the anti-GDF15 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 43 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 43; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 54 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 54. In some embodiments, the anti-GDF15 antibody comprises V H, the V H Comprising the amino acid sequence SEQ ID NO: 43, and V L , the V L Comprising the amino acid sequence SEQ ID NO:54.

[0164] In some embodiments, the anti-GDF15 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 44 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 44; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 54 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 54. In some embodiments, the anti-GDF15 antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO: 44, and V L , the V L Comprising the amino acid sequence SEQ ID NO:54.

[0165] In some embodiments, the anti-GDF15 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 39 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 39; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 55 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 55. In some embodiments, the anti-GDF15 antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO: 39, and V L , the V L Comprising the amino acid sequence SEQ ID NO:55.

[0166] In some embodiments, the anti-GDF15 antibody comprises: VH , the V H comprising the amino acid sequence of SEQ ID NO: 40 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 40; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 55 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 55. In some embodiments, the anti-GDF15 antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO: 40, and V L , the V L Comprising the amino acid sequence SEQ ID NO:55.

[0167] In some embodiments, the anti-GDF15 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 41 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 41; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 55 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 55. In some embodiments, the anti-GDF15 antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO: 41, and V L , the V L Comprising the amino acid sequence SEQ ID NO:55.

[0168] In some embodiments, the anti-GDF15 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 42 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 42; and V L, the V L comprising the amino acid sequence of SEQ ID NO: 55 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 55. In some embodiments, the anti-GDF15 antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO: 42, and V L , the V L Comprising the amino acid sequence SEQ ID NO:55.

[0169] In some embodiments, the anti-GDF15 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 43 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 43; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 55 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 55. In some embodiments, the anti-GDF15 antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO: 43, and V L , the V L Comprising the amino acid sequence SEQ ID NO:55.

[0170] In some embodiments, the anti-GDF15 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 44 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 44; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 55 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 55. In some embodiments, the anti-GDF15 antibody comprises VH , the V H Comprising the amino acid sequence SEQ ID NO: 44, and V L , the V L Comprising the amino acid sequence SEQ ID NO:55.

[0171] In some embodiments, the anti-GDF15 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 45 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 45; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 56 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 56. In some embodiments, the anti-GDF15 antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO: 45, and V L , the V L Comprising the amino acid sequence SEQ ID NO:56.

[0172] In some embodiments, the anti-GDF15 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 45 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 45; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 57 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-GDF15 antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO: 45, and V L , the V L Comprising the amino acid sequence SEQ ID NO:57.

[0173] In some embodiments, the anti-GDF15 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 46 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 46; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 58 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-GDF15 antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO: 46, and V L , the V L Comprising the amino acid sequence SEQ ID NO:58.

[0174] In some embodiments, the anti-GDF15 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 47 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 47; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 59 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-GDF15 antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO: 47, and V L , the V L Comprising the amino acid sequence SEQ ID NO:59.

[0175] In some embodiments, the anti-GDF15 antibody comprises V H , the V Hcomprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 14, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 19, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 31, or the V L A variant comprising up to about 5 amino acid substitutions in its LC-CDRs.

[0176] In some embodiments, the anti-GDF15 antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 14; and V L , the V L It comprises: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 19, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 31.

[0177] In some embodiments, the anti-GDF15 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:48 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO: 60 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0178] In some embodiments, the anti-GDF15 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 48 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 48; and V L , the VL comprising the amino acid sequence of SEQ ID NO: 60 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-GDF15 antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO: 48, and V L , the V L Comprising the amino acid sequence SEQ ID NO:60.

[0179] In some embodiments, the anti-GDF15 antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 10, HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 15, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 20, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 27, LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 32, or the V L A variant comprising up to about 5 amino acid substitutions in its LC-CDRs.

[0180] In some embodiments, the anti-GDF15 antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 15; and V L , the V L It comprises: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 20, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 27, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 32.

[0181] In some embodiments, the anti-GDF15 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:49 HHC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:61 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0182] In some embodiments, the anti-GDF15 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 49 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 49; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 61 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 61. In some embodiments, the anti-GDF15 antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO: 49, and V L , the V L Comprising the amino acid sequence SEQ ID NO:61.

[0183] In some embodiments, the anti-GDF15 antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 5, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 16, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 28, LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 33, or the V L A variant comprising up to about 5 amino acid substitutions in its LC-CDRs.

[0184] In some embodiments, the anti-GDF15 antibody comprises V H , the V Hcomprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 5, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 16; and V L , the V L It comprises: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:21, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:28, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:33.

[0185] In some embodiments, the anti-GDF15 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO: 50 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO: 62 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0186] In some embodiments, the anti-GDF15 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 50 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 50; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 62 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 62. In some embodiments, the anti-GDF15 antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO: 50, and V L , the V L Comprising the amino acid sequence SEQ ID NO:62.

[0187] In some embodiments, the anti-GDF15 antibody comprises a heavy chain variable domain (V H ), the V HThe invention comprises: a heavy chain complementarity determining region (HC-CDR) 1 comprising SYDMT (SEQ ID NO: 6); HC-CDR2 comprising IIX1X2SGX3TYYASWAKG (SEQ ID NO: 79), wherein X1 is N or S, X2 is G, N or S, and X3 is N or S; and HC-CDR3 comprising GILVYADYGDHNL (SEQ ID NO: 17); and a light chain variable domain (V L ), the V L Comprising: a light chain complementarity determining region (LC-CDR) 1 comprising QASEDIYTNLA (SEQ ID NO: 22); a LC-CDR2 comprising AASTLAS (SEQ ID NO: 29); and a LC-CDR3 comprising LGVYTYISAX1GA (SEQ ID NO: 81), wherein X1 is D or E.

[0188] In some embodiments, the anti-GDF15 antibody comprises V H , the V H comprising: an HC-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 6 or a variant thereof, wherein the variant comprises a substitution of up to about 3 (e.g., 1, 2, or 3) amino acids; an HC-CDR2 comprising the amino acid sequence shown in any one of SEQ ID NOs: 12, 75-78 or a variant thereof, wherein the variant comprises a substitution of up to about 3 (e.g., 1, 2, or 3) amino acids; and an HC-CDR3 comprising the amino acid sequence shown in SEQ ID NO: 17 or a variant thereof, wherein the variant comprises a substitution of up to about 3 (e.g., 1, 2, or 3) amino acids.

[0189] In some embodiments, the anti-GDF15 antibody comprises V H , the V H It comprises: HC-CDR1, which comprises the amino acid sequence shown in SEQ ID NO: 6, HC-CDR2, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 12, 75-78, and HC-CDR3, which comprises the amino acid sequence shown in SEQ ID NO: 17.

[0190] In some embodiments, the anti-GDF15 antibody comprises V L , the V LComprising: LC-CDR1, which comprises the amino acid sequence shown in SEQ ID NO: 22 or a variant thereof, wherein the variant comprises a substitution of up to about 3 (e.g., 1, 2 or 3) amino acids; LC-CDR2, which comprises the amino acid sequence shown in SEQ ID NO: 29 or a variant thereof, wherein the variant comprises a substitution of up to about 3 (e.g., 1, 2 or 3) amino acids; and LC-CDR3, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 34 or 80 or a variant thereof, wherein the variant comprises a substitution of up to about 3 (e.g., 1, 2 or 3) amino acids.

[0191] In some embodiments, the anti-GDF15 antibody comprises V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence shown in SEQ ID NO: 22, LC-CDR2, which comprises the amino acid sequence shown in SEQ ID NO: 29, and LC-CDR3, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 34 or 80.

[0192] In some embodiments, the anti-GDF15 antibody comprises V H , the V H comprising: an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6 or a variant thereof, wherein the variant comprises a substitution of up to about 3 (e.g., 1, 2, or 3) amino acids; an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 12, 75-78 or a variant thereof, wherein the variant comprises a substitution of up to about 3 (e.g., 1, 2, or 3) amino acids; and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 17 or a variant thereof, wherein the variant comprises a substitution of up to about 3 (e.g., 1, 2, or 3) amino acids; and V L , the V L Comprising: LC-CDR1, which comprises the amino acid sequence shown in SEQ ID NO: 22 or a variant thereof, wherein the variant comprises a substitution of up to about 3 (e.g., 1, 2 or 3) amino acids; LC-CDR2, which comprises the amino acid sequence shown in SEQ ID NO: 29 or a variant thereof, wherein the variant comprises a substitution of up to about 3 (e.g., 1, 2 or 3) amino acids; and LC-CDR3, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 34 or 80 or a variant thereof, wherein the variant comprises a substitution of up to about 3 (e.g., 1, 2 or 3) amino acids.

[0193] In some embodiments, the anti-GDF15 antibody comprises V H , the V Hcomprising: an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 12, 75-78, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 17; and V L , the V L Comprising: LC-CDR1, which comprises the amino acid sequence shown in SEQ ID NO: 22, LC-CDR2, which comprises the amino acid sequence shown in SEQ ID NO: 29, and LC-CDR3, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 34 or 80.

[0194] In some embodiments, the anti-GDF15 antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 12, HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 17, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 34, or the V L A variant comprising up to about 5 amino acid substitutions in its LC-CDRs.

[0195] In some embodiments, the anti-GDF15 antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 12, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 17; and V L , the V L It comprises: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:22, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:29, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:34.

[0196] In some embodiments, the anti-GDF15 antibody comprises V H , the V Hcomprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 75, HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 17, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 80, or the V L A variant comprising up to about 5 amino acid substitutions in its LC-CDRs.

[0197] In some embodiments, the anti-GDF15 antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 75, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 17; and V L , the V L It comprises: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 80.

[0198] In some embodiments, the anti-GDF15 antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 76, HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 17, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 80, or the V L A variant comprising up to about 5 amino acid substitutions in its LC-CDRs.

[0199] In some embodiments, the anti-GDF15 antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 76, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 17; and V L , the V L It comprises: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 80.

[0200] In some embodiments, the anti-GDF15 antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 77, HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 17, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 80, or the V L A variant comprising up to about 5 amino acid substitutions in its LC-CDRs.

[0201] In some embodiments, the anti-GDF15 antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 77, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 17; and V L , the V L It comprises: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 80.

[0202] In some embodiments, the anti-GDF15 antibody comprises V H , the VH comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 78, HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 17, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 80, or the V L A variant comprising up to about 5 amino acid substitutions in its LC-CDRs.

[0203] In some embodiments, the anti-GDF15 antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 78, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 17; and V L , the V L It comprises: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 80.

[0204] In some embodiments, the anti-GDF15 antibody comprises V H , the V H Comprising V as shown in any one of the amino acid sequences of SEQ ID NOs: 51, 82-89 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , the V L Comprising V as shown in any one of the amino acid sequences of SEQ ID NOs: 63, 90-91 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0205] In some embodiments, the anti-GDF15 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:51 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and VL , which comprises V as shown in the amino acid sequence SEQ ID NO: 63 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0206] In some embodiments, the anti-GDF15 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO: 82 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:90 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0207] In some embodiments, the anti-GDF15 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO: 83 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:90 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0208] In some embodiments, the anti-GDF15 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO: 84 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:90 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0209] In some embodiments, the anti-GDF15 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO: 85 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:90 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0210] In some embodiments, the anti-GDF15 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO: 86H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:91 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0211] In some embodiments, the anti-GDF15 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO: 87 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:91 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0212] In some embodiments, the anti-GDF15 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO: 88 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:91 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0213] In some embodiments, the anti-GDF15 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO: 89 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:91 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0214] In some embodiments, the anti-GDF15 antibody comprises: V H , the V H comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 51, 82-89, or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence as set forth in any one of SEQ ID NOs: 51, 82-89; and V L , the V Lcomprising an amino acid sequence as set forth in any one of SEQ ID NOs: 63, 90-91 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence as set forth in any one of SEQ ID NOs: 63, 90-91. In some embodiments, the anti-GDF15 antibody comprises V H , the V H comprising the amino acid sequence shown in any one of SEQ ID NOs: 51, 82-89, and V L , the V L It comprises the amino acid sequence shown in any one of SEQ ID NOs: 63, 90-91.

[0215] In some embodiments, the anti-GDF15 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 51 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 51; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 63 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 63. In some embodiments, the anti-GDF15 antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO: 51, and V L , the V L Comprising the amino acid sequence SEQ ID NO:63.

[0216] In some embodiments, the anti-GDF15 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 82 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 82; and V L , the V Lcomprising the amino acid sequence of SEQ ID NO: 90 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 90. In some embodiments, the anti-GDF15 antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO: 82, and V L , the V L Comprising the amino acid sequence SEQ ID NO:90.

[0217] In some embodiments, the anti-GDF15 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 83 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 83; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 90 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 90. In some embodiments, the anti-GDF15 antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO: 83, and V L , the V L Comprising the amino acid sequence SEQ ID NO:90.

[0218] In some embodiments, the anti-GDF15 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 84 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 84; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 90 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 90. In some embodiments, the anti-GDF15 antibody comprises V H , the VH Comprising the amino acid sequence SEQ ID NO: 84, and V L , the V L Comprising the amino acid sequence SEQ ID NO:90.

[0219] In some embodiments, the anti-GDF15 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 85 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 85; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 90 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 90. In some embodiments, the anti-GDF15 antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO: 85, and V L , the V L Comprising the amino acid sequence SEQ ID NO:90.

[0220] In some embodiments, the anti-GDF15 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 86 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 86; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 91 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 91. In some embodiments, the anti-GDF15 antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO: 86, and V L , the V L Comprising the amino acid sequence SEQ ID NO:91.

[0221] In some embodiments, the anti-GDF15 antibody comprises: V H, the V H comprising the amino acid sequence of SEQ ID NO: 87 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 87; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 91 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 91. In some embodiments, the anti-GDF15 antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO: 87, and V L , the V L Comprising the amino acid sequence SEQ ID NO:91.

[0222] In some embodiments, the anti-GDF15 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 88 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 88; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 91 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 91. In some embodiments, the anti-GDF15 antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO: 88, and V L , the V L Comprising the amino acid sequence SEQ ID NO:91.

[0223] In some embodiments, the anti-GDF15 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO: 89 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 89; and V L , the VL comprising the amino acid sequence of SEQ ID NO: 91 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 91. In some embodiments, the anti-GDF15 antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO: 89, and V L , the V L Comprising the amino acid sequence SEQ ID NO:91.

[0224] In some embodiments, the above-mentioned amino acid substitutions are limited to the "exemplary substitutions" shown herein in Table 4. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown herein in Table 4.

[0225] In some embodiments, functional epitopes can be resolved using combinatorial alanine scanning. In this process, combinatorial alanine scanning can be used to identify amino acids in the GDF15 protein that are essential for interaction with the anti-GDF15 antibody. In some embodiments, the epitope is conformational, and the epitope can be identified using a crystal structure of an anti-GDF15 antibody bound to the GDF15 protein.

[0226] In some embodiments, the present application provides antibodies that competitively bind to GDF15 with any of the anti-GDF15 antibodies described herein. In some embodiments, antibodies that can competitively bind to an epitope on GDF15 with any of the anti-GDF15 antibodies described herein are provided. In some embodiments, anti-GDF15 antibodies are provided that are combined with a V H and V L The anti-GDF15 antibody molecules bind to the same epitope, wherein the V H comprising the amino acid sequence shown in any one of SEQ ID NOs: 38-51, 82-89, and the V L In some embodiments, an anti-GDF15 antibody is provided, which is combined with a V H and V L The anti-GDF15 antibody competitively binds to GDF15, wherein the V H comprising the amino acid sequence shown in any one of SEQ ID NOs: 38-51, 82-89, and the V L It comprises the amino acid sequence shown in any one of SEQ ID NOs: 52-63, 90-91.

[0227] In some embodiments, competition assays can be used to identify monoclonal antibodies that compete with the anti-GDF15 antibodies described herein for binding to GDF15. Competition assays can determine whether two antibodies bind to the same epitope by recognizing the same or spatially overlapping epitopes or by competitively inhibiting binding of one antibody to the antigen. In certain embodiments, such competing antibodies bind to the same epitope as the antibodies described herein. Some exemplary competition assays include, but are not limited to, conventional assays described in Harlow and Lane (1988) Antibodies: A Laboratory Manual ch. 14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY). Detailed exemplary methods for resolving epitopes bound by antibodies are described in Morris (1996) "Epitope Mapping Protocols," in Methods in Molecular Biology vol. 66 (Humana Press, Totowa, NJ). In some embodiments, each antibody is said to bind to the same epitope if it blocks 50% or more of the binding of the other antibody. In some embodiments, the antibody that competes with the anti-GDF15 antibodies described herein is a chimeric antibody, a humanized antibody, or a fully human antibody.

[0228] Exemplary anti-GDF15 antibody sequences are shown in Table 2-2A and Table 3-3A, wherein CDR numbering is performed according to the Kabat definition. Those skilled in the art will recognize that there are a variety of known algorithms for predicting the position of CDRs and defining the variable regions of antibody light and heavy chains. H and / or V L Sequences, but based on prediction algorithms other than those exemplified in the table below, are also within the scope of this application.

[0229] Table 2 Exemplary anti-GDF15 antibody CDR sequences

[0230] Table 2A Exemplary Anti-GDF15 Antibody CDR Sequences

[0231] Table 3 Exemplary sequences

[0232] Table 3A Exemplary sequences

[0233] GDF15

[0234] Growth differentiation factor-15 (GDF15), also known as macrophage inhibitory cytokine 1 (MIC-1), is an atypical member of the transforming growth factor β (TGF-β) superfamily. The TGF-β superfamily consists of over 30 members and was initially identified as playing a key role in regulating development, differentiation, and tissue repair. The TGF-β superfamily encompasses multiple ligands, including TGF-β, activins, bone morphogenetic proteins (BMPs), and GDFs. GDFs belong to the activin / myostatin subclass. Several members of this subfamily have been described, designated GDF1-GDF15 (Herpin, A. et al., Dev. Comp. Immunol. 2004). Human GDF15 undergoes a series of post-translational modifications during maturation. The unprocessed GDF15 protein (pre-pro-GDF15) consists of 308 amino acids, including a signal peptide sequence (29 aa), a propeptide (167 aa), and a mature protein (112 aa). The synthesized precursor form of pro-GDF15 protein forms a pro-GDF15 homodimer through cysteine ​​residues; it is then cleaved at the RXXR site, releasing the mature dimeric GDF15 protein and a propeptide at the C-terminus (Wang X et al., Biochem Pharmacol, 2013).

[0235] GDF15 receptor GFRAL

[0236] The glial cell-derived neurotrophic factor (GDNF) receptor α-like protein, GFRAL, serves as a brainstem-restricted receptor for the GDF15 protein and is primarily expressed in the central nervous system (CNS), particularly in the nucleus tractus solitarius (NTS) and area posterior pole (AP) of mice, rats, monkeys, and humans (Hsu et al., Nature, 2017; SEMullican et al., 2017). GFRAL mRNA expression has been analyzed in various embryonic and adult mouse tissues. Two isoforms of GFRAL mRNA were detected in the adult mouse CNS. In contrast, GFRAL mRNA was not detected in peripheral organs examined, such as the heart, liver, spleen, lung, kidney, placenta, skeletal muscle, and small intestine. Among various regions of the CNS, GFRAL mRNA is more abundant in certain brain regions, such as the substantia nigra, hippocampus, and hindbrain (Li et al., J. Neurochem., 2005).

[0237] GFRAL is a transmembrane protein anchored to the plasma membrane by glycosylphosphatidylinositol (GPI) residues located within lipid rafts. This receptor protein is composed of three cysteine-rich domains. GDF15 can activate GFRAL-expressing neurons specifically located in the area posterior pole and nucleus tractus solitarius in mice (Hsu et al., Nature, 2017). The GFRAL co-receptor tyrosine kinase RET is expressed in the AP and nucleus tractus solitarius (NTS), with additional expression observed in several regions of the hypothalamus (Hsu et al., 2017). The GDF15 dimer binds to two GFRALs and then recruits RET molecules to form a complex, triggering phosphorylation and intracellular signaling from RET, further activating its intracellular kinase domain and initiating multiple signaling pathways in brainstem neurons (Shannon E. Mullican & Rangwala, 2018; L. Yang et al., 2017).

[0238] GDF15-GFRAL signaling plays an important role in controlling body weight. Recombinant GDF15 induces weight loss in mice fed a high-fat diet and in spontaneously obese non-human primates. In this study, mice with germline Gfral knockout (Gfral- / -) lost the anorexia and metabolic-related effects caused by recombinant GDF15. In addition, diet-induced obesity and insulin resistance were exacerbated in GFRAL-deficient mice, indicating that this receptor plays a balancing role in metabolism (Mullican, SE et al. Nat Med. 2017).

[0239] Full-length anti-GDF15 antibody

[0240] In some embodiments, the anti-GDF15 antibody is a full-length anti-GDF15 antibody. In some embodiments, the full-length anti-GDF15 antibody is IgA, IgD, IgE, IgG, or IgM. In some embodiments, the full-length anti-GDF15 antibody comprises an IgG constant region, such as a constant region of IgG1, IgG2, IgG3, IgG4, or a variant thereof. In some embodiments, the full-length anti-GDF15 antibody comprises a lambda light chain constant region. In some embodiments, the full-length anti-GDF15 antibody comprises a kappa light chain constant region. In some embodiments, the full-length anti-GDF15 antibody is a full-length human anti-GDF15 antibody. In some embodiments, the full-length anti-GDF15 antibody comprises a mouse immunoglobulin Fc sequence. In some embodiments, the full-length anti-GDF15 antibody comprises an altered or otherwise modified Fc sequence such that it has enhanced effector functions of antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).

[0241] Thus, for example, in some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody specifically binds to GDF15. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0242] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG2 constant region is provided, wherein the anti-GDF15 antibody specifically binds to GDF15. In some embodiments, the IgG2 is human IgG2. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0243] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG3 constant region is provided, wherein the anti-GDF15 antibody specifically binds to GDF15. In some embodiments, the IgG3 is human IgG3. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0244] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody specifically binds to GDF15. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0245] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: a) a heavy chain variable domain comprising: an HC-CDR1 comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 1-6, or a variant thereof, wherein the variant comprises up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; an HC-CDR2 comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 7-12, 75-78, or a variant thereof, wherein the variant comprises up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; and an HC-CDR3 comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 13-17, or a variant thereof, wherein the variant comprises up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; and b) a light chain variable domain comprising: an LC-CDR1 comprising an amino acid sequence as set forth in any one of SEQ ID NOs: NOs: 18-22 or a variant thereof, the variant comprising a substitution of up to about 3 (e.g., 1, 2, or 3) amino acids, LC-CDR2 comprising an amino acid sequence as shown in any one of SEQ ID NOs: 23-29 or a variant thereof, the variant comprising a substitution of up to about 3 (e.g., 1, 2, or 3) amino acids; and LC-CDR3 comprising an amino acid sequence as shown in any one of SEQ ID NOs: 30-34, 80 or a variant thereof, the variant comprising a substitution of up to about 3 (e.g., 1, 2, or 3) amino acids. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:67.

[0246] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG2 constant region is provided, wherein the anti-GDF15 antibody comprises: a) a heavy chain variable domain comprising: an HC-CDR1 comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 1-6, or a variant thereof, wherein the variant comprises up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; an HC-CDR2 comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 7-12, 75-78, or a variant thereof, wherein the variant comprises up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; and an HC-CDR3 comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 13-17, or a variant thereof, wherein the variant comprises up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; and b) a light chain variable domain comprising: an LC-CDR1 comprising an amino acid sequence as set forth in any one of SEQ ID NOs: NOs: 18-22 or a variant thereof, wherein the variant comprises a substitution of up to about 3 (e.g., 1, 2, or 3) amino acids; LC-CDR2, comprising an amino acid sequence as shown in any one of SEQ ID NOs: 23-29 or a variant thereof, wherein the variant comprises a substitution of up to about 3 (e.g., 1, 2, or 3) amino acids; and LC-CDR3, comprising an amino acid sequence as shown in any one of SEQ ID NOs: 30-34, 80 or a variant thereof, wherein the variant comprises a substitution of up to about 3 (e.g., 1, 2, or 3) amino acids. In some embodiments, the IgG2 is a human IgG2. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0247] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG3 constant region is provided, wherein the anti-GDF15 antibody comprises: a) a heavy chain variable domain comprising: an HC-CDR1 comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 1-6 or a variant thereof, wherein the variant comprises up to about 3 (e.g., 1, 2, or 3) amino acid substitutions, an HC-CDR2 comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 7-12, 75-78 or a variant thereof, wherein the variant comprises up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; and an HC-CDR3 comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 13-17 or a variant thereof, wherein the variant comprises up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; and b) a light chain variable domain comprising: an LC-CDR1 comprising an amino acid sequence as set forth in any one of SEQ ID NOs: NOs: 18-22 or a variant thereof, the variant comprising a substitution of up to about 3 (e.g., 1, 2, or 3) amino acids; LC-CDR2 comprising an amino acid sequence as shown in any one of SEQ ID NOs: 23-29 or a variant thereof, the variant comprising a substitution of up to about 3 (e.g., 1, 2, or 3) amino acids; and LC-CDR3 comprising an amino acid sequence as shown in any one of SEQ ID NOs: 30-34, 80 or a variant thereof, the variant comprising a substitution of up to about 3 (e.g., 1, 2, or 3) amino acids. In some embodiments, the IgG3 is a human IgG3. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0248] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: a) a heavy chain variable domain comprising: an HC-CDR1 comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 1-6 or a variant thereof, wherein the variant comprises up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; an HC-CDR2 comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 7-12, 75-78 or a variant thereof, wherein the variant comprises up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; and an HC-CDR3 comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 13-17 or a variant thereof, wherein the variant comprises up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; and b) a light chain variable domain comprising: an LC-CDR1 comprising an amino acid sequence as set forth in any one of SEQ ID NOs: NOs: 18-22 or a variant thereof, the variant comprising a substitution of up to about 3 (e.g., 1, 2, or 3) amino acids, LC-CDR2 comprising an amino acid sequence as shown in any one of SEQ ID NOs: 23-29 or a variant thereof, the variant comprising a substitution of up to about 3 (e.g., 1, 2, or 3) amino acids, and LC-CDR3 comprising an amino acid sequence as shown in any one of SEQ ID NOs: 30-34, 80 or a variant thereof, the variant comprising a substitution of up to about 3 (e.g., 1, 2, or 3) amino acids. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:67.

[0249] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: a) a heavy chain variable domain comprising: an HC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 1-6, an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 7-12, 75-78, and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 13-17, or a variant of the heavy chain variable domain comprising up to about 5 (e.g., 1, 2, 3, 4, or 5) amino acid substitutions in the HC-CDR sequence; and b) a light chain variable domain comprising: an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 18-22, an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 23-29, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NOs: NOs:30-34, 80, or a variant of the light chain variable domain, wherein the LC-CDR sequence comprises a substitution of up to about 5 (e.g., 1, 2, 3, 4, or 5) amino acids. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0250] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises a) a heavy chain variable domain comprising: an HC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 1-6, an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 7-12, 75-78, and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 13-17, or a variant of the heavy chain variable domain comprising up to about 5 (e.g., 1, 2, 3, 4, or 5) amino acid substitutions in the HC-CDR sequence; and b) a light chain variable domain comprising: an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 18-22, an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 23-29, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NOs: NOs: 30-34, 80, or a variant of the light chain variable domain, comprising a substitution of up to about 5 (e.g., 1, 2, 3, 4, or 5) amino acids in its LC-CDR sequence. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0251] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: a) a heavy chain variable domain comprising: an HC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 1-6, an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 7-12, 75-78, and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 13-17; and b) a light chain variable domain comprising: an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 18-22, an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 23-29, and an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 30-34, 80. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0252] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: a) a heavy chain variable domain comprising: an HC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 1-6, an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 7-12, 75-78, and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 13-17; and b) a light chain variable domain comprising: an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 18-22, an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 23-29, and an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 30-34, 80. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0253] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: a) a heavy chain variable domain comprising: an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 13; and b) a light chain variable domain comprising: an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0254] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: a) a heavy chain variable domain comprising: an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 13; and b) a light chain variable domain comprising: an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 24, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0255] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: a) a heavy chain variable domain comprising: an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 13; and b) a light chain variable domain comprising: an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0256] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: a) a heavy chain variable domain comprising: an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 2, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 13; and b) a light chain variable domain comprising: an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0257] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: a) a heavy chain variable domain comprising: an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 13; and b) a light chain variable domain comprising: an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0258] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: a) a heavy chain variable domain comprising: an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 14; and b) a light chain variable domain comprising: an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 19, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 31. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0259] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: a) a heavy chain variable domain comprising: an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 15; and b) a light chain variable domain comprising: an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 20, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 27, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 32. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0260] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: a) a heavy chain variable domain comprising: an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 5, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 16; and b) a light chain variable domain comprising: an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 28, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 33. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0261] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: a) a heavy chain variable domain comprising: an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 12, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 17; and b) a light chain variable domain comprising: an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 34. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0262] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: a) a heavy chain variable domain comprising: an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 75, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 17; and b) a light chain variable domain comprising: an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 80. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0263] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: a) a heavy chain variable domain comprising: an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 76, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 17; and b) a light chain variable domain comprising: an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 80. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0264] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: a) a heavy chain variable domain comprising: an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 77, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 17; and b) a light chain variable domain comprising: an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 80. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0265] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: a) a heavy chain variable domain comprising: an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 78, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 17; and b) a light chain variable domain comprising: an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 80. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0266] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: a) a heavy chain variable domain comprising: an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 13; and b) a light chain variable domain comprising: an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0267] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: a) a heavy chain variable domain comprising: an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 13; and b) a light chain variable domain comprising: an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 24, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0268] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: a) a heavy chain variable domain comprising: an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 13; and b) a light chain variable domain comprising: an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0269] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: a) a heavy chain variable domain comprising: an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 2, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 13; and b) a light chain variable domain comprising: an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0270] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: a) a heavy chain variable domain comprising: an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 13; and b) a light chain variable domain comprising: an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0271] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: a) a heavy chain variable domain comprising: an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 14; and b) a light chain variable domain comprising: an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 19, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 31. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0272] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: a) a heavy chain variable domain comprising: an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 15; and b) a light chain variable domain comprising: an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 20, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 27, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 32. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0273] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: a) a heavy chain variable domain comprising: an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 5, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 16; and b) a light chain variable domain comprising: an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 28, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 33. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0274] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: a) a heavy chain variable domain comprising: an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 12, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 17; and b) a light chain variable domain comprising: an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 34. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0275] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: a) a heavy chain variable domain comprising: an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 75, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 17; and b) a light chain variable domain comprising: an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 80. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0276] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: a) a heavy chain variable domain comprising: an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 76, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 17; and b) a light chain variable domain comprising: an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 80. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0277] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: a) a heavy chain variable domain comprising: an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 77, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 17; and b) a light chain variable domain comprising: an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 80. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0278] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: a) a heavy chain variable domain comprising: an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 78, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 17; and b) a light chain variable domain comprising: an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 80. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0279] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: a heavy chain variable domain (V H ), the V H comprising an amino acid sequence as shown in any one of SEQ ID NOs: 38-51, 82-89 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence as shown in any one of SEQ ID NOs: 38-51, 82-89; and a light chain variable domain (V L ), the V Lcomprising the amino acid sequence of any one of SEQ ID NOs: 52-63, 90-91, or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of any one of SEQ ID NOs: 52-63, 90-91. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0280] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG2 constant region is provided, wherein the anti-GDF15 antibody comprises: a heavy chain variable domain (V H ), the V H comprising an amino acid sequence as shown in any one of SEQ ID NOs: 38-51, 82-89 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence as shown in any one of SEQ ID NOs: 38-51, 82-89; and a light chain variable domain (V L ), the V L The invention also provides an IgG2 antibody comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 52-63, 90-91, or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence as set forth in any one of SEQ ID NOs: 52-63, 90-91. In some embodiments, the IgG2 antibody is a human IgG2 antibody. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0281] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG3 constant region is provided, wherein the anti-GDF15 antibody comprises: a heavy chain variable domain (V H), the V H comprising an amino acid sequence as shown in any one of SEQ ID NOs: 38-51, 82-89 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence as shown in any one of SEQ ID NOs: 38-51, 82-89; and a light chain variable domain (V L ), the V L The invention also provides an IgG3 antibody comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 52-63, 90-91, or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence as set forth in any one of SEQ ID NOs: 52-63, 90-91. In some embodiments, the IgG3 antibody is a human IgG3 antibody. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0282] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: a heavy chain variable domain (V H ), the V H comprising an amino acid sequence as shown in any one of SEQ ID NOs: 38-51, 82-89 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence as shown in any one of SEQ ID NOs: 38-51, 82-89; and a light chain variable domain (V L ), the V Lcomprising the amino acid sequence of any one of SEQ ID NOs: 52-63, 90-91, or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of any one of SEQ ID NOs: 52-63, 90-91. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0283] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: a heavy chain variable domain (V H ), the (V H ) comprises the amino acid sequence shown in any one of SEQ ID NOs: 38-51, 82-89, and a light chain variable domain (V L ), the (V L ) comprises the amino acid sequence shown in any one of SEQ ID NOs: 52-63, 90-91. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0284] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: a heavy chain variable domain (V H ), the VH comprising the amino acid sequence shown in any one of SEQ ID NOs: 38-51, 82-89, and a light chain variable domain (V L ), the V L comprising the amino acid sequence of any one of SEQ ID NOs: 52-63, 90-91. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0285] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 38 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 38; and V L , which comprises the amino acid sequence of SEQ ID NO: 52 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 52. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0286] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H, comprising the amino acid sequence of SEQ ID NO: 39 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 39; and V L , which comprises the amino acid sequence of SEQ ID NO: 53 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 53. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0287] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 40 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 40; and V L , which comprises the amino acid sequence of SEQ ID NO: 53 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 53. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0288] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H, comprising the amino acid sequence of SEQ ID NO: 41 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 41; and V L , which comprises the amino acid sequence of SEQ ID NO: 53 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 53. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0289] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 42 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 42; and V L , which comprises the amino acid sequence of SEQ ID NO: 53 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 53. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0290] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H, comprising the amino acid sequence of SEQ ID NO: 43 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 43; and V L , which comprises the amino acid sequence of SEQ ID NO: 53 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 53. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0291] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 44 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 44; and V L , which comprises the amino acid sequence of SEQ ID NO: 53 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 53. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0292] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H, comprising the amino acid sequence of SEQ ID NO: 39 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 39; and V L , which comprises the amino acid sequence of SEQ ID NO: 54 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 54. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0293] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 40 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 40; and V L , which comprises the amino acid sequence of SEQ ID NO: 54 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 54. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0294] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H, comprising the amino acid sequence of SEQ ID NO: 41 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 41; and V L , which comprises the amino acid sequence of SEQ ID NO: 54 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 54. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0295] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 42 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 42; and V L , which comprises the amino acid sequence of SEQ ID NO: 54 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 54. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0296] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H, comprising the amino acid sequence of SEQ ID NO: 43 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 43; and V L , which comprises the amino acid sequence of SEQ ID NO: 54 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 54. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0297] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 44 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 44; and V L , which comprises the amino acid sequence of SEQ ID NO: 54 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 54. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0298] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H, comprising the amino acid sequence of SEQ ID NO: 39 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 39; and V L , which comprises the amino acid sequence of SEQ ID NO: 55 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 55. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0299] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 40 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 40; and V L , which comprises the amino acid sequence of SEQ ID NO: 55 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 55. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0300] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H, comprising the amino acid sequence of SEQ ID NO: 41 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 41; and V L , which comprises the amino acid sequence of SEQ ID NO: 55 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 55. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0301] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 42 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 42; and V L , which comprises the amino acid sequence of SEQ ID NO: 55 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 55. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0302] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H, comprising the amino acid sequence of SEQ ID NO: 43 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 43; and V L , which comprises the amino acid sequence of SEQ ID NO: 55 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 55. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0303] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 44 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 44; and V L , which comprises the amino acid sequence of SEQ ID NO: 55 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 55. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0304] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H, comprising the amino acid sequence of SEQ ID NO: 45 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 45; and V L , which comprises the amino acid sequence of SEQ ID NO: 56 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 56. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0305] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 45 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 45; and V L , which comprises the amino acid sequence of SEQ ID NO: 57 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0306] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H, comprising the amino acid sequence of SEQ ID NO: 46 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 46; and V L , which comprises the amino acid sequence of SEQ ID NO: 58 or a variant thereof having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0307] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 47 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 47; and V L , which comprises the amino acid sequence of SEQ ID NO: 59 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0308] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H, comprising the amino acid sequence of SEQ ID NO: 48 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 48; and V L , which comprises the amino acid sequence of SEQ ID NO: 60 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0309] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 49 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 49; and V L , which comprises the amino acid sequence of SEQ ID NO: 61 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 61. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0310] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H, comprising the amino acid sequence of SEQ ID NO: 50 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 50; and V L , which comprises the amino acid sequence of SEQ ID NO: 62 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 62. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0311] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 51 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 51; and V L , which comprises the amino acid sequence of SEQ ID NO: 63 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 63. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0312] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H, comprising the amino acid sequence of SEQ ID NO: 82 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 82; and V L , which comprises the amino acid sequence of SEQ ID NO: 90 or a variant thereof having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 90. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0313] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 83 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 83; and V L , which comprises the amino acid sequence of SEQ ID NO: 90 or a variant thereof having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 90. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0314] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H, comprising the amino acid sequence of SEQ ID NO: 84 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 84; and V L , which comprises the amino acid sequence of SEQ ID NO: 90 or a variant thereof having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 90. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0315] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 85 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 85; and V L , which comprises the amino acid sequence of SEQ ID NO: 90 or a variant thereof having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 90. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0316] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H, comprising the amino acid sequence of SEQ ID NO: 86 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 86; and V L , which comprises the amino acid sequence of SEQ ID NO: 91 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 91. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0317] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 87 or a variant thereof having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 87; and V L , which comprises the amino acid sequence of SEQ ID NO: 91 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 91. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0318] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H, comprising the amino acid sequence of SEQ ID NO: 88 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 88; and V L , which comprises the amino acid sequence of SEQ ID NO: 91 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 91. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0319] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 89 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 89; and V L , which comprises the amino acid sequence of SEQ ID NO: 91 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 91. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 64 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0320] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V H, comprising the amino acid sequence of SEQ ID NO: 38 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 38; and V L , which comprises the amino acid sequence of SEQ ID NO: 52 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 52. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0321] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 39 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 39; and V L , which comprises the amino acid sequence of SEQ ID NO: 53 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 53. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0322] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V H, comprising the amino acid sequence of SEQ ID NO: 40 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 40; and V L , which comprises the amino acid sequence of SEQ ID NO: 53 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 53. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0323] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 41 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 41; and V L , which comprises the amino acid sequence of SEQ ID NO: 53 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 53. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0324] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V H, comprising the amino acid sequence of SEQ ID NO: 42 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 42; and V L , which comprises the amino acid sequence of SEQ ID NO: 53 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 53. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0325] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 43 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 43; and V L , which comprises the amino acid sequence of SEQ ID NO: 53 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 53. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0326] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V H, comprising the amino acid sequence of SEQ ID NO: 44 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 44; and V L , which comprises the amino acid sequence of SEQ ID NO: 53 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 53. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0327] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 39 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 39; and V L , which comprises the amino acid sequence of SEQ ID NO: 54 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 54. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0328] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V H, comprising the amino acid sequence of SEQ ID NO: 40 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 40; and V L , which comprises the amino acid sequence of SEQ ID NO: 54 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 54. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0329] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 41 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 41; and V L , which comprises the amino acid sequence of SEQ ID NO: 54 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 54. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0330] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V H, comprising the amino acid sequence of SEQ ID NO: 42 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 42; and V L , which comprises the amino acid sequence of SEQ ID NO: 54 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 54. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0331] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 43 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 43; and V L , which comprises the amino acid sequence of SEQ ID NO: 54 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 54. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0332] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V H, comprising the amino acid sequence of SEQ ID NO: 44 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 44; and V L , which comprises the amino acid sequence of SEQ ID NO: 54 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 54. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0333] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 39 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 39; and V L , which comprises the amino acid sequence of SEQ ID NO: 55 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 55. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0334] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V H, comprising the amino acid sequence of SEQ ID NO: 40 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 40; and V L , which comprises the amino acid sequence of SEQ ID NO: 55 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 55. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0335] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 41 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 41; and V L , which comprises the amino acid sequence of SEQ ID NO: 55 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 55. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0336] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V H, comprising the amino acid sequence of SEQ ID NO: 42 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 42; and V L , which comprises the amino acid sequence of SEQ ID NO: 55 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 55. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0337] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 43 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 43; and V L , which comprises the amino acid sequence of SEQ ID NO: 55 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 55. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0338] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V H, comprising the amino acid sequence of SEQ ID NO: 44 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 44; and V L , which comprises the amino acid sequence of SEQ ID NO: 55 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 55. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0339] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 45 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 45; and V L , which comprises the amino acid sequence of SEQ ID NO: 56 or a variant thereof having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 56. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 65 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0340] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V H, comprising the amino acid sequence of SEQ ID NO: 45 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 45; and V L , which comprises the amino acid sequence of SEQ ID NO: 57 or a variant thereof, said varia...

Claims

1. An isolated anti-GDF15 antibody, wherein the anti-GDF15 antibody comprises: Heavy chain variable domain (V H ), the V H Include: a heavy chain complementarity determining region (HC-CDR) 1 comprising X1YYMX2 (SEQ ID NO: 35), wherein X1 is D or N, and X2 is S or T; HC-CDR2 comprising MISFSGTTX1ATWAKG (SEQ ID NO: 36), wherein X1 is H or Y; and HC-CDR3 comprising VVYAGWTYPLGI (SEQ ID NO: 13); and Light chain variable domain (V L ), the V L Include: Light chain complementarity determining region (LC-CDR) 1 comprising QASQSISSVLS (SEQ ID NO: 18); LC-CDR2 comprising EASX1X2AS (SEQ ID NO: 37), wherein X1 is I or T, and X2 is L or Q; and LC-CDR3 comprising QANYDVYNYGNP (SEQ ID NO: 30).

2. An isolated anti-GDF15 antibody comprising V H , The V H Include: HC-CDR1 comprising the amino acid sequence shown in any one of SEQ ID NOs: 1-2 or a variant thereof, wherein the variant comprises a substitution of up to about 3 amino acids; HC-CDR2 comprising the amino acid sequence shown in any one of SEQ ID NOs: 7-8 or a variant thereof, wherein the variant comprises a substitution of up to about 3 amino acids; and HC-CDR3 comprising the amino acid sequence shown in SEQ ID NO: 13 or a variant thereof, wherein the variant comprises a substitution of up to about 3 amino acids; and V L , the V L Include: LC-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 18 or a variant thereof, wherein the variant comprises a substitution of up to about 3 amino acids; LC-CDR2 comprising the amino acid sequence shown in any one of SEQ ID NOs: 23-25 ​​or a variant thereof, wherein the variant comprises a substitution of up to about 3 amino acids; and LC-CDR3 comprising the amino acid sequence shown in SEQ ID NO: 30 or a variant thereof, wherein the variant comprises a substitution of up to about 3 amino acids.

3. An isolated anti-GDF15 antibody comprising V H , the V H Comprising V as shown in any one of the amino acid sequences of SEQ ID NOs: 38-47 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , the V L Comprising V as shown in any one of the amino acid sequences of SEQ ID NOs: 52-59 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

4. The isolated anti-GDF15 antibody according to claim 3, comprising: (i)V H , which comprises V as shown in the amino acid sequence SEQ ID NO: 38 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:52 L Contains LC-CDR1, LC-CDR2, and LC-CDR3; (ii)V H , which comprises V as shown in the amino acid sequence SEQ ID NO:45 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:56 L Contains LC-CDR1, LC-CDR2, and LC-CDR3; (iii)V H , which comprises V as shown in the amino acid sequence SEQ ID NO:45 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO: 57 L Contains LC-CDR1, LC-CDR2, and LC-CDR3; (iv)V H , which comprises V as shown in the amino acid sequence SEQ ID NO:46 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO: 58 L comprising LC-CDR1, LC-CDR2 and LC-CDR3; or (v)V H , which comprises V as shown in the amino acid sequence SEQ ID NO:47 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO: 59 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

5. The isolated anti-GDF15 antibody according to any one of claims 1 to 4, comprising: (i)V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 13, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30, or the V L A variant comprising up to about 5 amino acid substitutions in its LC-CDRs; (ii)V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 13, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L Comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO: 18, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO: 24, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO: 30, or the V L A variant comprising up to about 5 amino acid substitutions in its LC-CDRs; (iii)V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 13, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30, or the V L A variant comprising up to about 5 amino acid substitutions in its LC-CDRs; (iv)V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 2, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 13, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30, or the V L a variant comprising up to about 5 amino acid substitutions in its LC-CDRs; or (v)V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 13, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30, or the V L A variant comprising up to about 5 amino acid substitutions in its LC-CDRs.

6. The isolated anti-GDF15 antibody according to any one of claims 1 to 5, comprising: V H , comprising an amino acid sequence as shown in any one of SEQ ID NOs: 38-47 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence as shown in any one of SEQ ID NOs: 38-47; and V L , which comprises the amino acid sequence shown in any one of SEQ ID NOs: 52-59 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence shown in any one of SEQ ID NOs: 52-59.

7. The isolated anti-GDF15 antibody according to claim 6, comprising: (i)V H , comprising the amino acid sequence of SEQ ID NO: 38 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 38; and V L , comprising the amino acid sequence of SEQ ID NO: 52 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 52; (ii)V H , comprising the amino acid sequence of SEQ ID NO: 39 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 39; and V L , comprising the amino acid sequence of SEQ ID NO: 53 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 53; (iii)V H , comprising the amino acid sequence of SEQ ID NO: 40 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 40; and V L , comprising the amino acid sequence of SEQ ID NO: 53 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 53; (iv)V H , comprising the amino acid sequence of SEQ ID NO: 41 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 41; and V L , comprising the amino acid sequence of SEQ ID NO: 53 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 53; (v)V H , comprising the amino acid sequence of SEQ ID NO: 42 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 42; and V L , comprising the amino acid sequence of SEQ ID NO: 53 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 53; (vi)V H , comprising the amino acid sequence of SEQ ID NO: 43 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 43; and V L , comprising the amino acid sequence of SEQ ID NO: 53 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 53; (vii)V H , comprising the amino acid sequence of SEQ ID NO: 44 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 44; and V L , comprising the amino acid sequence of SEQ ID NO: 53 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 53; (viii)V H , comprising the amino acid sequence of SEQ ID NO: 39 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 39; and V L , comprising the amino acid sequence of SEQ ID NO: 54 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 54; (ix)V H , comprising the amino acid sequence of SEQ ID NO: 40 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 40; and V L , comprising the amino acid sequence of SEQ ID NO: 54 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 54; (x)V H , comprising the amino acid sequence of SEQ ID NO: 41 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 41; and V L , comprising the amino acid sequence of SEQ ID NO: 54 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 54; (xi)V H , comprising the amino acid sequence of SEQ ID NO: 42 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 42; and V L , comprising the amino acid sequence of SEQ ID NO: 54 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 54; (xii)V H , comprising the amino acid sequence of SEQ ID NO: 43 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 43; and V L , comprising the amino acid sequence of SEQ ID NO: 54 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 54; (xiii)V H , comprising the amino acid sequence of SEQ ID NO: 44 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 44; and V L , comprising the amino acid sequence of SEQ ID NO: 54 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 54; (xiv)V H , comprising the amino acid sequence of SEQ ID NO: 39 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 39; and V L , comprising the amino acid sequence of SEQ ID NO: 55 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 55; (xv)V H , comprising the amino acid sequence of SEQ ID NO: 40 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 40; and V L , which comprises the amino acid sequence SEQ ID NO:55 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO:55; (xvi)V H , comprising the amino acid sequence of SEQ ID NO: 41 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 41; and V L , comprising the amino acid sequence of SEQ ID NO: 55 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 55; (xvii)V H , comprising the amino acid sequence of SEQ ID NO: 42 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 42; and V L , comprising the amino acid sequence of SEQ ID NO: 55 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 55; (xviii)V H , comprising the amino acid sequence of SEQ ID NO: 43 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 43; and V L , comprising the amino acid sequence of SEQ ID NO: 55 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 55; (xix)V H , comprising the amino acid sequence of SEQ ID NO: 44 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 44; and V L , comprising the amino acid sequence of SEQ ID NO: 55 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 55; (xx)V H , comprising the amino acid sequence of SEQ ID NO: 45 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 45; and V L , comprising the amino acid sequence of SEQ ID NO: 56 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 56; (xxi)V H , comprising the amino acid sequence of SEQ ID NO: 45 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 45; and V L , comprising the amino acid sequence of SEQ ID NO: 57 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 57; (xxii)V H , comprising the amino acid sequence of SEQ ID NO: 46 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 46; and V L , comprising the amino acid sequence of SEQ ID NO: 58 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 58; or (xxiii)V H , comprising the amino acid sequence of SEQ ID NO: 47 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 47; and V L , comprising the amino acid sequence of SEQ ID NO: 59 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO:

59.

8. An isolated anti-GDF15 antibody comprising: (i)V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 14, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 19, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 31, or the V L A variant comprising up to about 5 amino acid substitutions in its LC-CDRs; (ii)V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 15, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 20, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 27, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 32, or the V L a variant comprising up to about 5 amino acid substitutions in its LC-CDRs; or (iii)V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 5, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 16, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 28, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 33, or the V L A variant comprising up to about 5 amino acid substitutions in its LC-CDRs.

9. The isolated anti-GDF15 antibody according to claim 8, comprising: V H , comprising an amino acid sequence as shown in any one of SEQ ID NOs: 48-50 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence as shown in any one of SEQ ID NOs: 48-50; and V L , which comprises an amino acid sequence shown in any one of SEQ ID NOs: 60-62 or a variant thereof, The variant has at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 60-62.

10. The isolated anti-GDF15 antibody according to any one of claims 8-9, comprising: (i)V H , comprising the amino acid sequence shown in SEQ ID NO: 48 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 48; and V L , comprising the amino acid sequence set forth in SEQ ID NO: 60 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO: 60; (ii)V H , comprising the amino acid sequence shown in SEQ ID NO: 49 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 49; and V L , which comprises the amino acid sequence shown in SEQ ID NO: 61 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 61; or (iii)V H , comprising the amino acid sequence shown in SEQ ID NO: 50 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 50; and V L , which comprises the amino acid sequence shown in SEQ ID NO: 62 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:

62.

11. The isolated anti-GDF15 antibody according to any one of claims 8 to 10, comprising V H , the V H Comprising V as shown in any one of the amino acid sequences of SEQ ID NOs: 48-50 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , the V L Comprising V as shown in any one of the amino acid sequences of SEQ ID NOs: 60-62 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

12. The isolated anti-GDF15 antibody according to any one of claims 8 to 11, comprising: (i)V H , which comprises V as shown in the amino acid sequence SEQ ID NO:48 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO: 60 L Contains LC-CDR1, LC-CDR2, and LC-CDR3; (ii)V H , which comprises V as shown in the amino acid sequence SEQ ID NO:49 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:61 L comprising LC-CDR1, LC-CDR2 and LC-CDR3; or (iii)V H , which comprises V as shown in the amino acid sequence SEQ ID NO: 50 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO: 62 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

13. An isolated anti-GDF15 antibody, wherein the anti-GDF15 antibody comprises: Heavy chain variable domain (V H ), the V H Include: heavy chain complementarity determining region (HC-CDR) 1 comprising SYDMT (SEQ ID NO: 6); HC-CDR2 comprising IIX1X2SGX3TYYASWAKG (SEQ ID NO: 79), wherein X1 is N or S, X2 is G, N, or S, and X3 is N or S; and HC-CDR3 comprising GILVYADYGDHNL (SEQ ID NO: 17); and Light chain variable domain (V L ), the V L Include: light chain complementarity determining region (LC-CDR) 1 comprising QASEDIYTNLA (SEQ ID NO: 22); LC-CDR2 comprising AASTLAS (SEQ ID NO: 29); and LC-CDR3 comprising LGVYTYISAX1GA (SEQ ID NO: 81), wherein X1 is D or E.

14. An isolated anti-GDF15 antibody comprising: V H , the V H comprising: an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6 or a variant thereof, wherein the variant comprises at most about 3 amino acid substitutions; an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 12, 75-78 or a variant thereof, wherein the variant comprises at most about 3 amino acid substitutions; and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 17 or a variant thereof, wherein the variant comprises at most about 3 amino acid substitutions; and V L , the V L Comprising: LC-CDR1, which comprises the amino acid sequence shown in SEQ ID NO:22 or a variant thereof, wherein the variant comprises substitutions of up to about 3 amino acids; LC-CDR2, which comprises the amino acid sequence shown in SEQ ID NO:29 or a variant thereof, wherein the variant comprises substitutions of up to about 3 amino acids; and LC-CDR3, which comprises the amino acid sequence shown in any one of SEQ ID NOs:34 or 80 or a variant thereof, wherein the variant comprises substitutions of up to about 3 amino acids.

15. An isolated anti-GDF15 antibody comprising V H , the V H Comprising V as shown in any one of the amino acid sequences of SEQ ID NOs: 51, 82-89 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , the V L Comprising V as shown in any one of the amino acid sequences of SEQ ID NOs: 63, 90-91 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

16. The isolated anti-GDF15 antibody according to claim 15, comprising: (i)V H , which comprises V as shown in the amino acid sequence SEQ ID NO:51 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO: 63 L Contains LC-CDR1, LC-CDR2, and LC-CDR3; (ii)V H , which comprises V as shown in the amino acid sequence SEQ ID NO:82 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:90 L Contains LC-CDR1, LC-CDR2, and LC-CDR3; (iii)V H , which comprises V as shown in the amino acid sequence SEQ ID NO: 83 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:90 L Contains LC-CDR1, LC-CDR2, and LC-CDR3; (iv)V H , which comprises V as shown in the amino acid sequence SEQ ID NO: 84 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:90 L comprising LC-CDR1, LC-CDR2 and LC-CDR3; or (v)V H , which comprises V as shown in the amino acid sequence SEQ ID NO: 85 H HC-CDR1, HC-CDR2 and HC-CDR3 included; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:90 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

17. The isolated anti-GDF15 antibody according to any one of claims 13-16, comprising: (i)V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 12, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 17, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 34, or the V L A variant comprising up to about 5 amino acid substitutions in its LC-CDRs; (ii)V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 75, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 17, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 80, or the V L A variant comprising up to about 5 amino acid substitutions in its LC-CDRs; (iii)V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 76, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 17, or the V H A variant comprising up to about 5 amino acids in its HC-CDRs substitution of amino acids; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 80, or the V L A variant comprising up to about 5 amino acid substitutions in its LC-CDRs; (iv)V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 77, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 17, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 80, or the V L a variant comprising up to about 5 amino acid substitutions in its LC-CDRs; or (v)V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 78, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 17, or the V H A variant comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 80, or the V L A variant comprising up to about 5 amino acid substitutions in its LC-CDRs.

18. The isolated anti-GDF15 antibody of any one of claims 13-17, comprising: V H , comprising an amino acid sequence as shown in any one of SEQ ID NOs: 51, 82-89 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence as shown in any one of SEQ ID NOs: 51, 82-89; and V L , which comprises the amino acid sequence shown in any one of SEQ ID NOs: 63, 90-91 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence shown in any one of SEQ ID NOs: 63, 90-91.

19. The isolated anti-GDF15 antibody according to claim 18, comprising: (i)V H , comprising the amino acid sequence of SEQ ID NO: 51 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 51; and V L , comprising the amino acid sequence of SEQ ID NO: 63 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 63; (ii)V H , comprising the amino acid sequence of SEQ ID NO: 82 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 82; and V L , which comprises the amino acid sequence SEQ ID NO: 90 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 90; (iii)V H , comprising the amino acid sequence of SEQ ID NO: 83 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 83; and V L , comprising the amino acid sequence of SEQ ID NO: 90 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 90; (iv)V H , comprising the amino acid sequence of SEQ ID NO: 84 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 84; and V L , comprising the amino acid sequence of SEQ ID NO: 90 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 90; (v)V H , comprising the amino acid sequence of SEQ ID NO: 85 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 85; and V L , comprising the amino acid sequence of SEQ ID NO: 90 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 90; (vi)V H , comprising the amino acid sequence of SEQ ID NO: 86 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 86; and V L , comprising the amino acid sequence of SEQ ID NO: 91 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 91; (vii)V H , comprising the amino acid sequence of SEQ ID NO: 87 or a variant thereof having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 87; and V L , comprising the amino acid sequence of SEQ ID NO: 91 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 91; (viii)V H , comprising the amino acid sequence of SEQ ID NO: 88 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 88; and V L , comprising the amino acid sequence of SEQ ID NO: 91 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 91; or (ix)V H , comprising the amino acid sequence of SEQ ID NO: 89 or a variant thereof having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 89; and V L , comprising the amino acid sequence of SEQ ID NO: 91 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO:

91.

20. The isolated anti-GDF15 antibody of any one of claims 1-19, wherein the anti-GDF15 antibody binds to human GDF15 with a Kd value of about 0.1 pM to about 10 nM.

21. An isolated anti-GDF15 antibody that competes with the isolated anti-GDF15 antibody of any one of claims 1-20 for specific binding to GDF15, or specifically binds to the same epitope as the isolated anti-GDF15 antibody of any one of claims 1-20.

22. The isolated anti-GDF15 antibody according to any one of claims 1-21, wherein the anti-GDF15 antibody comprises an Fc fragment.

23. The isolated anti-GDF15 antibody of claim 22, wherein the anti-GDF15 antibody is a full-length IgA, IgD, IgE, IgG, or IgM antibody.

24. The isolated anti-GDF15 antibody of claim 23, wherein the anti-GDF15 antibody is a full-length IgG1, IgG2, IgG3, or IgG4 antibody.

25. The isolated anti-GDF15 antibody according to any one of claims 1-24, wherein the anti-GDF15 antibody is a chimeric, human or humanized antibody.

26. The isolated anti-GDF15 antibody according to any one of claims 1 to 21, wherein the anti-GDF15 antibody is an antigen-binding fragment selected from the group consisting of Fab, Fab', F(ab)'2, Fab'-SH, single-chain Fv (scFv), Fv fragment, dAb, Fd, nanobody, diabody, and linear antibody.

27. An isolated nucleic acid molecule encoding the anti-GDF15 antibody of any one of claims 1-26.

28. A vector comprising the nucleic acid molecule of claim 27.

29. An isolated host cell comprising the anti-GDF15 antibody of any one of claims 1-26, the nucleic acid molecule of claim 27, or the vector of claim 28.

30. A method for preparing an anti-GDF15 antibody, comprising: a) culturing the host cell of claim 29 under conditions that effectively express the anti-GDF15 antibody; and b) Obtaining the expressed anti-GDF15 antibody from the host cells.

31. A pharmaceutical composition comprising the anti-GDF15 antibody of any one of claims 1-26, the nucleic acid molecule of claim 27, the vector of claim 28, the isolated host cell of claim 29, or the antibody produced by the method of claim 30, and a pharmaceutically acceptable carrier.

32. Use of the antibody of any one of claims 1-26, the nucleic acid molecule of claim 27, the vector of claim 28, the host cell of claim 29, the antibody produced by the method of claim 30, or the pharmaceutical composition of claim 31 in the preparation of a medicament for treating a disease or condition in an individual in need thereof.

33. The use according to claim 32, wherein the disease or condition is a disease and / or condition caused by dysregulation of the GDF15 signaling pathway, such as cancer, cachexia and / or metabolic disease.

34. The method according to claim 33, wherein the disease or condition is selected from cancer (such as brain cancer, melanoma, lung cancer, gastrointestinal tumors, colon cancer, pancreatic cancer, prostate cancer, breast cancer, oral cancer, liver cancer, leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, bladder cancer, cervical cancer, uterine body cancer, testicular cancer, thyroid cancer, kidney cancer, gallbladder cancer, multiple myeloma, nasopharyngeal cancer, laryngeal cancer, pharyngeal cancer, esophageal cancer, etc.), cachexia, renal failure, sepsis, AIDS, cachexia caused by chronic obstructive pulmonary disease, cachexia-related weight loss, nausea and vomiting caused by radiotherapy and chemotherapy, late chronic tubulointerstitial nephritis, morning sickness, cirrhosis, sarcopenia, metabolic diseases (such as imbalance of fat and energy metabolism, regulation of appetite, regulation of weight).

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