Antibodies specifically recognizing gdf15 and uses thereof

Abstract

An antibody or antigen-binding fragment that specifically recognizes growth differentiation factor-15 (GDF15), and its preparation method and uses.

Description

[0001] Submitting sequence lists as XML text files

[0002] This application claims priority to Chinese Patent Application No. 202210497637.0, filed on May 9, 2022, entitled "Antibody that specifically recognizes GDF15 and its application", the entire contents of which are incorporated herein by reference.

[0003] Submitting the sequence list as an XML file

[0004] The contents of the electronic sequence list are incorporated into this document by reference in their entirety: (Text name: GDF15-seq.xml, Record date: 2023.03.16, Size: 87KB). Technical Field

[0005] This invention relates to antibodies that specifically recognize GDF15, their preparation methods and uses, including methods for treating cancer, cachexia and / or metabolic diseases. Background Technology

[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 involves a series of post-translational modifications. The post-translational unprocessed GDF15 protein (pre-pro-GDF15) has 308 amino acids, including a signal peptide sequence (29 amino acids), a propeptide (167 amino acids), and a mature protein (112 amino acids). The synthesized 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 from the C-terminus (Wang X et al., Biochem Pharmacol, 2013).

[0007] Mature GDF15 dimer 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 is no sex difference in healthy older adults. GDF15 concentrations are correlated with cystatin C and C-reactive protein concentrations (Brown, D.A. 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 normally not expressed in adult cardiac muscle; however, it is significantly induced in injured 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, the production of GDF15 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 confirmed the TGFβ receptor that GDF15 directly binds to. Four different research teams simultaneously identified GFRAL as the receptor for GDF15 (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 study found that GDF15 does not bind to any known TGFβ receptor. By resolving the crystal structure of the GDF15 protein, they discovered an additional disulfide bond in the protein, different from other TGFβ family members, and screened and confirmed the glial cell-derived neurotrophic factor (GDNF) receptor α-like protein GFRAL as the brainstem-restricted receptor for GDF15 (Hsu et al., Nature, 2017). This receptor mediates downstream signal transduction via the tyrosine kinase co-receptor RET. In the GDF15-GFRAL signaling pathway, the GDF15 dimer protein binds 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 AKT, ERK1 / 2, and phospholipase C (PLCγ) (Shannon E. Mullican & Rangwala, 2018; L. Yang, et al., 2017). Although the GDF15 / GFRAL signaling pathway is not fully understood, and more research is needed to link the GDF15 receptor to the biological activity of mature GDF15, it is certain that the molecular basis of GDF15 activity is through GFRAL / RET, rather than through TGFβ signaling transduction (Hsu et al., Nature, 2017).

[0009] GDF15 protein is associated with various diseases such as obesity and insulin resistance (SNBreit et al., GrowthFactors, 2011). Knockout of GDF15 in genetically engineered mice leads to increased body weight; while overexpression of GDF15 results in decreased body weight and fat content, 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 reduction in body weight, validating these phenotypes, including: widespread expression of hGDF15 in mice did not reduce food intake, but improved glucose tolerance, insulin sensitivity, and 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 condition caused by cancer, typically involving weight loss, muscle atrophy, fatigue, weakness, and severe loss of appetite in individuals who do not actively lose weight. It is a major 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 factor in inducing refractory cachexia. It is conservatively estimated that more than 1.5 million new cases of cancer cachexia are diagnosed in my country each year (accounting for approximately 36.4% of new cancer patients), and about 20% of cancer patients die from cachexia itself (Murphy KT. et al., Expert Opin Emerg Drugs. 2009). Many malignant cancers, especially invasive brain cancer, melanoma, lung cancer, gastrointestinal tumors, colon cancer, pancreatic cancer, prostate cancer, and breast cancer, show significantly elevated GDF15 levels in both the tumor and serum (Huang CY et al., Clin Cancer Res. 2009.). Studies by L. Lerner et al. have shown that cancer patients who lost weight had significantly increased circulating GDF15 levels compared to cancer patients without weight loss and non-cancer control groups (Lerner L et al., J Cachexia Sarcopenia Muscle. 2015.). Furthermore, GDF15 levels were associated with weight loss, reduced fat mass, muscle mass, strength, physical performance score, and survival in cancer patients, while decreased lean body mass (LBM) was a negative and independent prognostic factor for cancer patients (Reuben DB et al., Arch Intern Med. 1988.), and decreased grip strength was associated with reduced survival in this population (Gale CR. et al., Int J Epidemiol. 2007.).

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

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

[0013] All publications, patents, patent applications, and disclosed information in published patent applications mentioned herein are incorporated herein 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 It includes: a heavy chain complementarity determination region (HC-CDR)1 containing X1YYMX2 (SEQ ID NO:35), where X1 is D or N and X2 is S or T; HC-CDR2 containing MISFSGTTX1ATWAKG (SEQ ID NO:36), where X1 is H or Y; and HC-CDR3 containing VVYAGWTYPLGI (SEQ ID NO:13); and a light chain variable structural domain (V L ), the V L It includes: a light chain complementarity determination region (LC-CDR)1, which contains QASQSISSVLS (SEQ ID NO:18); LC-CDR2, which contains EASX1X2AS (SEQ ID NO:37), wherein X1 is I or T and X2 is L or Q; and LC-CDR3, which contains QANYDVYNYGNP (SEQ ID NO:30).

[0016] In some embodiments, an isolated anti-GDF15 antibody is provided, which comprises V H The V H Contains: HC-CDR1, comprising any of the amino acid sequences shown in SEQ ID NOs:1-2 or variants thereof, the variants comprising substitutions of up to about 3 amino acids; HC-CDR2, comprising any of the amino acid sequences shown in SEQ ID NOs:7-8 or variants thereof, the variants comprising substitutions of up to about 3 amino acids; and HC-CDR3, comprising the amino acid sequence shown in SEQ ID NO:13 or variants thereof, the variants comprising substitutions of up to about 3 amino acids; and V L The V L It comprises: LC-CDR1, which comprises the amino acid sequence shown in SEQ ID NO:18 or a variant thereof, the variant comprising substitutions of up to about 3 amino acids; LC-CDR2, which comprises the amino acid sequence shown in any of SEQ ID NOs:23-25 ​​or a variant thereof, the variant comprising 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, the variant comprising 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 V containing any of the amino acid sequences shown in SEQ ID NOs:38-47 H Includes HC-CDR1, HC-CDR2, and HC-CDR3, as well as V L The V L V containing any of the amino acid sequences shown in SEQ ID NOs:52-59 L It includes LC-CDR1, LC-CDR2 and LC-CDR3.

[0018] In some embodiments, an isolated anti-GDF15 antibody is provided, comprising: (i) V H It contains V as shown in the amino acid sequence SEQ ID NO:38. H Includes HC-CDR1, HC-CDR2, and HC-CDR3; and V L It contains V as shown in the amino acid sequence SEQ ID NO:52. L Includes LC-CDR1, LC-CDR2 and LC-CDR3; (ii)V H It contains V as shown in the amino acid sequence SEQ ID NO:39 H Includes HC-CDR1, HC-CDR2, and HC-CDR3; and V L It contains V as shown in the amino acid sequence SEQ ID NO:53. L Includes LC-CDR1, LC-CDR2 and LC-CDR3; (iii)V H It contains V as shown in the amino acid sequence SEQ ID NO:40. H Includes HC-CDR1, HC-CDR2, and HC-CDR3; and V L It contains V as shown in the amino acid sequence SEQ ID NO:53. L Includes LC-CDR1, LC-CDR2 and LC-CDR3; (iv)V H It contains V as shown in the amino acid sequence SEQ ID NO:41. H Includes HC-CDR1, HC-CDR2, and HC-CDR3; and V L It contains V as shown in the amino acid sequence SEQ ID NO:53. L Includes LC-CDR1, LC-CDR2 and LC-CDR3; (v)V H It contains V as shown in the amino acid sequence SEQ ID NO:42.H Includes HC-CDR1, HC-CDR2, and HC-CDR3; and V L It contains V as shown in the amino acid sequence SEQ ID NO:53. L Includes LC-CDR1, LC-CDR2 and LC-CDR3; (vi)V H It contains V as shown in the amino acid sequence SEQ ID NO:43. H Includes HC-CDR1, HC-CDR2, and HC-CDR3; and V L It contains V as shown in the amino acid sequence SEQ ID NO:53. L Includes LC-CDR1, LC-CDR2 and LC-CDR3; (vii)V H It contains V as shown in the amino acid sequence SEQ ID NO:44. H Includes HC-CDR1, HC-CDR2, and HC-CDR3; and V L It contains V as shown in the amino acid sequence SEQ ID NO:53. L Includes LC-CDR1, LC-CDR2 and LC-CDR3; (viii)V H It contains V as shown in the amino acid sequence SEQ ID NO:39 H Includes HC-CDR1, HC-CDR2, and HC-CDR3; and V L It contains V as shown in the amino acid sequence SEQ ID NO:54. L Includes LC-CDR1, LC-CDR2, and LC-CDR3; (ix)V H It contains V as shown in the amino acid sequence SEQ ID NO:40. H Includes HC-CDR1, HC-CDR2, and HC-CDR3; and V L It contains V as shown in the amino acid sequence SEQ ID NO:54. L Includes LC-CDR1, LC-CDR2, and LC-CDR3; (x)V H It contains V as shown in the amino acid sequence SEQ ID NO:41. H Includes HC-CDR1, HC-CDR2, and HC-CDR3; and V L It contains V as shown in the amino acid sequence SEQ ID NO:54. L Includes LC-CDR1, LC-CDR2, and LC-CDR3; (xi)V H It contains V as shown in the amino acid sequence SEQ ID NO:42. HIncludes HC-CDR1, HC-CDR2, and HC-CDR3; and V L It contains V as shown in the amino acid sequence SEQ ID NO:54. L Includes LC-CDR1, LC-CDR2, and LC-CDR3; (xii)V H It contains V as shown in the amino acid sequence SEQ ID NO:43. H Includes HC-CDR1, HC-CDR2, and HC-CDR3; and V L It contains V as shown in the amino acid sequence SEQ ID NO:54. L Includes LC-CDR1, LC-CDR2 and LC-CDR3; (xiii)V H It contains V as shown in the amino acid sequence SEQ ID NO:44. H Includes HC-CDR1, HC-CDR2, and HC-CDR3; and V L It contains V as shown in the amino acid sequence SEQ ID NO:54. L Includes LC-CDR1, LC-CDR2, and LC-CDR3; (xiv)V H It contains V as shown in the amino acid sequence SEQ ID NO:39 H Includes HC-CDR1, HC-CDR2, and HC-CDR3; and V L It contains V as shown in the amino acid sequence SEQ ID NO:55. L Includes LC-CDR1, LC-CDR2, and LC-CDR3; (xv)V H It contains V as shown in the amino acid sequence SEQ ID NO:40. H Includes HC-CDR1, HC-CDR2, and HC-CDR3; and V L It contains V as shown in the amino acid sequence SEQ ID NO:55. L Includes LC-CDR1, LC-CDR2, and LC-CDR3; (xvi)V H It contains V as shown in the amino acid sequence SEQ ID NO:41. H Includes HC-CDR1, HC-CDR2, and HC-CDR3; and V L It contains V as shown in the amino acid sequence SEQ ID NO:55. L Includes LC-CDR1, LC-CDR2, and LC-CDR3; (xvii)V H It contains V as shown in the amino acid sequence SEQ ID NO:42. HIncludes HC-CDR1, HC-CDR2, and HC-CDR3; and V L It contains V as shown in the amino acid sequence SEQ ID NO:55. L Includes LC-CDR1, LC-CDR2, and LC-CDR3; (xviii)V H It contains V as shown in the amino acid sequence SEQ ID NO:43. H Includes HC-CDR1, HC-CDR2, and HC-CDR3; and V L It contains V as shown in the amino acid sequence SEQ ID NO:55. L Includes LC-CDR1, LC-CDR2, and LC-CDR3; (xix)V H It contains V as shown in the amino acid sequence SEQ ID NO:44. H Includes HC-CDR1, HC-CDR2, and HC-CDR3; and V L It contains V as shown in the amino acid sequence SEQ ID NO:55. L Includes LC-CDR1, LC-CDR2 and LC-CDR3; (xx)V H It contains V as shown in the amino acid sequence SEQ ID NO:45. H Includes HC-CDR1, HC-CDR2, and HC-CDR3; and V L It contains V as shown in the amino acid sequence SEQ ID NO:56. L Includes LC-CDR1, LC-CDR2, and LC-CDR3; (xxi)V H It contains V as shown in the amino acid sequence SEQ ID NO:45. H Includes HC-CDR1, HC-CDR2, and HC-CDR3; and V L It contains V as shown in the amino acid sequence SEQ ID NO:57. L Includes LC-CDR1, LC-CDR2 and LC-CDR3; (xxii)V H It contains V as shown in the amino acid sequence SEQ ID NO:46. H Includes HC-CDR1, HC-CDR2, and HC-CDR3; and V L It contains V as shown in the amino acid sequence SEQ ID NO:58. L Includes LC-CDR1, LC-CDR2 and LC-CDR3; (xxiii)V H It contains V as shown in the amino acid sequence SEQ ID NO:47.H Includes HC-CDR1, HC-CDR2, and HC-CDR3; and V L It contains V as shown in the amino acid sequence SEQ ID NO:59. L It includes 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 Contains: HC-CDR1, which contains the amino acid sequence SEQ ID NO:1; HC-CDR2, which contains the amino acid sequence SEQ ID NO:7; and HC-CDR3, which contains the amino acid sequence SEQ ID NO:13, or the V H Variants of which contain up to about 5 amino acid substitutions in their HC-CDRs; and V L The V L Contains: LC-CDR1, which contains the amino acid sequence SEQ ID NO:18; LC-CDR2, which contains the amino acid sequence SEQ ID NO:23; and LC-CDR3, which contains the amino acid sequence SEQ ID NO:30, or the V L (ii) V variants, whose LC-CDRs contain substitutions of up to about 5 amino acids; H The V H Contains: HC-CDR1, which contains the amino acid sequence SEQ ID NO:1; HC-CDR2, which contains the amino acid sequence SEQ ID NO:7; and HC-CDR3, which contains the amino acid sequence SEQ ID NO:13, or the V H Variants of which contain up to about 5 amino acid substitutions in their HC-CDRs; and V L The V L Contains: LC-CDR1, which contains the amino acid sequence SEQ ID NO:18; LC-CDR2, which contains the amino acid sequence SEQ ID NO:24; and LC-CDR3, which contains the amino acid sequence SEQ ID NO:30, or the V L (iii) V variants, whose LC-CDRs contain substitutions of up to about 5 amino acids; H The V H Contains: HC-CDR1, which contains the amino acid sequence SEQ ID NO:1; HC-CDR2, which contains the amino acid sequence SEQ ID NO:7; and HC-CDR3, which contains the amino acid sequence SEQ ID NO:13, or the V HVariants of which contain up to about 5 amino acid substitutions in their HC-CDRs; and V L The V L Contains: LC-CDR1, which contains the amino acid sequence SEQ ID NO:18; LC-CDR2, which contains the amino acid sequence SEQ ID NO:25; and LC-CDR3, which contains the amino acid sequence SEQ ID NO:30, or the V L (iv) V variants, whose LC-CDRs contain substitutions of up to about 5 amino acids; H The V H Contains: HC-CDR1, which contains the amino acid sequence SEQ ID NO:2; HC-CDR2, which contains the amino acid sequence SEQ ID NO:7; and HC-CDR3, which contains the amino acid sequence SEQ ID NO:13, or the V H Variants of which contain up to about 5 amino acid substitutions in their HC-CDRs; and V L The V L Contains: LC-CDR1, which contains the amino acid sequence SEQ ID NO:18; LC-CDR2, which contains the amino acid sequence SEQ ID NO:25; and LC-CDR3, which contains the amino acid sequence SEQ ID NO:30, or the V L The variants, whose LC-CDRs contain substitutions of up to about 5 amino acids; (v)V H The V H Contains: HC-CDR1, which contains the amino acid sequence SEQ ID NO:1; HC-CDR2, which contains the amino acid sequence SEQ ID NO:8; and HC-CDR3, which contains the amino acid sequence SEQ ID NO:13, or the V H Variants of which contain up to about 5 amino acid substitutions in their HC-CDRs; and V L The V L Contains: LC-CDR1, which contains the amino acid sequence SEQ ID NO:18; LC-CDR2, which contains the amino acid sequence SEQ ID NO:25; and LC-CDR3, which contains the amino acid sequence SEQ ID NO:30, or the V L Variants of which contain up to about 5 amino acid substitutions in their LC-CDRs.

[0020] In some embodiments, any of the isolated anti-GDF15 antibodies described above comprises: V HIt comprises any of the amino acid sequences shown in SEQ ID NOs:38-47 or variants thereof, said variants having at least about 80% sequence identity with any of the amino acid sequences shown in SEQ ID NOs:38-47; and V L It comprises any of the amino acid sequences shown in SEQ ID NOs:52-59 or variants thereof, wherein the variants have at least about 80% sequence identity with any of the amino acid sequences shown in SEQ ID NOs:52-59.

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

[0022] In some embodiments, an isolated anti-GDF15 antibody is provided, comprising: (i) V H It contains V as shown in the amino acid sequence SEQ ID NO:48. H Includes HC-CDR1, HC-CDR2, and HC-CDR3; and V L It contains V as shown in the amino acid sequence SEQ ID NO:60. L It includes 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 Contains: HC-CDR1, which contains the amino acid sequence SEQ ID NO:3; HC-CDR2, which contains the amino acid sequence SEQ ID NO:9; and HC-CDR3, which contains the amino acid sequence SEQ ID NO:14, or the V H Variants of which contain up to about 5 amino acid substitutions in their HC-CDRs; and V L The V L Contains: LC-CDR1, which contains the amino acid sequence SEQ ID NO:19; LC-CDR2, which contains the amino acid sequence SEQ ID NO:26; and LC-CDR3, which contains the amino acid sequence SEQ ID NO:31, or the V L Variants of which contain up to about 5 amino acid substitutions in their LC-CDRs.

[0024] In some embodiments, any of the isolated anti-GDF15 antibodies described above comprises: V H It comprises the amino acid sequence shown in SEQ ID NO:48 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:48; and V L It contains the amino acid sequence shown in SEQ ID NO:60 or a variant thereof, the variant having 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 It contains V as shown in the amino acid sequence SEQ ID NO:49.H Includes HC-CDR1, HC-CDR2, and HC-CDR3; and V L It contains V as shown in the amino acid sequence SEQ ID NO:61. L It includes 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 Contains: HC-CDR1, which contains the amino acid sequence SEQ ID NO:4; HC-CDR2, which contains the amino acid sequence SEQ ID NO:10; and HC-CDR3, which contains the amino acid sequence SEQ ID NO:15, or the V H Variants of which contain up to about 5 amino acid substitutions in their HC-CDRs; and V L The V L Contains: LC-CDR1, which contains the amino acid sequence SEQ ID NO:20; LC-CDR2, which contains the amino acid sequence SEQ ID NO:27; and LC-CDR3, which contains the amino acid sequence SEQ ID NO:32, or the V L Variants of which contain up to about 5 amino acid substitutions in their LC-CDRs.

[0027] In some embodiments, any of the isolated anti-GDF15 antibodies described above comprises: V H It comprises the amino acid sequence shown in SEQ ID NO:49 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:49; and V L It contains the amino acid sequence shown in SEQ ID NO:61 or a variant thereof, the variant having 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 It contains V as shown in the amino acid sequence SEQ ID NO:50. H Includes HC-CDR1, HC-CDR2, and HC-CDR3; and V L It contains V as shown in the amino acid sequence SEQ ID NO:62. L It includes 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 Contains: HC-CDR1, which contains the amino acid sequence SEQ ID NO:5; HC-CDR2, which contains the amino acid sequence SEQ ID NO:11; and HC-CDR3, which contains the amino acid sequence SEQ ID NO:16, or the V H Variants of which contain up to about 5 amino acid substitutions in their HC-CDRs; and V L The V L Contains: LC-CDR1, which contains the amino acid sequence SEQ ID NO:21; LC-CDR2, which contains the amino acid sequence SEQ ID NO:28; and LC-CDR3, which contains the amino acid sequence SEQ ID NO:33, or the V L Variants of which contain up to about 5 amino acid substitutions in their LC-CDRs.

[0030] In some embodiments, any of the isolated anti-GDF15 antibodies described above comprises: V H It comprises the amino acid sequence shown in SEQ ID NO:50 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:50; and V L It contains the amino acid sequence shown in SEQ ID NO:62 or a variant thereof, the variant having 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 It includes: a heavy chain complementarity-determining region (HC-CDR)1 containing SYDMT (SEQ ID NO:6); HC-CDR2 containing IIX1X2SGX3TYYASWAKG (SEQ ID NO:79), where X1 is N or S, X2 is G, N or S, and X3 is N or S; and HC-CDR3 containing GILVYADYGDHNL (SEQ ID NO:17); and a light chain variable structural domain (V L ), the V LIt includes: a light chain complementarity determination region (LC-CDR)1, which includes QASEDIYTNLA (SEQ ID NO:22); LC-CDR2, which includes AASTLAS (SEQ ID NO:29); and LC-CDR3, which includes LGVYTYISAX1GA (SEQ ID NO:81), wherein X1 is D or E.

[0032] In some embodiments, an isolated anti-GDF15 antibody is provided, which comprises V H The V H Contains: HC-CDR1, comprising the amino acid sequence shown in SEQ ID NO:6 or a variant thereof, the variant comprising substitutions of up to about 3 amino acids; HC-CDR2, comprising the amino acid sequence shown in any of SEQ ID NOs:12, 75-78 or a variant thereof, the variant comprising substitutions of up to about 3 amino acids; and HC-CDR3, comprising the amino acid sequence shown in SEQ ID NO:17 or a variant thereof, the variant comprising substitutions of up to about 3 amino acids; and V L The V L It comprises: LC-CDR1, which comprises the amino acid sequence shown in SEQ ID NO:22 or a variant thereof, the variant comprising 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, the variant comprising 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, the variant comprising 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 V containing any of the amino acid sequences shown in SEQ ID NOs:51,82-89 H Includes HC-CDR1, HC-CDR2, and HC-CDR3; and V L The V L V containing any of the amino acid sequences shown in SEQ ID NOs:63,90-91 L It includes LC-CDR1, LC-CDR2 and LC-CDR3.

[0034] In some embodiments, an isolated anti-GDF15 antibody is provided, comprising: (i) V H It contains V as shown in the amino acid sequence SEQ ID NO:51. H Includes HC-CDR1, HC-CDR2, and HC-CDR3; and VL It contains V as shown in the amino acid sequence SEQ ID NO:63. L Includes LC-CDR1, LC-CDR2 and LC-CDR3; (ii)V H It contains V as shown in the amino acid sequence SEQ ID NO:82. H Includes HC-CDR1, HC-CDR2, and HC-CDR3; and V L It contains V as shown in the amino acid sequence SEQ ID NO:90. L Includes LC-CDR1, LC-CDR2 and LC-CDR3; (iii)V H It contains V as shown in the amino acid sequence SEQ ID NO:83. H Includes HC-CDR1, HC-CDR2, and HC-CDR3; and V L It contains V as shown in the amino acid sequence SEQ ID NO:90. L Includes LC-CDR1, LC-CDR2 and LC-CDR3; (iv)V H It contains V as shown in the amino acid sequence SEQ ID NO:84. H Includes HC-CDR1, HC-CDR2, and HC-CDR3; and V L It contains V as shown in the amino acid sequence SEQ ID NO:90. L Includes LC-CDR1, LC-CDR2 and LC-CDR3; (v)V H It contains V as shown in the amino acid sequence SEQ ID NO:85. H Includes HC-CDR1, HC-CDR2, and HC-CDR3; and V L It contains V as shown in the amino acid sequence SEQ ID NO:90. L Includes LC-CDR1, LC-CDR2 and LC-CDR3; (vi)V H It contains V as shown in the amino acid sequence SEQ ID NO:86. H Includes HC-CDR1, HC-CDR2, and HC-CDR3; and V L It contains V as shown in the amino acid sequence SEQ ID NO:91. L Includes LC-CDR1, LC-CDR2 and LC-CDR3; (vii)V H It contains V as shown in the amino acid sequence SEQ ID NO:87. H Includes HC-CDR1, HC-CDR2, and HC-CDR3; and V LIt contains V as shown in the amino acid sequence SEQ ID NO:91. L Includes LC-CDR1, LC-CDR2 and LC-CDR3; (viii)V H It contains V as shown in the amino acid sequence SEQ ID NO:88. H Includes HC-CDR1, HC-CDR2, and HC-CDR3; and V L It contains V as shown in the amino acid sequence SEQ ID NO:91. L Includes LC-CDR1, LC-CDR2, and LC-CDR3; (ix)V H It contains V as shown in the amino acid sequence SEQ ID NO:89. H Includes HC-CDR1, HC-CDR2, and HC-CDR3; and V L It contains V as shown in the amino acid sequence SEQ ID NO:91. L It includes 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 Contains: HC-CDR1, which contains the amino acid sequence SEQ ID NO:6; HC-CDR2, which contains the amino acid sequence SEQ ID NO:12; and HC-CDR3, which contains the amino acid sequence SEQ ID NO:17, or the V H Variants of which contain up to about 5 amino acid substitutions in their HC-CDRs; and V L The V L Contains: LC-CDR1, which contains the amino acid sequence SEQ ID NO:22; LC-CDR2, which contains the amino acid sequence SEQ ID NO:29; and LC-CDR3, which contains the amino acid sequence SEQ ID NO:34, or the V L (ii) V variants, whose LC-CDRs contain substitutions of up to about 5 amino acids; H The V H Contains: HC-CDR1, which contains the amino acid sequence SEQ ID NO:6; HC-CDR2, which contains the amino acid sequence SEQ ID NO:75; and HC-CDR3, which contains the amino acid sequence SEQ ID NO:17, or the V H Variants of which contain up to about 5 amino acid substitutions in their HC-CDRs; and V L The V LContains: LC-CDR1, which contains the amino acid sequence SEQ ID NO:22; LC-CDR2, which contains the amino acid sequence SEQ ID NO:29; and LC-CDR3, which contains the amino acid sequence SEQ ID NO:80, or the V L (iii) V variants, whose LC-CDRs contain substitutions of up to about 5 amino acids; H The V H Contains: HC-CDR1, which contains the amino acid sequence SEQ ID NO:6; HC-CDR2, which contains the amino acid sequence SEQ ID NO:76; and HC-CDR3, which contains the amino acid sequence SEQ ID NO:17, or the V H Variants of which contain up to about 5 amino acid substitutions in their HC-CDRs; and V L The V L Contains: LC-CDR1, which contains the amino acid sequence SEQ ID NO:22; LC-CDR2, which contains the amino acid sequence SEQ ID NO:29; and LC-CDR3, which contains the amino acid sequence SEQ ID NO:80, or the V L (iv) V variants, whose LC-CDRs contain substitutions of up to about 5 amino acids; H The V H Contains: HC-CDR1, which contains the amino acid sequence SEQ ID NO:6; HC-CDR2, which contains the amino acid sequence SEQ ID NO:77; and HC-CDR3, which contains the amino acid sequence SEQ ID NO:17, or the V H Variants of which contain up to about 5 amino acid substitutions in their HC-CDRs; and V L The V L Contains: LC-CDR1, which contains the amino acid sequence SEQ ID NO:22; LC-CDR2, which contains the amino acid sequence SEQ ID NO:29; and LC-CDR3, which contains the amino acid sequence SEQ ID NO:80, or the V L The variants, whose LC-CDRs contain substitutions of up to about 5 amino acids; (v)V H The V H Contains: HC-CDR1, which contains the amino acid sequence SEQ ID NO:6; HC-CDR2, which contains the amino acid sequence SEQ ID NO:78; and HC-CDR3, which contains the amino acid sequence SEQ ID NO:17, or the V H Variants of which contain up to about 5 amino acid substitutions in their HC-CDRs; and V L The VL Contains: LC-CDR1, which contains the amino acid sequence SEQ ID NO:22; LC-CDR2, which contains the amino acid sequence SEQ ID NO:29; and LC-CDR3, which contains the amino acid sequence SEQ ID NO:80, or the V L Variants of which contain up to about 5 amino acid substitutions in their LC-CDRs.

[0036] In some embodiments, any of the isolated anti-GDF15 antibodies described above comprises: V H It comprises any of the amino acid sequences shown in SEQ ID NOs:51,82-89 or variants thereof, said variants having at least about 80% sequence identity with any of the amino acid sequences shown in SEQ ID NOs:51,82-89; and V L It comprises any of the amino acid sequences shown in SEQ ID NOs:63,90-91 or variants thereof, wherein the variants have at least about 80% sequence identity with any of the amino acid sequences shown in SEQ ID NOs:63,90-91.

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

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

[0039] In some embodiments, an isolated anti-GDF15 antibody is provided that competes with any of the isolated anti-GDF15 antibodies described above 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 isolated anti-GDF15 antibodies described above.

[0040] In some embodiments, the isolated anti-GDF15 antibody, as 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 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, the nucleic acid molecule encoding any of the anti-GDF15 antibodies described above. In some embodiments, a vector is provided, the vector comprising any of the nucleic acid molecules described above. In some embodiments, a host cell is provided, the host cell 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 above-described host cells under conditions that enable efficient expression of 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 desired individual disease or condition is provided, comprising administering an effective amount of any of the anti-GDF15 antibodies described above to the individual. In some embodiments, the use of any of the anti-GDF15 antibodies described above in the preparation of a pharmaceutical composition for treating a desired individual disease or condition is provided. In some embodiments, the 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 and includes cancer, cachexia, 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, endometrial cancer, testicular cancer, thyroid cancer, kidney cancer, gallbladder cancer, multiple myeloma, nasopharyngeal carcinoma, laryngeal cancer, pharyngeal cancer, esophageal cancer, etc.), cachexia, cachexia-related weight loss, anorexia nervosa, and metabolic diseases (such as fat and energy metabolism imbalance, appetite regulation, and weight regulation).

[0043] It also provides pharmaceutical compositions, kits, and manufactured products containing any of the anti-GDF15 antibodies described above. Attached Figure Description

[0044] Figure 1 The figure shows the effect of the exemplary lead anti-GDF15 antibody GDF-R37-rabIg1 on changes in mouse body weight in the HT1080 tumor cachexia animal model.

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

[0046] Figures 3A-3C The figure shows the neutralization effect of the humanized anti-GDF15 antibody derived from the lead antibody GDF-R37-rabIg1 on the binding of GDF15 and GFRAL, as analyzed by ELISA.

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

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

[0049] Detailed description of this application

[0050] This application provides an anti-GDF15 antibody molecule. Through screening a constructed 293T cell display library, antibody humanization, affinity maturation, and a combination of appropriately designed biochemical and biological experiments, a highly efficient 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 antibody in this application is even more effective than or comparable to Hu01G06-127 in various biological experiments.

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

[0052] On the other hand, this application provides an anti-GDF15 antibody, said anti-GDF15 antibody comprising: a heavy chain variable domain (V H ), the V H It includes: a heavy chain complementarity determination region (HC-CDR)1 containing X1YYMX2 (SEQ ID NO:35), where X1 is D or N and X2 is S or T; HC-CDR2 containing MISFSGTTX1ATWAKG (SEQ ID NO:36), where X1 is H or Y; and HC-CDR3 containing VVYAGWTYPLGI (SEQ ID NO:13); and a light chain variable structural domain (V L ), the V L It includes: a light chain complementarity determination region (LC-CDR)1, which contains QASQSISSVLS (SEQ ID NO:18); LC-CDR2, which contains EASX1X2AS (SEQ ID NO:37), wherein X1 is I or T and X2 is L or Q; and LC-CDR3, which contains QANYDVYNYGNP (SEQ ID NO:30).

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

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

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

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

[0057] It also provides nucleic acids encoding anti-GDF15 antibodies, compositions containing anti-GDF15 antibodies, and methods for preparing and using anti-GDF15 antibodies.

[0058] definition

[0059] As described herein, “treatment” or “treating” is a method of obtaining a beneficial or desired outcome, including clinical outcomes. For the purposes of this application, the beneficial or desired clinical outcome includes, but is not limited to, one or more of the following: relief of one or more symptoms caused by a disease, reduction of disease severity, stabilization of the disease (e.g., prevention or delay of disease exacerbation), prevention or delay of disease spread (e.g., metastasis), prevention or delay of disease recurrence, delay or slowing of disease progression, improvement of disease status, relief of the disease (partial or complete), reduction of the dosage of one or more other medications required to treat the disease, delay of disease progression, improvement or enhancement of quality of life, weight gain, and / or prolonged survival. Simultaneously, “treatment” also includes a reduction in disease pathological outcomes (e.g., tumor volume in the case of cancer). The methods of this application consider any one or more aspects of these treatments.

[0060] The term "antibody" includes both full-length antibodies and their antigen-binding fragments. Full-length antibodies consist of two heavy chains and two light chains. Variable regions in both 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; 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 according to the Kabat, Chothia, or Al-Lazikani conventions (Al-Lazikani 1997; Chothia 1985; Chothia 1987; Chothia 1989; Kabat 1987; Kabat 1991). Three CDR regions of the heavy or light chain are inserted between flanking segments called framework regions (FRs), which are more conserved than the CDR regions and form a scaffold supporting the hypervariable loop. The constant regions of the heavy and light chains do not participate in antigen binding but exhibit a variety of effector functions. Antibodies are classified based on the amino acid sequence of their heavy chain constant regions. The five main classes or isotypes of antibodies are IgA, IgD, IgE, IgG, and IgM, characterized by having α, δ, ε, γ, and μ-type heavy chains, respectively. Several major antibody classes are subclassed, 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).

[0061] As described herein, the term "antigen-binding fragment" includes antibody fragments, such as diabody, Fab, Fab', F(ab')2, Fv fragments, disulfide-stabilized Fv fragments (dsFv), (dsFv)2, bispecific dsFv (dsFv-dsFv'), disulfide-stabilized diabody (ds-diabody), single-chain Fv (scFv), scFv dimers (bivalent diabody), multispecific antibodies, single-domain antibodies, nanobodies, domain antibodies, divalent domain antibodies, or any other antibody fragment capable of binding to an antigen but not containing a complete antibody structure. The antigen-binding fragment is capable of binding the same antigen to a parent antibody or a parent antibody fragment (such as a parental scFv). The antigen-binding fragment also includes fusion proteins comprising the antibody fragments described above. In some embodiments, the antigen-binding fragment may include one or more CDRs from a specific human antibody that have been grafted into a frame region from one or more different human antibodies.

[0062] As described herein, the term "epitope" refers to a specific set of atoms or amino acids on an antigen that an antibody or antibody portion binds to. If two antibodies or antibody portions exhibit competitive binding to an antigen, they may bind to the same epitope on the antigen.

[0063] As used herein, when the first antibody inhibits the 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%) at an equimolar concentration, the first antibody “competitively” binds to the GDF15 target with the second antibody, and vice versa. PCT Publication WO 03 / 48731 describes a high-throughput antibody “epitope classification” method based on cross-competition.

[0064] As described herein, the terms "specifically bind," "specifically recognize," or "specific to" refer to measurable and reproducible interactions, such as antibody binding to a target that confirms the presence of that target in a heterogeneous group of molecules, including biomolecules. For example, an antibody's ability to specifically recognize a target (which may be an epitope) means that the antibody binds to that target with higher affinity, stronger binding, and / or more persistent binding compared to binding to other targets. In some embodiments, an antibody that specifically recognizes an antigen reacts with one or more antigenic determinants of the antigen with a binding affinity at least 10 times greater than its binding affinity to other targets.

[0065] As described herein, an “isolated” anti-GDF15 antibody is an anti-GDF15 antibody that (1) is not related to a naturally occurring protein, (2) does not contain other proteins of the same origin, (3) is expressed by cells of a different species, or (4) does not exist in nature.

[0066] As described herein, the term “isolated nucleic acid” refers to a nucleic acid or combination thereof of genomic, cDNA, or synthetic origin. Depending on its origin, “isolated nucleic acid” means that it is (1) unrelated to all or part of the polynucleotides in “isolated nucleic acids” found in nature, (2) operablely ligable to polynucleotides not naturally associated with it, or (3) not present in nature as part of a longer sequence.

[0067] As used herein, the term “CDR” or “complementarity-determining region” refers to a discontinuous antigen-binding site 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 have been described in al., Dev. Comp. Immunol., 27:55-77 (2003); and Honegger and Plückthun, J. Mol. Biol., 309:657-670 (2001), where these definitions include overlaps or subsets of amino acid residues when compared with each other. However, any definition used to indicate a CDR of an antibody or transplanted antibody or its variants is included within the scope of the terminology defined and used herein. Table 1 lists the positions of the amino acid residues included in the CDRs defined by the aforementioned references for comparison. Algorithms and interfaces for CDR prediction are known in the art, including, for example, those described in 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 entire contents of the references cited in this paragraph are incorporated herein by reference for the purposes of this application and one or more claims that may be included herein.

[0068] Table 1: CDR Definition

[0069] <![CDATA[V H CDR1]]> 31-35 26-32 30-35 27-38 25-40 <![CDATA[V H CDR2]]> 50-65 53-55 47-58 56-65 58-77 <![CDATA[V H CDR3]]> 95-102 96-101 93-101 105-117 109-137 <![CDATA[V L CDR1]]> 24-34 26-32 30-36 27-38 25-40 <![CDATA[V L CDR2]]> 50-56 50-52 46-55 56-65 58-77 <![CDATA[V L CDR3]]> 89-97 91-96 89-96 105-117 109-137

[0070] 1 The amino acid residue numbering follows the nomenclature method described in Kabat et al. above.

[0071] 2 The amino acid residue numbering follows the nomenclature method described in Chothia et al. above.

[0072] 3 The amino acid residue numbering follows the nomenclature method described in MacCallum et al. above.

[0073] 4 The amino acid residue numbering follows the nomenclature method described in Lefranc et al. above.

[0074] 5 The amino acid residue numbering follows the nomenclature method described in 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 species or subclass, while the remainder of the chain is identical or homologous to the corresponding sequence in an antibody from another genus or belonging to another antibody species or subclass, as well as fragments of such antibodies, provided they possess the biological activity described in this 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 containing 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 and non-covalently linked. The folding of these two domains derives six hypervariable rings (three in the light chain and three in the heavy chain), which provide the antibody with amino acid residues for binding to the antigen and confer the antibody's specificity for antigen binding. However, even a single variable domain (or half of the Fv fragment, containing only three antigen-specific CDRs) can recognize and bind to antigens, although its affinity is lower than that of the complete binding site.

[0077] "Single-chain Fv", also abbreviated as "sFv" or "scFv", is a type of Fv containing V molecules linked together to form a single polypeptide chain. H and V L Antibody fragments of antibody domains. In some embodiments, the scFv polypeptide further includes V H and V LThe linker polypeptide between the domains allows 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 Small antibody fragments are prepared by constructing scFv fragments (see above) using short linkers (e.g., 5–10 residues) between domains. This allows the variable domains to pair between chains rather than within chains, resulting in a bivalent fragment, i.e., a fragment with two antigen-binding sites. Bispecific double-chain antibodies are heterodimers of two “crossed” scFv fragments, where the V0 of the two antibodies... H and V L The domains are located on different polypeptide chains. Double-chain antibodies are fully described in EP404,097; WO 93 / 11161; Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993).

[0079] The “humanized” form of non-human (e.g., rodent) antibodies is a chimeric antibody, which includes a minimal sequence derived from the non-human antibody. In most cases, humanized antibodies are human immunoglobulins (receptor antibodies), where the hypervariable region (HVR) residues of the receptor antibody are replaced by hypervariable region residues from non-human species such as mice, rats, rabbits, or non-human mammals that possess desirable antibody specificity, affinity, and performance (donor antibody). In some cases, residues in the human immunoglobulin framework region are replaced by corresponding non-human residues. Additionally, humanized antibodies may include residues not present in either the receptor or donor antibody. These modifications can further improve antibody performance. Typically, humanized antibodies contain substantially all, at least one, and usually two variable domains, where 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. Humanized antibodies may also optionally include at least a portion of the immunoglobulin constant region (Fc), typically the constant region of a human immunoglobulin. For details, please refer to 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 "percentage of amino acid sequence identity (%)" or "homology" of the peptide and antibody sequences identified in this paper is defined as the percentage of identical amino acid residues in a candidate sequence compared to a peptide sequence, assuming that conserved substitutions are part of sequence identity. The percentage of amino acid sequence identity can be determined using various alignment methods within the scope of the art, such as publicly available computer software like BLAST, BLAST-2, ALIGN, Megalign (DNASTAR), or MUSCLE software. Those skilled in the art can determine suitable parameters for measuring alignment, including any algorithm required to maximize alignment across the full length of the compared sequences. However, for the purposes of this paper, the percentage of amino acid sequence identity values ​​were 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 receptors that bind to the Fc region of antibodies. In some embodiments, the FcR described in this application is an FcR that binds to IgG antibodies (a type of γ receptor), including receptors of the FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants and alternative splicing forms of these receptors. FcγRII receptors include FcγRIIA ("activating receptor") and FcγRIIB ("inhibiting receptor"), which have similar amino acid sequences and differ primarily in their cytoplasmic domains. The cytoplasmic domain of the activating receptor FcγRIIA contains an immunoreceptor tyrosine activation motif (ITAM). The cytoplasmic domain of the inhibitory receptor FcγRIIB contains an immunoreceptor tyrosine inhibitory motif (ITIM) (see M.in.). Annu.Rev.Immunol.15:203-234 (1997)). The term also includes allotypes, such as 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). In this application, the term FcR covers other types of FcRs, including those to be identified in the future. The term FcR also includes the neonatal receptor FcRn, which is responsible for transferring 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), consisting 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 immunoglobulin IgGs from the mother to the newborn and in regulating serum IgG levels. As a rescue receptor, FcRn can bind and transport endocytotic IgG in its intact form both intracellularly and intercellularly, protecting it from the default degradation pathway.

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

[0084] The "hinge region" is typically defined as extending from Glu at position 216 to Pro at position 230 of human IgG1 (Burton, Molec. Immunol. 22:161-206 (1985)). By placing the first and last cysteine ​​residues that form the inter-heavy chain disulfide bond at the same positions as IgG1, it is possible to align the hinge regions of other IgG isotypes with the IgG1 sequence.

[0085] The "CH2 domain" of the human IgG Fc region typically extends from amino acid 231 to amino acid 340. The unique feature of the CH2 domain is that it does not pair tightly with another region; instead, two N-terminal branched sugar chains are inserted between the two CH2 domains of the intact native IgG molecule. It is speculated that the sugars may act as a substitute for domain-to-domain pairing, helping to maintain the stability of the CH2 domain. (Burton, Molec. Immunol. 22:161-206 (1985)).

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

[0087] "Functional Fc fragments" possess the "effective functions" inherent in the natural Fc region sequence. Exemplary "effective functions" include C1q binding; complement-dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; and downregulation of cell surface receptors (such as B cell receptors; BCR). These effector functions typically require the Fc region to bind to a binding domain (such as the antibody variable region) and can be evaluated using a variety of experimental methods known in the art.

[0088] Antibodies with IgG Fc variants exhibiting "altered" FcR binding affinity or ADCC activity show enhanced or weakened FcR binding and / or ADCC activity compared to the parent peptide or peptides containing the native Fc sequence. Fc variants exhibiting "enhanced binding" to FcRs have higher binding affinity (e.g., lower apparent Kd or IC50) to at least one FcR compared to the parent peptide or peptides containing the native IgG Fc sequence. 50(Value). In some embodiments, the binding affinity is enhanced by 3 times compared to the parent peptide, for example, 5, 10, 25, 50, 60, 100, 150, 200, or even up to 500 times, or the binding affinity is increased by 25% to 1000%. Fc variants exhibit “reduced binding” to FcRs, having a lower affinity for at least one FcR compared to the parent peptide (e.g., higher apparent Kd or IC). 50 (Value). Compared with the parent peptide, its binding ability is reduced by 40% or more.

[0089] Antibody-dependent cell-mediated cytotoxicity (ADCC) is a form of cytotoxicity in which secreted Ig binds to Fc receptors (FcRs) present on certain cytotoxic cells, such as natural killer (NK) cells, neutrophils, and macrophages. This allows these cytotoxic effector cells to specifically bind to target cells carrying antigens and subsequently kill the target cells using cytotoxins. Antibodies "arm" the cytotoxic cells and are essential for this killing. Among the main cell types mediating 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). The ADCC activity of target molecules can be assessed by in vitro ADCC experiments, described in U.S. Patent Nos. 5,500,362 or 5,821,337. Effector cells suitable for such experiments include peripheral blood mononuclear cells (PBMCs) and natural killer cells (NK cells). Alternatively, or additionally, the ADCC activity of the target molecule can also be assessed in vivo, as described, for example, in animal models disclosed in Clynes et al. PNAS (USA) 95:652-656 (1998).

[0090] Peptides containing Fc region variants exhibit "enhanced ADCC activity" or are more effective at mediating ADCC effects in the presence of human effector cells compared to peptides containing wild-type IgG Fc or parental peptides. These peptides, when experimentally present in substantially the same quantity as those containing wild-type IgG Fc (or parental peptides), mediate ADCC more effectively both in vitro and in vivo. Such variants are typically identified using any in vitro ADCC assay known in the art, such as experiments or methods for identifying ADCC activity, for example in animal models. In some embodiments, such variants mediate ADCC with a 5 to 100-fold, for example, 25 to 50-fold, efficiency improvement compared to wild-type Fc (or parental peptide).

[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 (C1q) to an antibody (a subclass with a suitable structure) that binds to a homologous antigen. To assess complement activation, CDC assays can be performed, as described in Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996). Peptide variants with altered Fc region amino acid sequences and increased or decreased C1q binding capacity are described in U.S. Patent Nos. 6,194,551B1 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 stated, a "nucleotide sequence encoding an amino acid sequence" includes all nucleotide sequences that are degenerate forms of each other and encode the same amino acid sequence. Nucleotide sequences encoding proteins or RNA may also include introns; for example, nucleotide sequences encoding proteins may contain introns in certain forms.

[0093] The term "operationally ligated" refers to a functional link between a regulatory sequence and a heterologous nucleotide sequence, thereby enabling the latter to be expressed. For example, the first and second nucleotide sequences are operably ligated when they are in a functional relationship. Similarly, if a promoter affects the transcription or expression of a coding sequence, the promoter and coding sequence are operably ligated. Typically, operably ligated DNA sequences are contiguous, and, if necessary, two protein-coding regions can be ligated within the same reading frame.

[0094] "Homology" refers to the sequence similarity or identity between two polypeptides or two nucleic acid molecules. If the same position in two compared sequences is the same base or amino acid monomer subunit, for example, if both DNA molecules have adenine at the same position, then the two DNA molecules are homologous at that position. The percentage of homology between two sequences is a function calculated by multiplying the number of matching or homologous positions in the two sequences to the total number of positions, and then multiplying by 100. For example, if 6 out of 10 positions in two sequences are matching or homologous, then the two sequences are 60% homologous. For instance, the DNA sequences ATTGCC and TATGGC have 50% homology. Generally, when comparing two sequences, the goal is to obtain the maximum homology.

[0095] The “effective amount” of the anti-GDF15 antibody or composition disclosed herein refers to an amount sufficient to achieve a specific purpose. The “effective amount” can be determined empirically and by known methods associated with the stated purpose.

[0096] The term "therapeutic effective dose" refers to the dosage of the anti-GDF15 antibody or its composition disclosed herein that is effective in treating an individual's disease or symptoms. For example, in the case of cancer, a therapeutic effective dose of the anti-GDF15 antibody or its composition means the ability to reduce the number of cancer cells; reduce the size or weight of the tumor; inhibit (i.e., to some extent slow down or preferably stop) the invasion of tumor cells into surrounding organs; inhibit (i.e., to some extent slow down or preferably stop) tumor metastasis; inhibit tumor growth to some extent; and / or alleviate one or more symptoms associated with cancer to some extent. For example, in the case of cancer-related cachexia, a therapeutic effective dose of the anti-GDF15 antibody or its composition means the ability to inhibit (i.e., to some extent slow down or preferably stop) the loss of muscle mass; inhibit (i.e., to some extent slow down or preferably stop) the loss of fat mass; restore involuntary weight loss to some extent; inhibit organ mass loss to some extent; and / or alleviate one or more symptoms of the underlying disease associated with cachexia to some extent. The anti-GDF15 antibody or its composition disclosed herein can, to some extent, prevent and / or kill existing tumor cells; it can be cytoseptic or cytotoxic. In some embodiments, a therapeutic effective dose refers to the dosage that prolongs the patient's survival. In some embodiments, a therapeutically effective dose refers to a dose that improves a patient’s progression-free survival.

[0097] As used herein, "pharmaceuticalally acceptable" or "pharmacologically compatible" means a material that has no biological activity or other undesirable properties, such as the ability to be incorporated into a pharmaceutical composition given to a patient without causing significant adverse biological reactions, or that does not interact harmfully with any other components contained in the composition. Pharmaceutically acceptable carriers or excipients preferably meet the required standards for toxicological or manufacturing testing and / or are included in the inactive ingredient guidelines prepared by the U.S. Food and Drug Administration.

[0098] The embodiments of this application described herein should be understood to include embodiments that are “composed of” and / or “substantially composed of”.

[0099] In this article, “about” is used to refer to a numerical value or parameter, including (and descriptions) variations for that value or parameter itself. For example, a description involving “about X” includes a description of “X”.

[0100] As used in this article, mentioning "not" a value or parameter usually means and describes something other than a certain value or parameter. For example, "This method cannot be used to treat type X cancer" means that this method is generally used to treat other types of cancer besides type X cancer.

[0101] Unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the” used herein and in the claims include plural objects.

[0102] Anti-GDF15 antibody

[0103] On one hand, this application provides anti-GDF15 antibodies that specifically bind to GDF15 in humans, rhesus monkeys, and / or mice. These 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. On the other hand, this application provides isolated antibodies that bind to GDF15. Anticipated 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 its antigen-binding fragment that specifically binds to GDF15. In some embodiments, the anti-GDF15 antibody is 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's affinity for GDF15 is at least 10 times greater than its affinity for binding to non-target antibodies (including, for example, 10, 10). 2 10 3 10 4 10 5 10 6 , or 10 7 (Multiple times). In some embodiments, non-target refers to 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 (RIA). Kd value can be determined by methods known in the art, such as surface plasmon resonance (SPR) technology or biolayer interference (BLI) technology.

[0104] While this document discusses anti-GDF15 antibodies containing human sequences (e.g., human heavy and light chain variable domains containing human CDR sequences), non-human anti-GDF15 antibodies are also considered. In some embodiments, a non-human anti-GDF15 antibody comprises the human CDR sequence and non-human frame region sequence of the anti-GDF15 antibody described herein. In some embodiments, the non-human frame region sequence comprises 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, buffalo), deer, sheep, goats, chickens, cats, dogs, ferrets, primates (e.g., apes, macaques), etc. In some embodiments, a non-human anti-GDF15 antibody comprises an anti-GDF15 antibody generated by transplanting one or more human CDR sequences described herein into a non-human frame region (e.g., a mouse or chicken frame region sequence).

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

[0106] In some embodiments, the anti-GDF15 antibody described herein specifically recognizes an epitope in human GDF15. In some embodiments, the anti-GDF15 antibody cross-reacts with GDF15 from species other than humans. In some embodiments, the anti-GDF15 antibody is completely specific to human GDF15 and does 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 the GDF15 protein (or a fragment thereof). In some embodiments, the allelic variant has up to 30 amino acid substitutions (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or 30) compared to the naturally occurring GDF15 protein (or a fragment thereof) (e.g., conserved substitutions). In some embodiments, the anti-GDF15 antibody does not cross-react with any allelic variant of the 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 a fragment thereof) is human GDF15, and the interspecies variant of the GDF15 protein (or a fragment thereof) is a variant found in rhesus monkeys. In some embodiments, the anti-GDF15 antibody does not cross-react with any interspecies variant of the GDF15 protein.

[0109] In some embodiments, any anti-GDF15 antibody as described herein comprises an antibody heavy chain constant region and an antibody light chain constant region. In some embodiments, the anti-GDF15 antibody comprises an IgG1 type heavy chain constant region. In some embodiments, the anti-GDF15 antibody comprises an IgG2 type heavy chain constant region. In some embodiments, the anti-GDF15 antibody comprises an IgG3 type heavy chain constant region. In some embodiments, the anti-GDF15 antibody comprises an IgG4 type heavy chain constant region. In some embodiments, the heavy chain constant region comprises (including a sequence consisting of or substantially consisting of) the amino acid sequence SEQ ID NO:64. In some embodiments, the heavy chain constant region comprises (including a sequence consisting of or substantially consisting of) the amino acid sequence SEQ ID NO:65. In some embodiments, the anti-GDF15 antibody comprises a κ light chain constant region. In some embodiments, the light chain constant region comprises (including a sequence consisting of or substantially consisting of) the amino acid sequence SEQ ID NO:66. In some embodiments, the anti-GDF15 antibody comprises a λ light chain constant region. In some embodiments, the light chain constant region comprises (including a sequence consisting of or substantially consisting of) the amino acid sequence 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 It includes: a heavy chain complementarity determination region (HC-CDR)1 containing X1YYMX2 (SEQ ID NO:35), where X1 is D or N and X2 is S or T; HC-CDR2 containing MISFSGTTX1ATWAKG (SEQ ID NO:36), where X1 is H or Y; and HC-CDR3 containing VVYAGWTYPLGI (SEQ ID NO:13); and a light chain variable structural domain (V L ), the V LIt includes: a light chain complementarity determination region (LC-CDR)1, which contains QASQSISSVLS (SEQ ID NO:18); LC-CDR2, which contains EASX1X2AS (SEQ ID NO:37), wherein X1 is I or T and X2 is L or Q; and LC-CDR3, which contains QANYDVYNYGNP (SEQ ID NO:30).

[0111] In some embodiments, the anti-GDF15 antibody comprises V H The V H It comprises: HC-CDR1, which comprises any of the amino acid sequences shown in SEQ ID NOs:1-2 or variants thereof, the variants comprising substitutions of up to about 3 (e.g., 1, 2 or 3) amino acids; HC-CDR2, which comprises any of the amino acid sequences shown in SEQ ID NOs:7-8 or variants thereof, the variants comprising substitutions of up to about 3 (e.g., 1, 2 or 3) amino acids; and HC-CDR3, which comprises the amino acid sequence shown in SEQ ID NO:13 or variants thereof, the variants comprising substitutions 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 includes: HC-CDR1, which contains any of the amino acid sequences shown in SEQ ID NOs:1-2; HC-CDR2, which contains any of the amino acid sequences shown in SEQ ID NOs:7-8; and HC-CDR3, which contains the amino acid sequence shown in SEQ ID NO:13.

[0113] 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:18 or a variant thereof, the variant comprising substitutions of up to about 3 amino acids (e.g., 1, 2 or 3); LC-CDR2, which comprises the amino acid sequence shown in any of SEQ ID NOs:23-25 ​​or a variant thereof, the variant comprising substitutions of up to about 3 amino acids (e.g., 1, 2 or 3); and LC-CDR3, which comprises the amino acid sequence shown in SEQ ID NO:30 or a variant thereof, the variant comprising substitutions of up to about 3 amino acids (e.g., 1, 2 or 3).

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

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

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

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

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

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

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

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

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

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

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

[0125] In some embodiments, the anti-GDF15 antibody comprises V H The V H Contains: HC-CDR1, which contains the amino acid sequence SEQ ID NO:1; HC-CDR2, which contains the amino acid sequence SEQ ID NO:8; HC-CDR3, which contains the amino acid sequence SEQ ID NO:13; or the V H Variants of which contain up to about 5 amino acid substitutions in their HC-CDRs; and V L The V L Contains: LC-CDR1, which contains the amino acid sequence SEQ ID NO:18; LC-CDR2, which contains the amino acid sequence SEQ ID NO:25; LC-CDR3, which contains the amino acid sequence SEQ ID NO:30; or the V LVariants of which contain up to about 5 amino acid substitutions in their LC-CDRs.

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

[0127] In some embodiments, the anti-GDF15 antibody comprises V H The V H V containing any of the amino acid sequences shown in SEQ ID NOs:38-47 H Includes HC-CDR1, HC-CDR2, and HC-CDR3; and V L The V L V containing any of the amino acid sequences shown in SEQ ID NOs:52-59 L It includes LC-CDR1, LC-CDR2 and LC-CDR3.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0151] In some embodiments, the anti-GDF15 antibody comprises: V H The V H Contains any of the amino acid sequences shown in SEQ ID NOs:38-47 or variants thereof, wherein the variants have at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with any of the amino acid sequences shown in SEQ ID NOs:38-47; and V L The V L The antibody comprises any of the amino acid sequences shown in SEQ ID NOs:52-59 or variants thereof, wherein the variants have at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with any of the amino acid sequences shown in SEQ ID NOs:52-59. In some embodiments, the anti-GDF15 antibody comprises V H The V H Contains any of the amino acid sequences shown in SEQ ID NOs:38-47, and V L The V L It contains any of the amino acid sequences shown in SEQ ID NOs:52-59.

[0152] In some embodiments, the anti-GDF15 antibody comprises: V H The V HContains the amino acid sequence SEQ ID NO:38 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence SEQ ID NO:38; and V L The V L The antibody comprises the amino acid sequence SEQ ID NO:52 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence SEQ ID NO:52. In some embodiments, the anti-GDF15 antibody comprises V H The V H Contains the amino acid sequence SEQ ID NO:38, and V L The V L It contains the amino acid sequence SEQ ID NO:52.

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

[0154] In some embodiments, the anti-GDF15 antibody comprises: V H The V H Contains the amino acid sequence SEQ ID NO:40 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence SEQ ID NO:40; and V L The V LThe antibody comprises the amino acid sequence SEQ ID NO:53 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence SEQ ID NO:53. In some embodiments, the anti-GDF15 antibody comprises V H The V H Contains the amino acid sequence SEQ ID NO:40, and V L The V L It contains the amino acid sequence SEQ ID NO:53.

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

[0156] In some embodiments, the anti-GDF15 antibody comprises: V H The V H Contains the amino acid sequence SEQ ID NO:42 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence SEQ ID NO:42; and V L The V L The antibody comprises the amino acid sequence SEQ ID NO:53 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence SEQ ID NO:53. In some embodiments, the anti-GDF15 antibody comprises V H The V HContains the amino acid sequence SEQ ID NO:42, and V L The V L It contains the amino acid sequence SEQ ID NO:53.

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

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

[0159] In some embodiments, the anti-GDF15 antibody comprises: V H The VH Contains the amino acid sequence SEQ ID NO:39 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence SEQ ID NO:39; and V L The V L The antibody comprises the amino acid sequence SEQ ID NO:54 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence SEQ ID NO:54. In some embodiments, the anti-GDF15 antibody comprises V H The V H Contains the amino acid sequence SEQ ID NO:39, and V L The V L It contains the amino acid sequence SEQ ID NO:54.

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

[0161] In some embodiments, the anti-GDF15 antibody comprises: V H The V H Contains the amino acid sequence SEQ ID NO:41 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence SEQ ID NO:41; and V L The V LThe antibody comprises the amino acid sequence SEQ ID NO:54 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence SEQ ID NO:54. In some embodiments, the anti-GDF15 antibody comprises V H The V H Contains the amino acid sequence SEQ ID NO:41, and V L The V L It contains the amino acid sequence SEQ ID NO:54.

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

[0163] In some embodiments, the anti-GDF15 antibody comprises: V H The V H Contains the amino acid sequence SEQ ID NO:43 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence SEQ ID NO:43; and V L The V L The antibody comprises the amino acid sequence SEQ ID NO:54 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence SEQ ID NO:54. In some embodiments, the anti-GDF15 antibody comprises V H The V HContains the amino acid sequence SEQ ID NO:43, and V L The V L It contains the amino acid sequence SEQ ID NO:54.

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

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

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

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

[0168] In some embodiments, the anti-GDF15 antibody comprises: V H The V H Contains the amino acid sequence SEQ ID NO:42 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence SEQ ID NO:42; and V L The V LThe antibody comprises the amino acid sequence SEQ ID NO:55 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence SEQ ID NO:55. In some embodiments, the anti-GDF15 antibody comprises V H The V H Contains the amino acid sequence SEQ ID NO:42, and V L The V L It contains the amino acid sequence SEQ ID NO:55.

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

[0170] In some embodiments, the anti-GDF15 antibody comprises: V H The V H Contains the amino acid sequence SEQ ID NO:44 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence SEQ ID NO:44; and V L The V L The antibody comprises the amino acid sequence SEQ ID NO:55 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence SEQ ID NO:55. In some embodiments, the anti-GDF15 antibody comprises V H The V HContains the amino acid sequence SEQ ID NO:44, and V L The V L It contains the amino acid sequence SEQ ID NO:55.

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

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

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

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

[0175] In some embodiments, the anti-GDF15 antibody comprises V H The V H Contains: HC-CDR1, which contains the amino acid sequence SEQ ID NO:3; HC-CDR2, which contains the amino acid sequence SEQ ID NO:9; HC-CDR3, which contains the amino acid sequence SEQ ID NO:14; or the V H Variants of which contain up to about 5 amino acid substitutions in their HC-CDRs; and VL The V L Contains: LC-CDR1, which contains the amino acid sequence SEQ ID NO:19; LC-CDR2, which contains the amino acid sequence SEQ ID NO:26; LC-CDR3, which contains the amino acid sequence SEQ ID NO:31; or the V L Variants of which contain up to about 5 amino acid substitutions in their LC-CDRs.

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

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

[0178] In some embodiments, the anti-GDF15 antibody comprises: V H The V H Contains the amino acid sequence SEQ ID NO:48 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence SEQ ID NO:48; and V L The V L The antibody comprises the amino acid sequence SEQ ID NO:60 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence SEQ ID NO:60. In some embodiments, the anti-GDF15 antibody comprises V HThe V H Contains the amino acid sequence SEQ ID NO:48, and V L The V L It contains the amino acid sequence SEQ ID NO:60.

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

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

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

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

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

[0184] In some embodiments, the anti-GDF15 antibody comprises V H The V H Contains: HC-CDR1, which contains the amino acid sequence SEQ ID NO:5; HC-CDR2, which contains the amino acid sequence SEQ ID NO:11; and HC-CDR3, which contains the amino acid sequence SEQ ID NO:16; and V L The V LIt includes: LC-CDR1, which contains the amino acid sequence SEQ ID NO:21; LC-CDR2, which contains the amino acid sequence SEQ ID NO:28; and LC-CDR3, which contains the amino acid sequence SEQ ID NO:33.

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

[0186] In some embodiments, the anti-GDF15 antibody comprises: V H The V H Contains the amino acid sequence SEQ ID NO:50 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence SEQ ID NO:50; and V L The V L The antibody comprises the amino acid sequence SEQ ID NO:62 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence SEQ ID NO:62. In some embodiments, the anti-GDF15 antibody comprises V H The V H Contains the amino acid sequence SEQ ID NO:50, and V L The V L It contains 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 H It includes: a heavy chain complementarity-determining region (HC-CDR)1 containing SYDMT (SEQ ID NO:6); HC-CDR2 containing IIX1X2SGX3TYYASWAKG (SEQ ID NO:79), where X1 is N or S, X2 is G, N or S, and X3 is N or S; and HC-CDR3 containing GILVYADYGDHNL (SEQ ID NO:17); and a light chain variable structural domain (V L ), the VL It includes: a light chain complementarity determination region (LC-CDR)1, which includes QASEDIYTNLA (SEQ ID NO:22); LC-CDR2, which includes AASTLAS (SEQ ID NO:29); and LC-CDR3, which includes 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 It comprises: HC-CDR1, which comprises the amino acid sequence shown in SEQ ID NO:6 or a variant thereof, the variant comprising substitutions of up to about 3 amino acids (e.g., 1, 2 or 3); HC-CDR2, which comprises the amino acid sequence shown in any of SEQ ID NOs:12, 75-78 or a variant thereof, the variant comprising substitutions of up to about 3 amino acids (e.g., 1, 2 or 3); and HC-CDR3, which comprises the amino acid sequence shown in SEQ ID NO:17 or a variant thereof, the variant comprising substitutions of up to about 3 amino acids (e.g., 1, 2 or 3).

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

[0190] 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 or a variant thereof, the variant comprising substitutions of up to about 3 amino acids (e.g., 1, 2 or 3); LC-CDR2, which comprises the amino acid sequence shown in SEQ ID NO:29 or a variant thereof, the variant comprising substitutions of up to about 3 amino acids (e.g., 1, 2 or 3); and LC-CDR3, which comprises the amino acid sequence shown in any of SEQ ID NOs:34 or 80 or a variant thereof, the variant comprising substitutions of up to about 3 amino acids (e.g., 1, 2 or 3).

[0191] In some embodiments, the anti-GDF15 antibody comprises V L The V LIt includes: LC-CDR1, which contains the amino acid sequence shown in SEQ ID NO:22; LC-CDR2, which contains the amino acid sequence shown in SEQ ID NO:29; and LC-CDR3, which contains the amino acid sequence shown in either SEQ ID NOs:34 or 80.

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

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

[0194] In some embodiments, the anti-GDF15 antibody comprises VH The V H Contains: HC-CDR1, which contains the amino acid sequence SEQ ID NO:6; HC-CDR2, which contains the amino acid sequence SEQ ID NO:12; HC-CDR3, which contains the amino acid sequence SEQ ID NO:17; or the V H Variants of which contain up to about 5 amino acid substitutions in their HC-CDRs; and V L The V L Contains: LC-CDR1, which contains the amino acid sequence SEQ ID NO:22; LC-CDR2, which contains the amino acid sequence SEQ ID NO:29; LC-CDR3, which contains the amino acid sequence SEQ ID NO:34; or the V L Variants of which contain up to about 5 amino acid substitutions in their LC-CDRs.

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

[0196] In some embodiments, the anti-GDF15 antibody comprises V H The V H Contains: HC-CDR1, which contains the amino acid sequence SEQ ID NO:6; HC-CDR2, which contains the amino acid sequence SEQ ID NO:75; HC-CDR3, which contains the amino acid sequence SEQ ID NO:17; or the V H Variants of which contain up to about 5 amino acid substitutions in their HC-CDRs; and V L The V L Contains: LC-CDR1, which contains the amino acid sequence SEQ ID NO:22; LC-CDR2, which contains the amino acid sequence SEQ ID NO:29; LC-CDR3, which contains the amino acid sequence SEQ ID NO:80; or the V L Variants of which contain up to about 5 amino acid substitutions in their LC-CDRs.

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

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

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

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

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

[0202] In some embodiments, the anti-GDF15 antibody comprises V H The V H Contains: HC-CDR1, which contains the amino acid sequence SEQ ID NO:6; HC-CDR2, which contains the amino acid sequence SEQ ID NO:78; HC-CDR3, which contains the amino acid sequence SEQ ID NO:17; or the V H Variants of which contain up to about 5 amino acid substitutions in their HC-CDRs; and V L The V L Contains: LC-CDR1, which contains the amino acid sequence SEQ ID NO:22; LC-CDR2, which contains the amino acid sequence SEQ ID NO:29; LC-CDR3, which contains the amino acid sequence SEQ ID NO:80; or the V LVariants of which contain up to about 5 amino acid substitutions in their LC-CDRs.

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

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

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

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

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

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

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

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

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

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

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

[0214] In some embodiments, the anti-GDF15 antibody comprises: V H The V H Contains any of the amino acid sequences shown in SEQ ID NOs:51,82-89 or variants thereof, wherein the variants have at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with any of the amino acid sequences shown in SEQ ID NOs:51,82-89; and V L The V L The antibody comprises any of the amino acid sequences shown in SEQ ID NOs:63,90-91 or variants thereof, wherein the variants have at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with any of the amino acid sequences shown in SEQ ID NOs:63,90-91. In some embodiments, the anti-GDF15 antibody comprises V H The V H Contains any of the amino acid sequences shown in SEQ ID NOs:51,82-89, and V L The V L It contains any of the amino acid sequences shown in SEQ ID NOs:63,90-91.

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

[0216] SEQ ID NO:51, and V L The V L It contains the amino acid sequence SEQ ID NO:63.

[0217] In some embodiments, the anti-GDF15 antibody comprises: V H The V H Contains the amino acid sequence SEQ ID NO:82 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence SEQ ID NO:82; and V L The V L The antibody comprises the amino acid sequence SEQ ID NO:90 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence SEQ ID NO:90. In some embodiments, the anti-GDF15 antibody comprises V H The V H Contains amino acid sequence

[0218] SEQ ID NO:82, and V L The V L It contains the amino acid sequence SEQ ID NO:90.

[0219] In some embodiments, the anti-GDF15 antibody comprises: V H The V HContains the amino acid sequence SEQ ID NO:83 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence SEQ ID NO:83; and V L The V L The antibody comprises the amino acid sequence SEQ ID NO:90 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence SEQ ID NO:90. In some embodiments, the anti-GDF15 antibody comprises V H The V H Contains amino acid sequence

[0220] SEQ ID NO:83, and V L The V L It contains the amino acid sequence SEQ ID NO:90.

[0221] In some embodiments, the anti-GDF15 antibody comprises: V H The V H Contains the amino acid sequence SEQ ID NO:84 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence SEQ ID NO:84; and V L The V L The antibody comprises the amino acid sequence SEQ ID NO:90 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence SEQ ID NO:90. In some embodiments, the anti-GDF15 antibody comprises V H The V H Contains amino acid sequence

[0222] SEQ ID NO:84, and V L The V L It contains the amino acid sequence SEQ ID NO:90.

[0223] In some embodiments, the anti-GDF15 antibody comprises: V H The V HContains the amino acid sequence SEQ ID NO:85 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence SEQ ID NO:85; and V L The V L The antibody comprises the amino acid sequence SEQ ID NO:90 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence SEQ ID NO:90. In some embodiments, the anti-GDF15 antibody comprises V H The V H Contains amino acid sequence

[0224] SEQ ID NO:85, and V L The V L It contains the amino acid sequence SEQ ID NO:90.

[0225] In some embodiments, the anti-GDF15 antibody comprises: V H The V H Contains the amino acid sequence SEQ ID NO:86 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence SEQ ID NO:86; and V L The V L The antibody comprises the amino acid sequence SEQ ID NO:91 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence SEQ ID NO:91. In some embodiments, the anti-GDF15 antibody comprises V H The V H Contains amino acid sequence

[0226] SEQ ID NO:86, and V L The V L It contains the amino acid sequence SEQ ID NO:91.

[0227] In some embodiments, the anti-GDF15 antibody comprises: V H The V HContains the amino acid sequence SEQ ID NO:87 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence SEQ ID NO:87; and V L The V L The antibody comprises the amino acid sequence SEQ ID NO:91 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence SEQ ID NO:91. In some embodiments, the anti-GDF15 antibody comprises V H The V H Contains amino acid sequence

[0228] SEQ ID NO:87, and V L The V L It contains the amino acid sequence SEQ ID NO:91.

[0229] In some embodiments, the anti-GDF15 antibody comprises: V H The V H Contains the amino acid sequence SEQ ID NO:88 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence SEQ ID NO:88; and V L The V L The antibody comprises the amino acid sequence SEQ ID NO:91 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence SEQ ID NO:91. In some embodiments, the anti-GDF15 antibody comprises V H The V H Contains amino acid sequence

[0230] SEQ ID NO:88, and V L The V L It contains the amino acid sequence SEQ ID NO:91.

[0231] In some embodiments, the anti-GDF15 antibody comprises: V H The V HContains the amino acid sequence SEQ ID NO:89 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence SEQ ID NO:89; and V L The V L The antibody comprises the amino acid sequence SEQ ID NO:91 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence SEQ ID NO:91. In some embodiments, the anti-GDF15 antibody comprises V H The V H Contains amino acid sequence

[0232] SEQ ID NO:89, and V L The V L It contains the amino acid sequence SEQ ID NO:91.

[0233] In some embodiments, the amino acid substitutions described above are limited to the “Exemplary Substitutions” shown in Table 4 herein. In some embodiments, the amino acid substitutions are limited to the “Preferred Substitutions” shown in Table 4 herein.

[0234] In some embodiments, the functional epitope can be resolved using a combined alanine scanning method. In this process, the combined alanine scanning technique can be used to identify the amino acids in the GDF15 protein essential for interaction with anti-GDF15 antibodies. In some embodiments, the epitope is conformational, and the epitope can also be identified using the crystal structure of an anti-GDF15 antibody that binds to the GDF15 protein.

[0235] In some embodiments, this application provides an antibody that competitively binds to GDF15, in conjunction with any of the anti-GDF15 antibodies described herein. In some embodiments, an antibody is provided that is capable of competitively binding to an epitope on GDF15, in conjunction with any of the anti-GDF15 antibodies described herein. In some embodiments, an anti-GDF15 antibody is provided, which, together with V H and V L The anti-GDF15 antibody molecule binds to the same epitope, wherein the V H Contains any of the amino acid sequences shown in SEQ ID NOs:38-51, 82-89, and the V L Contains the amino acid sequence shown in any of SEQ ID NOs:52-63, 90-91. In some embodiments, an anti-GDF15 antibody is provided, which, together with V H and V L The anti-GDF15 antibody competitively binds to GDF15, wherein the VH Contains any of the amino acid sequences shown in SEQ ID NOs:38-51, 82-89, and the V L It contains any of the amino acid sequences shown in SEQ ID NOs:52-63, 90-91.

[0236] In some embodiments, a competition assay can be used to identify monoclonal antibodies that competitively bind to GDF15 with the anti-GDF15 antibody described herein. A competition assay can determine whether two antibodies bind to the same epitope by identifying identical or spatially overlapping epitopes or by one antibody competitively inhibiting the binding of another antibody to the antigen. In some embodiments, such a competitive antibody binds to the same epitope as the antibody described herein. Some exemplary competition assays include, but are not limited to, conventional assays as 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 antibody-bound epitopes are described in Morris (1996) "Epitope Mapping Protocols," in Methods in Molecular Biology vol. 66 (Humana Press, Totowa, NJ). In some embodiments, if each antibody blocks 50% or more of the binding of another antibody, they are said to bind to the same epitope. In some embodiments, the antibody competing with the anti-GDF15 antibody described herein is a chimeric antibody, a humanized antibody, or a fully human antibody.

[0237] Exemplary anti-GDF15 antibody sequences are shown in Tables 2-2A and 3-3A, where CDRs are numbered according to the Kabat definition. Those skilled in the art will recognize that various known algorithms exist for predicting CDR locations and defining the variable regions of the antibody light and heavy chains. CDRs containing antibodies as described herein, V H and / or V L Sequences, but antibodies based on prediction algorithms rather than those exemplified in the table below are also within the scope of this application.

[0238] Table 2. Exemplary CDR sequences of anti-GDF15 antibodies

[0239]

[0240]

[0241]

[0242] Table 2A Exemplary CDR Sequences of Anti-GDF15 Antibody

[0243]

[0244]

[0245] Table 3 Exemplary Sequences

[0246]

[0247]

[0248]

[0249]

[0250] Table 3A Example Sequences

[0251]

[0252]

[0253] GDF15

[0254] 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 molecules playing important roles in regulating development, differentiation, and tissue repair. The TGF-β superfamily includes various ligands such as TGF-β, activin, bone morphogenetic protein (BMP), and GDFs. GDFs belong to the activin / myogenic inhibitory protein subclass. Several members of this subfamily have been described and named GDF1-GDF15 (Herpin, A. et al., Dev. Comp. Immunol. 2004). The maturation of human GDF15 involves a series of post-translational modifications. The pre-pro-GDF15 protein has 308 amino acids, including a signal peptide sequence (29 amino acids), a propeptide (167 amino acids), and a mature protein (112 amino acids). The synthesized pro-GDF15 protein precursor form a pro-GDF15 homodimer via cysteine ​​residues; it is then cleaved at the RXXR site, releasing the mature dimeric GDF15 protein and a propeptide from the C-terminus (Wang X et al., Biochem Pharmacol, 2013).

[0255] GDF15 receptor GFRAL

[0256] Glial cell-derived neurotrophic factor (GDNF) receptor α-like protein GFRAL, as a brainstem-restricted receptor for GDF15 protein, is primarily expressed in the central nervous system (CNS), particularly in the nucleus tractus solitarius (NTS) and posterior pole (AP) of mice, rats, monkeys, and humans (Hsu et al., Nature, 2017; SEMullican, et al., 2017). GFRAL mRNA expression was analyzed in various embryonic and adult mouse tissues. Two isoforms of GRAL mRNA were detected in the CNS of adult mice. In contrast, GFRAL mRNA was not detected in peripheral organs examined, such as the heart, liver, spleen, lungs, kidneys, placenta, skeletal muscle, and small intestine. Within the various regions of the CNS, GFRAL mRNAs are relatively more abundant in certain brain regions, such as the substantia nigra, hippocampus, and posterior brain regions (Li et al., J. Neurochem. 2005).

[0257] GFRAL is a transmembrane protein anchored to the plasma membrane via glycosylphosphatidylinositol (GPI) distributed within lipid rafts. This receptor protein consists of three cysteine-rich domains. GDF15 can activate GFRAL-expressing neurons specifically located in the posterior pole and nucleus tractus solitarius (NTS) of mice (Hsu et al., Nature, 2017). The GFRAL co-receptor tyrosine kinase RET is expressed in the AP and NTS, with additional expression observed in several regions of the hypothalamus (Hsu et al., 2017). The GDF15 dimer binds to two GFRAL molecules and then recruits RET molecules to form a complex, triggering phosphorylation and intracellular signaling from RET, further activating its intracellular kinase domains and initiating multiple signaling pathways through brainstem neurons (Shannon E. Mullican &

[0258] Rangwala, 2018; L. Yang, et al., 2017).

[0259] GDF15-GFRAL signaling plays a crucial 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, germline Gfral knockout mice (Gfral- / -) lost the anorexia and metabolic-related effects induced by recombinant GDF15. Furthermore, diet-induced obesity and insulin resistance were exacerbated in GFRAL-deficient mice, suggesting that this receptor plays a homeostatic role in metabolism (Mullican, SE et al. Nat Med. 2017).

[0260] Full-length anti-GDF15 antibody

[0261] 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 includes a constant IgG region, such as a constant region of IgG1, IgG2, IgG3, IgG4, or a variant thereof. In some embodiments, the full-length anti-GDF15 antibody includes a λ light chain constant region. In some embodiments, the full-length anti-GDF15 antibody includes a κ 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 includes a mouse immunoglobulin Fc sequence. In some embodiments, the full-length anti-GDF15 antibody includes 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).

[0262] Therefore, for example, in some embodiments, a full-length anti-GDF15 antibody comprising a constant region of IgG1 is provided, said anti-GDF15 antibody specifically binding to GDF15. In some embodiments, said IgG1 is human...

[0263] IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0264] The sequence is composed of SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64, and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0265] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG2 constant region is provided, the anti-GDF15 antibody specifically binding to GDF15. In some embodiments, the IgG2 is human IgG2. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0266] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG3 constant region is provided, the anti-GDF15 antibody specifically binding to GDF15. In some embodiments, the IgG3 is human IgG3. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0267] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, the anti-GDF15 antibody specifically binding to GDF15. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0268] 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: HC-CDR1, comprising any of the amino acid sequences shown in SEQ ID NOs: 1-6 or variants thereof, the variants comprising substitutions of up to about 3 (e.g., 1, 2, or 3) amino acids; HC-CDR2, comprising any of the amino acid sequences shown in SEQ ID NOs: 7-12, 75-78 or variants thereof, the variants comprising substitutions of up to about 3 (e.g., 1, 2, or 3) amino acids; and HC-CDR3, comprising any of the amino acid sequences shown in SEQ ID NOs: 13-17 or variants thereof, the variants comprising substitutions of up to about 3 (e.g., 1, 2, or 3) amino acids; and b) a light chain variable domain comprising: LC-CDR1, comprising SEQ ID NOs: 1-6 or variants thereof, the heavy chain variable domain comprising: HC-CDR1, comprising any of the amino acid sequences shown in ... The amino acid sequences or variants thereof shown in SEQ ID NOs: 18-22, wherein the variants contain substitutions of up to about 3 amino acids (e.g., 1, 2, or 3), LC-CDR2, which contains amino acid sequences or variants thereof shown in SEQ ID NOs: 23-29, wherein the variants contain substitutions of up to about 3 amino acids (e.g., 1, 2, or 3); and LC-CDR3, which contains amino acid sequences or variants thereof shown in SEQ ID NOs: 30-34, 80, wherein the variants contain substitutions of up to about 3 amino acids (e.g., 1, 2, or 3). In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO: 67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence

[0269] The heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0270] 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: HC-CDR1, comprising any of the amino acid sequences shown in SEQ ID NOs: 1-6 or variants thereof, the variants comprising substitutions of up to about 3 (e.g., 1, 2, or 3) amino acids; HC-CDR2, comprising any of the amino acid sequences shown in SEQ ID NOs: 7-12, 75-78 or variants thereof, the variants comprising substitutions of up to about 3 (e.g., 1, 2, or 3) amino acids; and HC-CDR3, comprising any of the amino acid sequences shown in SEQ ID NOs: 13-17 or variants thereof, the variants comprising substitutions of up to about 3 (e.g., 1, 2, or 3) amino acids; and b) a light chain variable domain comprising: LC-CDR1, comprising SEQ ID NOs: 1-6 or variants thereof, the heavy chain variable domain comprising: HC-CDR1, comprising any of the amino acid sequences shown in SEQ ID NOs: 1-6 or variants thereof, the heavy chain variable domain comprising: HC-CDR2 ... The amino acid sequences or variants thereof shown in SEQ ID NOs: 18-22, wherein the variants contain substitutions of up to about 3 amino acids (e.g., 1, 2, or 3); LC-CDR2, which contains amino acid sequences or variants thereof shown in SEQ ID NOs: 23-29, wherein the variants contain substitutions of up to about 3 amino acids (e.g., 1, 2, or 3); and LC-CDR3, which contains amino acid sequences or variants thereof shown in SEQ ID NOs: 30-34, 80, wherein the variants contain substitutions of up to about 3 amino acids (e.g., 1, 2, or 3). In some embodiments, the IgG2 is human IgG2. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO: 67.

[0271] 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: HC-CDR1, comprising any of the amino acid sequences shown in SEQ ID NOs: 1-6 or variants thereof, the variants comprising substitutions of up to about 3 (e.g., 1, 2, or 3) amino acids; HC-CDR2, comprising any of the amino acid sequences shown in SEQ ID NOs: 7-12, 75-78 or variants thereof, the variants comprising substitutions of up to about 3 (e.g., 1, 2, or 3) amino acids; and HC-CDR3, comprising any of the amino acid sequences shown in SEQ ID NOs: 13-17 or variants thereof, the variants comprising substitutions of up to about 3 (e.g., 1, 2, or 3) amino acids; and b) a light chain variable domain comprising: LC-CDR1, comprising SEQ ID NOs: 1-6 or variants thereof, the heavy chain variable domain comprising: HC-CDR1, comprising any of the amino acid sequences shown in SEQ ID NOs: 1-6 or variants thereof, the heavy chain variable domain comprising: HC-CDR1, comprising any of the amino acid sequences shown in SEQ ID NOs: 1-6 or variants thereof, the heavy chain variable domain comprising: HC-CDR2, comprising any of the amino acid sequences shown in SEQ ID NOs: 1-6 or variants thereof, the heavy chain variable domain comprising: HC-CDR3 ... The amino acid sequences or variants thereof shown in SEQ ID NOs: 18-22, wherein the variants contain substitutions of up to about 3 amino acids (e.g., 1, 2, or 3); LC-CDR2, which contains amino acid sequences or variants thereof shown in SEQ ID NOs: 23-29, wherein the variants contain substitutions of up to about 3 amino acids (e.g., 1, 2, or 3); and LC-CDR3, which contains amino acid sequences or variants thereof shown in SEQ ID NOs: 30-34, 80, wherein the variants contain substitutions of up to about 3 amino acids (e.g., 1, 2, or 3). In some embodiments, the IgG3 is human IgG3. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence 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: HC-CDR1, comprising any of the amino acid sequences shown in SEQ ID NOs: 1-6 or variants thereof, the variants comprising substitutions of up to about 3 (e.g., 1, 2, or 3) amino acids; HC-CDR2, comprising any of the amino acid sequences shown in SEQ ID NOs: 7-12, 75-78 or variants thereof, the variants comprising substitutions of up to about 3 (e.g., 1, 2, or 3) amino acids; and HC-CDR3, comprising any of the amino acid sequences shown in SEQ ID NOs: 13-17 or variants thereof, the variants comprising substitutions of up to about 3 (e.g., 1, 2, or 3) amino acids; and b) a light chain variable domain comprising: LC-CDR1, comprising SEQ ID NOs: 1-6 or variants thereof, the heavy chain variable domain comprising: HC-CDR1, comprising any of the amino acid sequences shown in SEQ ID NOs: 1-6 or variants thereof, the heavy chain variable domain comprising: HC-CDR2, comprising any of the amino acid sequences shown in SEQ ID NOs: 1-6 or variants thereof, the heavy chain variable domain comprising: HC-CDR3, comprising any of the amino acid sequences shown in SEQ ID NOs: 1-6 or variants thereof, the heavy chain variable domain comprising: HC-CDR1, comprising any of the amino acid sequences shown in SEQ ID NOs: 1-6 or variants thereof, the heavy chain variable domain comprising: HC-CDR2 ... The amino acid sequences or variants thereof shown in SEQ ID NOs:18-22, wherein the variants contain substitutions of up to about 3 amino acids (e.g., 1, 2, or 3), LC-CDR2, which contains amino acid sequences or variants thereof shown in SEQ ID NOs:23-29, wherein the variants contain substitutions of up to about 3 amino acids (e.g., 1, 2, or 3), and LC-CDR3, which contains amino acid sequences or variants thereof shown in SEQ ID NOs:30-34, 80, wherein the variants contain substitutions of up to about 3 amino acids (e.g., 1, 2, or 3). In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence

[0273] The heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65, and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65, and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0274] 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: HC-CDR1 comprising any of the amino acid sequences shown in SEQ ID NOs: 1-6, HC-CDR2 comprising any of the amino acid sequences shown in SEQ ID NOs: 7-12, 75-78, and HC-CDR3 comprising any of the amino acid sequences shown in SEQ ID NOs: 13-17, or a variant of the heavy chain variable domain comprising a substitution of up to about 5 amino acids (e.g., 1, 2, 3, 4, or 5) in its HC-CDR sequence; and b) a light chain variable domain comprising: LC-CDR1 comprising any of the amino acid sequences shown in SEQ ID NOs: 18-22, LC-CDR2 comprising any of the amino acid sequences shown in SEQ ID NOs: 23-29, and LC-CDR3 ...HC-CDR1 comprising any of the amino acid sequences shown in SEQ ID NOs: 18-22, LC-CDR2 comprising any of the amino acid sequences shown in SEQ ID NOs: 23-29, and LC-CDR3 comprising any of the amino acid sequences shown in SEQ ID NOs: 18-29, HC-CDR1 comprising any of the amino acid sequences shown in SEQ ID NOs: 18-29, HC-CDR1 comprising any of the amino acid sequences shown in SEQ ID NOs: 18-29, HC-CDR1 comprising any of the amino acid sequences shown in SEQ ID NOs: 18-29, HC-CDR The amino acid sequence represented by NOs:30-34, 80, or a variant of the light chain variable domain, contains substitutions of up to about 5 amino acids (e.g., 1, 2, 3, 4, or 5) in its LC-CDR sequence. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence 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: HC-CDR1 comprising any of the amino acid sequences shown in SEQ ID NOs: 1-6, HC-CDR2 comprising any of the amino acid sequences shown in SEQ ID NOs: 7-12, 75-78, and HC-CDR3 comprising any of the amino acid sequences shown in SEQ ID NOs: 13-17, or a variant of the heavy chain variable domain having an HC-CDR sequence comprising up to about 5 (e.g., 1, 2, 3, 4, or 5) amino acid substitutions; and b) a light chain variable domain comprising: LC-CDR1 comprising any of the amino acid sequences shown in SEQ ID NOs: 18-22, LC-CDR2 comprising any of the amino acid sequences shown in SEQ ID NOs: 23-29, and LC-CDR3 ...HC-CDR3 comprising any of the amino acid sequences shown in SEQ ID NOs: 18-29, HC-CDR1 comprising any of the amino acid sequences shown in SEQ ID NOs: 18-29, HC-CDR2 comprising any of the amino acid sequences shown in SEQ ID NOs: 18-29, and HC-CDR3 comprising any of the amino acid sequences shown in SEQ ID NOs: 18-29, HC-CDR1 comprising any of the amino acid sequences shown in SEQ ID NOs: 18-29, HC-CDR1 The amino acid sequence represented by NOs:30-34, 80, or a variant of the light chain variable domain, contains substitutions of up to about 5 amino acids (e.g., 1, 2, 3, 4, or 5) in its LC-CDR sequence. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0276] In some embodiments, a full-length anti-GDF15 antibody comprising a constant region of IgG1 is provided, wherein the anti-GDF15 antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising any of the amino acid sequences shown in SEQ ID NOs: 1-6, HC-CDR2 comprising any of the amino acid sequences shown in SEQ ID NOs: 7-12, 75-78, and HC-CDR3 comprising any of the amino acid sequences shown in SEQ ID NOs: 13-17; and b) a light chain variable domain comprising: LC-CDR1 comprising any of the amino acid sequences shown in SEQ ID NOs: 18-22, LC-CDR2 comprising any of the amino acid sequences shown in SEQ ID NOs: 23-29, and LC-CDR3 comprising any of the amino acid sequences shown in SEQ ID NOs: 30-34, 80. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO: 64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence 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: HC-CDR1 comprising any of the amino acid sequences shown in SEQ ID NOs: 1-6, HC-CDR2 comprising any of the amino acid sequences shown in SEQ ID NOs: 7-12, 75-78, and HC-CDR3 comprising any of the amino acid sequences shown in SEQ ID NOs: 13-17; and b) a light chain variable domain comprising: LC-CDR1 comprising any of the amino acid sequences shown in SEQ ID NOs: 18-22, LC-CDR2 comprising any of the amino acid sequences shown in SEQ ID NOs: 23-29, and LC-CDR3 comprising any of the amino acid sequences shown in SEQ ID NOs: 30-34, 80. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO: 65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0278] 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: HC-CDR1 containing the amino acid sequence SEQ ID NO:1, HC-CDR2 containing the amino acid sequence SEQ ID NO:7, and HC-CDR3 containing the amino acid sequence SEQ ID NO:13; and b) a light chain variable domain comprising: LC-CDR1 containing the amino acid sequence SEQ ID NO:18, LC-CDR2 containing the amino acid sequence SEQ ID NO:23, and LC-CDR3 containing the amino acid sequence SEQ ID NO:30. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64, and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64, and the light chain constant region comprises or is composed of the amino acid sequence 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) a heavy chain variable domain comprising: HC-CDR1 containing the amino acid sequence SEQ ID NO:1, HC-CDR2 containing the amino acid sequence SEQ ID NO:7, and HC-CDR3 containing the amino acid sequence SEQ ID NO:13; and b) a light chain variable domain comprising: LC-CDR1 containing the amino acid sequence SEQ ID NO:18, LC-CDR2 containing the amino acid sequence SEQ ID NO:24, and LC-CDR3 containing the amino acid sequence SEQ ID NO:30. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64, and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64, and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0280] 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: HC-CDR1 containing the amino acid sequence SEQ ID NO:1, HC-CDR2 containing the amino acid sequence SEQ ID NO:7, and HC-CDR3 containing the amino acid sequence SEQ ID NO:13; and b) a light chain variable domain comprising: LC-CDR1 containing the amino acid sequence SEQ ID NO:18, LC-CDR2 containing the amino acid sequence SEQ ID NO:25, and LC-CDR3 containing the amino acid sequence SEQ ID NO:30. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64, and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64, and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0281] 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: HC-CDR1 containing amino acid sequence SEQ ID NO:2, HC-CDR2 containing amino acid sequence SEQ ID NO:7, and HC-CDR3 containing amino acid sequence SEQ ID NO:13; and b) a light chain variable domain comprising: LC-CDR1 containing amino acid sequence SEQ ID NO:18, LC-CDR2 containing amino acid sequence SEQ ID NO:25, and LC-CDR3 containing amino acid sequence SEQ ID NO:30. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64, and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64, and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0282] 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: HC-CDR1 containing the amino acid sequence SEQ ID NO:1, HC-CDR2 containing the amino acid sequence SEQ ID NO:8, and HC-CDR3 containing the amino acid sequence SEQ ID NO:13; and b) a light chain variable domain comprising: LC-CDR1 containing the amino acid sequence SEQ ID NO:18, LC-CDR2 containing the amino acid sequence SEQ ID NO:25, and LC-CDR3 containing the amino acid sequence SEQ ID NO:30. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64, and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64, and the light chain constant region comprises or is composed of the amino acid sequence 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) a heavy chain variable domain comprising: HC-CDR1 containing the amino acid sequence SEQ ID NO:3, HC-CDR2 containing the amino acid sequence SEQ ID NO:9, and HC-CDR3 containing the amino acid sequence SEQ ID NO:14; and b) a light chain variable domain comprising: LC-CDR1 containing the amino acid sequence SEQ ID NO:19, LC-CDR2 containing the amino acid sequence SEQ ID NO:26, and LC-CDR3 containing the amino acid sequence SEQ ID NO:31. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64, and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64, and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0284] 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: HC-CDR1 containing the amino acid sequence SEQ ID NO:4, HC-CDR2 containing the amino acid sequence SEQ ID NO:10, and HC-CDR3 containing the amino acid sequence SEQ ID NO:15; and b) a light chain variable domain comprising: LC-CDR1 containing the amino acid sequence SEQ ID NO:20, LC-CDR2 containing the amino acid sequence SEQ ID NO:27, and LC-CDR3 containing the amino acid sequence SEQ ID NO:32. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64, and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64, and the light chain constant region comprises or is composed of the amino acid sequence 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: a) a heavy chain variable domain comprising: HC-CDR1 containing the amino acid sequence SEQ ID NO:5, HC-CDR2 containing the amino acid sequence SEQ ID NO:11, and HC-CDR3 containing the amino acid sequence SEQ ID NO:16; and b) a light chain variable domain comprising: LC-CDR1 containing the amino acid sequence SEQ ID NO:21, LC-CDR2 containing the amino acid sequence SEQ ID NO:28, and LC-CDR3 containing the amino acid sequence SEQ ID NO:33. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64, and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64, and the light chain constant region comprises or is composed of the amino acid sequence 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: a) a heavy chain variable domain comprising: HC-CDR1 containing the amino acid sequence SEQ ID NO:6, HC-CDR2 containing the amino acid sequence SEQ ID NO:12, and HC-CDR3 containing the amino acid sequence SEQ ID NO:17; and b) a light chain variable domain comprising: LC-CDR1 containing the amino acid sequence SEQ ID NO:22, LC-CDR2 containing the amino acid sequence SEQ ID NO:29, and LC-CDR3 containing the amino acid sequence SEQ ID NO:34. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64, and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64, and the light chain constant region comprises or is composed of the amino acid sequence 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: a) a heavy chain variable domain comprising: HC-CDR1 containing the amino acid sequence SEQ ID NO:6, HC-CDR2 containing the amino acid sequence SEQ ID NO:75, and HC-CDR3 containing the amino acid sequence SEQ ID NO:17; and b) a light chain variable domain comprising: LC-CDR1 containing the amino acid sequence SEQ ID NO:22, LC-CDR2 containing the amino acid sequence SEQ ID NO:29, and LC-CDR3 containing the amino acid sequence SEQ ID NO:80. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64, and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64, and the light chain constant region comprises or is composed of the amino acid sequence 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: a) a heavy chain variable domain comprising: HC-CDR1 containing the amino acid sequence SEQ ID NO:6, HC-CDR2 containing the amino acid sequence SEQ ID NO:76, and HC-CDR3 containing the amino acid sequence SEQ ID NO:17; and b) a light chain variable domain comprising: LC-CDR1 containing the amino acid sequence SEQ ID NO:22, LC-CDR2 containing the amino acid sequence SEQ ID NO:29, and LC-CDR3 containing the amino acid sequence SEQ ID NO:80. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64, and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64, and the light chain constant region comprises or is composed of the amino acid sequence 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: a) a heavy chain variable domain comprising: HC-CDR1 containing the amino acid sequence SEQ ID NO:6, HC-CDR2 containing the amino acid sequence SEQ ID NO:77, and HC-CDR3 containing the amino acid sequence SEQ ID NO:17; and b) a light chain variable domain comprising: LC-CDR1 containing the amino acid sequence SEQ ID NO:22, LC-CDR2 containing the amino acid sequence SEQ ID NO:29, and LC-CDR3 containing the amino acid sequence SEQ ID NO:80. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64, and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64, and the light chain constant region comprises or is composed of the amino acid sequence 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: a) a heavy chain variable domain comprising: HC-CDR1 containing the amino acid sequence SEQ ID NO:6, HC-CDR2 containing the amino acid sequence SEQ ID NO:78, and HC-CDR3 containing the amino acid sequence SEQ ID NO:17; and b) a light chain variable domain comprising: LC-CDR1 containing the amino acid sequence SEQ ID NO:22, LC-CDR2 containing the amino acid sequence SEQ ID NO:29, and LC-CDR3 containing the amino acid sequence SEQ ID NO:80. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64, and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64, and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0291] 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: HC-CDR1 comprising amino acid sequence SEQ ID NO:1, HC-CDR2 comprising amino acid sequence SEQ ID NO:7, and HC-CDR3 comprising amino acid sequence SEQ ID NO:13; and b) a light chain variable domain comprising: LC-CDR1 comprising amino acid sequence SEQ ID NO:18, LC-CDR2 comprising amino acid sequence SEQ ID NO:23, and LC-CDR3 comprising amino acid sequence SEQ ID NO:30. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0292] 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: HC-CDR1 containing the amino acid sequence SEQ ID NO:1, HC-CDR2 containing the amino acid sequence SEQ ID NO:7, and HC-CDR3 containing the amino acid sequence SEQ ID NO:13; and b) a light chain variable domain comprising: LC-CDR1 containing the amino acid sequence SEQ ID NO:18, LC-CDR2 containing the amino acid sequence SEQ ID NO:24, and LC-CDR3 containing the amino acid sequence SEQ ID NO:30. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0293] 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: HC-CDR1 containing the amino acid sequence SEQ ID NO:1, HC-CDR2 containing the amino acid sequence SEQ ID NO:7, and HC-CDR3 containing the amino acid sequence SEQ ID NO:13; and b) a light chain variable domain comprising: LC-CDR1 containing the amino acid sequence SEQ ID NO:18, LC-CDR2 containing the amino acid sequence SEQ ID NO:25, and LC-CDR3 containing the amino acid sequence SEQ ID NO:30. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0294] 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: HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:7, and HC-CDR3 comprising amino acid sequence SEQ ID NO:13; and b) a light chain variable domain comprising: LC-CDR1 comprising amino acid sequence SEQ ID NO:18, LC-CDR2 comprising amino acid sequence SEQ ID NO:25, and LC-CDR3 comprising amino acid sequence SEQ ID NO:30. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0295] 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: HC-CDR1 containing the amino acid sequence SEQ ID NO:1, HC-CDR2 containing the amino acid sequence SEQ ID NO:8, and HC-CDR3 containing the amino acid sequence SEQ ID NO:13; and b) a light chain variable domain comprising: LC-CDR1 containing the amino acid sequence SEQ ID NO:18, LC-CDR2 containing the amino acid sequence SEQ ID NO:25, and LC-CDR3 containing the amino acid sequence SEQ ID NO:30. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0296] 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: HC-CDR1 containing the amino acid sequence SEQ ID NO:3, HC-CDR2 containing the amino acid sequence SEQ ID NO:9, and HC-CDR3 containing the amino acid sequence SEQ ID NO:14; and b) a light chain variable domain comprising: LC-CDR1 containing the amino acid sequence SEQ ID NO:19, LC-CDR2 containing the amino acid sequence SEQ ID NO:26, and LC-CDR3 containing the amino acid sequence SEQ ID NO:31. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0297] 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: HC-CDR1 containing the amino acid sequence SEQ ID NO:4, HC-CDR2 containing the amino acid sequence SEQ ID NO:10, and HC-CDR3 containing the amino acid sequence SEQ ID NO:15; and b) a light chain variable domain comprising: LC-CDR1 containing the amino acid sequence SEQ ID NO:20, LC-CDR2 containing the amino acid sequence SEQ ID NO:27, and LC-CDR3 containing the amino acid sequence SEQ ID NO:32. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0298] 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: HC-CDR1 containing the amino acid sequence SEQ ID NO:5, HC-CDR2 containing the amino acid sequence SEQ ID NO:11, and HC-CDR3 containing the amino acid sequence SEQ ID NO:16; and b) a light chain variable domain comprising: LC-CDR1 containing the amino acid sequence SEQ ID NO:21, LC-CDR2 containing the amino acid sequence SEQ ID NO:28, and LC-CDR3 containing the amino acid sequence SEQ ID NO:33. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0299] 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: HC-CDR1 containing the amino acid sequence SEQ ID NO:6, HC-CDR2 containing the amino acid sequence SEQ ID NO:12, and HC-CDR3 containing the amino acid sequence SEQ ID NO:17; and b) a light chain variable domain comprising: LC-CDR1 containing the amino acid sequence SEQ ID NO:22, LC-CDR2 containing the amino acid sequence SEQ ID NO:29, and LC-CDR3 containing the amino acid sequence SEQ ID NO:34. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0300] 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: HC-CDR1 containing the amino acid sequence SEQ ID NO:6, HC-CDR2 containing the amino acid sequence SEQ ID NO:75, and HC-CDR3 containing the amino acid sequence SEQ ID NO:17; and b) a light chain variable domain comprising: LC-CDR1 containing the amino acid sequence SEQ ID NO:22, LC-CDR2 containing the amino acid sequence SEQ ID NO:29, and LC-CDR3 containing the amino acid sequence SEQ ID NO:80. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0301] 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: HC-CDR1 containing the amino acid sequence SEQ ID NO:6, HC-CDR2 containing the amino acid sequence SEQ ID NO:76, and HC-CDR3 containing the amino acid sequence SEQ ID NO:17; and b) a light chain variable domain comprising: LC-CDR1 containing the amino acid sequence SEQ ID NO:22, LC-CDR2 containing the amino acid sequence SEQ ID NO:29, and LC-CDR3 containing the amino acid sequence SEQ ID NO:80. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0302] 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: HC-CDR1 containing the amino acid sequence SEQ ID NO:6, HC-CDR2 containing the amino acid sequence SEQ ID NO:77, and HC-CDR3 containing the amino acid sequence SEQ ID NO:17; and b) a light chain variable domain comprising: LC-CDR1 containing the amino acid sequence SEQ ID NO:22, LC-CDR2 containing the amino acid sequence SEQ ID NO:29, and LC-CDR3 containing the amino acid sequence SEQ ID NO:80. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0303] 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: HC-CDR1 containing the amino acid sequence SEQ ID NO:6, HC-CDR2 containing the amino acid sequence SEQ ID NO:78, and HC-CDR3 containing the amino acid sequence SEQ ID NO:17; and b) a light chain variable domain comprising: LC-CDR1 containing the amino acid sequence SEQ ID NO:22, LC-CDR2 containing the amino acid sequence SEQ ID NO:29, and LC-CDR3 containing the amino acid sequence SEQ ID NO:80. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence 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: a heavy chain variable domain (V H ), the V H Contains any of the amino acid sequences shown in SEQ ID NOs:38-51, 82-89 or variants thereof, wherein the variants have at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with any of the amino acid sequences shown in SEQ ID NOs:38-51, 82-89; and a light chain variable domain (V L ), the V LThe IgG1 comprises any of the amino acid sequences shown in SEQ ID NOs:52-63, 90-91, or variants thereof, wherein the variants have at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with any of the amino acid sequences shown in 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 is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0305] 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 Contains any of the amino acid sequences shown in SEQ ID NOs:38-51, 82-89 or variants thereof, wherein the variants have at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with any of the amino acid sequences shown in SEQ ID NOs:38-51, 82-89; and a light chain variable domain (V L ), the V L The IgG2 comprises any of the amino acid sequences shown in SEQ ID NOs:52-63, 90-91, or variants thereof, wherein the variants have at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with any of the amino acid sequences shown in SEQ ID NOs:52-63, 90-91. In some embodiments, the IgG2 is human IgG2. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0306] 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 VH Contains any of the amino acid sequences shown in SEQ ID NOs:38-51, 82-89 or variants thereof, wherein the variants have at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with any of the amino acid sequences shown in SEQ ID NOs:38-51, 82-89; and a light chain variable domain (V L ), the V L The IgG3 comprises any of the amino acid sequences shown in SEQ ID NOs:52-63, 90-91, or variants thereof, wherein the variants have at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with any of the amino acid sequences shown in SEQ ID NOs:52-63, 90-91. In some embodiments, the IgG3 is human IgG3. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0307] 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 Contains any of the amino acid sequences shown in SEQ ID NOs:38-51, 82-89 or variants thereof, wherein the variants have at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with any of the amino acid sequences shown in SEQ ID NOs:38-51, 82-89; and a light chain variable domain (V L ), the V LThe IgG4 comprises any of the amino acid sequences shown in SEQ ID NOs:52-63, 90-91, or variants thereof, wherein the variants have at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with any of the amino acid sequences shown in SEQ ID NOs:52-63, 90-91. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence 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: a heavy chain variable domain (V H ), the (V) H It contains any of the amino acid sequences shown in SEQ ID NOs:38-51, 82-89, and a light chain variable domain (V L ), the (V) L The IgG1 comprises any of the amino acid sequences shown in 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 is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0309] 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 HContains any of the amino acid sequences shown in SEQ ID NOs:38-51, 82-89, and a light chain variable domain (V L ), the V L It comprises the amino acid sequence shown in any of SEQ ID NOs:52-63, 90-91. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence 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 It comprises the amino acid sequence SEQ ID NO:38 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:38; and V L It comprises the amino acid sequence SEQ ID NO:52 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:52. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence 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 HIt comprises the amino acid sequence SEQ ID NO:39 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:39; and V L It comprises the amino acid sequence SEQ ID NO:53 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:53. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence 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 It comprises the amino acid sequence SEQ ID NO:40 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:40; and V L It comprises the amino acid sequence SEQ ID NO:53 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:53. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence 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 HIt comprises the amino acid sequence SEQ ID NO:41 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:41; and V L It comprises the amino acid sequence SEQ ID NO:53 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:53. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence 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 It comprises the amino acid sequence SEQ ID NO:42 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:42; and V L It comprises the amino acid sequence SEQ ID NO:53 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:53. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence 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 HIt comprises the amino acid sequence SEQ ID NO:43 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:43; and V L It comprises the amino acid sequence SEQ ID NO:53 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:53. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence 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 It comprises the amino acid sequence SEQ ID NO:44 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:44; and V L It comprises the amino acid sequence SEQ ID NO:53 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:53. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence 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 HIt comprises the amino acid sequence SEQ ID NO:39 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:39; and V L It comprises the amino acid sequence SEQ ID NO:54 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:54. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence 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 It comprises the amino acid sequence SEQ ID NO:40 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:40; and V L It comprises the amino acid sequence SEQ ID NO:54 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:54. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence 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 HIt comprises the amino acid sequence SEQ ID NO:41 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:41; and V L It comprises the amino acid sequence SEQ ID NO:54 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:54. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0320] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H It comprises the amino acid sequence SEQ ID NO:42 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:42; and V L It comprises the amino acid sequence SEQ ID NO:54 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:54. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0321] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V HIt comprises the amino acid sequence SEQ ID NO:43 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:43; and V L It comprises the amino acid sequence SEQ ID NO:54 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:54. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0322] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H It comprises the amino acid sequence SEQ ID NO:44 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:44; and V L It comprises the amino acid sequence SEQ ID NO:54 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:54. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0323] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V HIt comprises the amino acid sequence SEQ ID NO:39 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:39; and V L It comprises the amino acid sequence SEQ ID NO:55 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:55. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0324] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H It comprises the amino acid sequence SEQ ID NO:40 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:40; and V L It comprises the amino acid sequence SEQ ID NO:55 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:55. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0325] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V HIt comprises the amino acid sequence SEQ ID NO:41 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:41; and V L It comprises the amino acid sequence SEQ ID NO:55 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:55. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0326] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H It comprises the amino acid sequence SEQ ID NO:42 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:42; and V L It comprises the amino acid sequence SEQ ID NO:55 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:55. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0327] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V HIt comprises the amino acid sequence SEQ ID NO:43 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:43; and V L It comprises the amino acid sequence SEQ ID NO:55 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:55. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0328] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H It comprises the amino acid sequence SEQ ID NO:44 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:44; and V L It comprises the amino acid sequence SEQ ID NO:55 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:55. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0329] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V HIt comprises the amino acid sequence SEQ ID NO:45 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:45; and V L It comprises the amino acid sequence SEQ ID NO:56 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:56. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0330] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H It comprises the amino acid sequence SEQ ID NO:45 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:45; and V L It comprises the amino acid sequence SEQ ID NO:57 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:57. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0331] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V HIt comprises the amino acid sequence SEQ ID NO:46 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:46; and V L It comprises the amino acid sequence SEQ ID NO:58 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:58. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0332] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H It comprises the amino acid sequence SEQ ID NO:47 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:47; and V L It comprises the amino acid sequence SEQ ID NO:59 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:59. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0333] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V HIt comprises the amino acid sequence SEQ ID NO:48 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:48; and V L It comprises the amino acid sequence SEQ ID NO:60 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:60. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0334] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H It comprises the amino acid sequence SEQ ID NO:49 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:49; and V L It comprises the amino acid sequence SEQ ID NO:61 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:61. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0335] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V HIt comprises the amino acid sequence SEQ ID NO:50 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:50; and V L It comprises the amino acid sequence SEQ ID NO:62 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:62. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0336] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H It comprises the amino acid sequence SEQ ID NO:51 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:51; and V L It comprises the amino acid sequence SEQ ID NO:63 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:63. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0337] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V HIt comprises the amino acid sequence SEQ ID NO:82 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:82; and V L It comprises the amino acid sequence SEQ ID NO:90 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:90. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0338] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H It comprises the amino acid sequence SEQ ID NO:83 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:83; and V L It comprises the amino acid sequence SEQ ID NO:90 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:90. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0339] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V HIt comprises the amino acid sequence SEQ ID NO:84 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:84; and V L It comprises the amino acid sequence SEQ ID NO:90 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:90. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0340] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H It comprises the amino acid sequence SEQ ID NO:85 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:85; and V L It comprises the amino acid sequence SEQ ID NO:90 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:90. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0341] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V HIt comprises the amino acid sequence SEQ ID NO:86 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:86; and V L It comprises the amino acid sequence SEQ ID NO:91 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:91. In some embodiments, said IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0342] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H It comprises the amino acid sequence SEQ ID NO:87 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:87; and V L It comprises the amino acid sequence SEQ ID NO:91 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:91. In some embodiments, said IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0343] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V HIt comprises the amino acid sequence SEQ ID NO:88 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:88; and V L It comprises the amino acid sequence SEQ ID NO:91 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:91. In some embodiments, said IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0344] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG1 constant region is provided, wherein the anti-GDF15 antibody comprises: V H It comprises the amino acid sequence SEQ ID NO:89 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:89; and V L It comprises the amino acid sequence SEQ ID NO:91 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:91. In some embodiments, said IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0345] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V HIt comprises the amino acid sequence SEQ ID NO:38 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:38; and V L It comprises the amino acid sequence SEQ ID NO:52 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:52. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0346] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V H It comprises the amino acid sequence SEQ ID NO:39 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:39; and V L It comprises the amino acid sequence SEQ ID NO:53 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:53. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0347] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V HIt comprises the amino acid sequence SEQ ID NO:40 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:40; and V L It comprises the amino acid sequence SEQ ID NO:53 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:53. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0348] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V H It comprises the amino acid sequence SEQ ID NO:41 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:41; and V L It comprises the amino acid sequence SEQ ID NO:53 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:53. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0349] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V HIt comprises the amino acid sequence SEQ ID NO:42 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:42; and V L It comprises the amino acid sequence SEQ ID NO:53 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:53. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0350] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V H It comprises the amino acid sequence SEQ ID NO:43 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:43; and V L It comprises the amino acid sequence SEQ ID NO:53 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:53. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0351] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V HIt comprises the amino acid sequence SEQ ID NO:44 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:44; and V L It comprises the amino acid sequence SEQ ID NO:53 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:53. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0352] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V H It comprises the amino acid sequence SEQ ID NO:39 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:39; and V L It comprises the amino acid sequence SEQ ID NO:54 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:54. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0353] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V HIt comprises the amino acid sequence SEQ ID NO:40 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:40; and V L It comprises the amino acid sequence SEQ ID NO:54 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:54. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0354] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V H It comprises the amino acid sequence SEQ ID NO:41 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:41; and V L It comprises the amino acid sequence SEQ ID NO:54 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:54. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0355] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V HIt comprises the amino acid sequence SEQ ID NO:42 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:42; and V L It comprises the amino acid sequence SEQ ID NO:54 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:54. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0356] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V H It comprises the amino acid sequence SEQ ID NO:43 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:43; and V L It comprises the amino acid sequence SEQ ID NO:54 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:54. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0357] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V HIt comprises the amino acid sequence SEQ ID NO:44 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:44; and V L It comprises the amino acid sequence SEQ ID NO:54 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:54. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0358] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V H It comprises the amino acid sequence SEQ ID NO:39 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:39; and V L It comprises the amino acid sequence SEQ ID NO:55 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:55. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0359] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V HIt comprises the amino acid sequence SEQ ID NO:40 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:40; and V L It comprises the amino acid sequence SEQ ID NO:55 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:55. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0360] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V H It comprises the amino acid sequence SEQ ID NO:41 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:41; and V L It comprises the amino acid sequence SEQ ID NO:55 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:55. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0361] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V HIt comprises the amino acid sequence SEQ ID NO:42 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:42; and V L It comprises the amino acid sequence SEQ ID NO:55 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:55. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0362] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V H It comprises the amino acid sequence SEQ ID NO:43 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:43; and V L It comprises the amino acid sequence SEQ ID NO:55 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:55. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0363] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V HIt comprises the amino acid sequence SEQ ID NO:44 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:44; and V L It comprises the amino acid sequence SEQ ID NO:55 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:55. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0364] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V H It comprises the amino acid sequence SEQ ID NO:45 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:45; and V L It comprises the amino acid sequence SEQ ID NO:56 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:56. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0365] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V HIt comprises the amino acid sequence SEQ ID NO:45 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:45; and V L It comprises the amino acid sequence SEQ ID NO:57 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:57. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:67.

[0366] In some embodiments, a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, wherein the anti-GDF15 antibody comprises: V H It comprises the amino acid sequence SEQ ID NO:46 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:46; and V L It comprises the amino acid sequence SEQ ID NO:58 or a variant thereof, said variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:58. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or is composed of the amino acid ...

Claims

1. An isolated anti-GDF15 antibody, wherein the anti-GDF15 antibody comprises: V H The V H Contains: HC-CDR1, with the amino acid sequence SEQ ID NO: 1; HC-CDR2, with the amino acid sequence SEQ ID NO: 7; and HC-CDR3, with the amino acid sequence SEQ ID NO: 13; and V L The V L It includes: LC-CDR1, whose amino acid sequence is SEQ ID NO: 18; LC-CDR2, whose amino acid sequence is SEQ ID NO: 23; and LC-CDR3, whose amino acid sequence is SEQ ID NO:

30.

2. The isolated anti-GDF15 antibody according to claim 1, comprising: (i) V H Its amino acid sequence is SEQ ID NO: 38 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 38; and V L Its amino acid sequence is SEQ ID NO: 52 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 52; (ii) V H Its amino acid sequence is SEQ ID NO: 39 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 39; and V L Its amino acid sequence is SEQ ID NO: 53 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 53; (iii) V H Its amino acid sequence is SEQ ID NO: 40 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 40; and V L Its amino acid sequence is SEQ ID NO: 53 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 53; (iv) V H Its amino acid sequence is SEQ ID NO: 41 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 41; and V L Its amino acid sequence is SEQ ID NO: 53 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 53; (v) V H Its amino acid sequence is SEQ ID NO: 42 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 42; and V L Its amino acid sequence is SEQ ID NO: 53 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 53; (vi) V H Its amino acid sequence is SEQ ID NO: 43 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 43; and V L Its amino acid sequence is SEQ ID NO: 53 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 53; (vii) V H Its amino acid sequence is SEQ ID NO: 44 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 44; and V L Its amino acid sequence is SEQ ID NO: 53 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 53; (viii) V H Its amino acid sequence is SEQ ID NO: 39 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 39; and V L Its amino acid sequence is SEQ ID NO: 54 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 54; (ix) V H Its amino acid sequence is SEQ ID NO: 40 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 40; and V L Its amino acid sequence is SEQ ID NO: 54 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 54; (x) V H Its amino acid sequence is SEQ ID NO: 41 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 41; and V L Its amino acid sequence is SEQ ID NO: 54 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 54; (xi) V H Its amino acid sequence is SEQ ID NO: 42 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 42; and V L Its amino acid sequence is SEQ ID NO: 54 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 54; (xii) V H Its amino acid sequence is SEQ ID NO: 43 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 43; and V L Its amino acid sequence is SEQ ID NO: 54 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 54; (xiii) V H Its amino acid sequence is SEQ ID NO: 44 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 44; and V L Its amino acid sequence is SEQ ID NO: 54 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 54; (xiv) V H Its amino acid sequence is SEQ ID NO: 39 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 39; and V L Its amino acid sequence is SEQ ID NO: 55 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 55; (xv) V H Its amino acid sequence is SEQ ID NO: 40 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 40; and V L Its amino acid sequence is SEQ ID NO: 55 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 55; (xvi) V H Its amino acid sequence is SEQ ID NO: 41 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 41; and V L Its amino acid sequence is SEQ ID NO: 55 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 55; (xvii) V H Its amino acid sequence is SEQ ID NO: 42 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 42; and V L Its amino acid sequence is SEQ ID NO: 55 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 55; (xviii) V H Its amino acid sequence is SEQ ID NO: 43 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 43; and V L Its amino acid sequence is SEQ ID NO: 55 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 55; (xix) V H Its amino acid sequence is SEQ ID NO: 44 or a variant thereof, said variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO: 44; and V L The amino acid sequence is SEQ ID NO: 55 or a variant thereof, the variant having at least 80% sequence identity with the amino acid sequence SEQ ID NO:

55.

3. The isolated anti-GDF15 antibody according to claim 1, wherein the Kd value of the anti-GDF15 antibody binding to human GDF15 is 0.1 pM to 10 nM.

4. The isolated anti-GDF15 antibody according to any one of claims 1-3, wherein the anti-GDF15 antibody comprises an Fc fragment.

5. The isolated anti-GDF15 antibody according to claim 4, wherein the anti-GDF15 antibody is a full-length IgA, IgD, IgE, IgG or IgM antibody.

6. The isolated anti-GDF15 antibody according to claim 5, wherein the anti-GDF15 antibody is a full-length IgG1, IgG2, IgG3 or IgG4 antibody.

7. The isolated anti-GDF15 antibody according to any one of claims 1-3, wherein the anti-GDF15 antibody is a chimeric, human, or humanized antibody.

8. The isolated anti-GDF15 antibody according to any one of claims 1-3, wherein the anti-GDF15 antibody is an antigen-binding fragment selected from Fab, Fab', F(ab)'2, single-chain Fv (scFv), and Fv fragment.

9. An isolated nucleic acid molecule encoding the anti-GDF15 antibody according to any one of claims 1-8.

10. A carrier comprising the nucleic acid molecule of claim 9.

11. An isolated host cell comprising the anti-GDF15 antibody of any one of claims 1-8, the nucleic acid molecule of claim 9, or the vector of claim 10.

12. A method for preparing an anti-GDF15 antibody, comprising: a) Culture the host cells of claim 11 under conditions that enable effective expression of anti-GDF15 antibody; and b) Obtain the expressed anti-GDF15 antibody from the host cell.

13. A pharmaceutical composition comprising the anti-GDF15 antibody of any one of claims 1-8, the nucleic acid molecule of claim 9, the carrier of claim 10, the isolated host cell of claim 11 or the antibody prepared by the method of claim 12, and a pharmaceutically acceptable carrier.

14. Use of the antibody of any one of claims 1-8, the nucleic acid molecule of claim 9, the vector of claim 10, the host cell of claim 11, the antibody prepared by the method of claim 12, or the pharmaceutical composition of claim 13 in the preparation of a medicament for treating an individual disease or condition requiring such treatment, wherein the disease or condition is cachexia caused by dysregulation of the GDF15 signaling pathway.

15. The use according to claim 14, wherein the cachexia is cancer-associated cachexia.

16. The use according to claim 15, wherein the cancer is selected from lung cancer, colon cancer, pancreatic cancer, and bladder cancer.

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