WO2023217068A1 - 特异性识别gdf15的抗体及其应用 - Google Patents

特异性识别gdf15的抗体及其应用 Download PDF

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WO2023217068A1
WO2023217068A1 PCT/CN2023/092690 CN2023092690W WO2023217068A1 WO 2023217068 A1 WO2023217068 A1 WO 2023217068A1 CN 2023092690 W CN2023092690 W CN 2023092690W WO 2023217068 A1 WO2023217068 A1 WO 2023217068A1
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amino acid
acid sequence
sequence seq
variant
seq
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PCT/CN2023/092690
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French (fr)
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黄杰
李萃
李平
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舒泰神（北京）生物制药股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants

Definitions

  • the present invention relates to antibodies that specifically recognize GDF15, their preparation methods and uses, including methods of using them to treat cancer, cachexia and/or metabolic diseases.
  • GDF15 Growth differentiation factor-15
  • TGF- ⁇ transforming growth factor beta
  • pre-pro-GDF15 The post-translational unprocessed GDF15 protein has 308 amino acids, including signal peptide sequence (29aa), propeptide (167aa) and mature protein (112aa).
  • pro-GDF15 protein forms a pro-GDF15 homodimer through cysteine residues; it is then cleaved at the RXXR site, releasing the mature dimeric GDF15 protein and a propeptide at the C terminus (Wang X et al., Biochem Pharmacol, 2013).
  • Mature dimeric GDF15 protein is secreted into the extracellular matrix, and its normal circulating concentration range in healthy humans is approximately 0.15-1.15ng/ml. Concentrations of GDF15 increase with age, but there are no sex differences in healthy older adults. The concentration of GDF15 is related to the concentration of cystatin C and C-reactive protein (Brown, DA et al. Lancet, 2002.; Kempf, T. et al. Clin. Chem, 2007.). Circulating GDF15 increases during exercise and post-exercise recovery in humans. GDF15 is expressed in most tissues including skeletal muscle. Studies have shown that GDF15 is secreted from muscles during cellular stress or injury and acts locally in an autocrine or paracrine manner (Kleinert, M.
  • GDF15 is not normally expressed in adult myocardium, 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, GDF15 production is weak in most tissues under physiological conditions but is strongly induced upon inflammation and tissue injury.
  • GDF15 is classified as a member of the TGF ⁇ family, current research has not confirmed the TGF ⁇ receptor to which GDF15 directly binds.
  • GFRAL as a receptor for GDF15 (Hsu et al., Nature, 2017; Yang, L. et al., Nat Med, 2017; Mullican, S.E. et al., Nat Med, 2017; Emmerson, P.J. et al., Nat Med, 2017.).
  • the GDF15 dimer protein binds to the GFRAL receptor, and the GDF15-GFRAL complex recruits the co-receptor RET, causing dimerization and phosphorylation of RET as well as intracellular signals AKT, ERK1/2 and phospholipids Phosphorylation of enzyme C (PLC ⁇ ) (Shannon E. Mullican & Rangwala, 2018; L. Yang, et al., 2017).
  • PLC ⁇ Phosphorylation of enzyme C
  • GDF15/GFRAL signaling pathway is still not fully understood, and more research is needed to link the GDF15 receptor to the biological activity of mature GDF15, it can be confirmed that the molecular basis of GDF15 activity is through GFRAL/RET, not through TGF ⁇ signaling (Hsu et al., Nature, 2017).
  • GDF15 protein is related to various diseases such as obesity, insulin resistance, etc. (S.N. Breit et al., Growth Factors, 2011.). Knockout of GDF15 in genetically engineered mice resulted in increased body weight; overexpression of GDF15 resulted in reduced body weight and fat content and altered metabolic parameters in mice (L. Maccia et al., PLOS ONE, 2012; V.W. Tsai et al., PLOS ONE, 2013).
  • GDF15 plays an important role in the occurrence of cancer cachexia.
  • Cachexia is a medical condition caused by cancer that usually involves weight loss, muscle atrophy, fatigue, weakness, and severe loss of appetite in people who have not actively lost weight. It is a disease of AIDS, chronic obstructive pulmonary disease (COPD), and congestive heart failure. , one of the leading causes of late-stage morbidity and mortality in chronic diseases such as multiple sclerosis, tuberculosis and cancer. Among them, malignant tumors are the main factor inducing refractory cachexia. It is conservatively estimated that the number of new cancer cachexia in my country every year exceeds 1.5 million (accounting for about 36.4% of new cancer patients), and about 20% of cancer patients die.
  • GDF15 levels are associated with weight loss, reduced fat mass, muscle mass, strength, physical performance scores, and survival in cancer patients, while reduced lean body mass (LBM) is a negative and independent prognostic factor in cancer patients (Reuben DB, wait, Arch Intern Med, 1988.), reduced grip strength is associated with reduced survival in this population (Gale CR. et al., Int J Epidemiol. 2007).
  • Patent application WO2014100689A1 discloses monoclonal antibodies that bind to human GDF15 and inhibit the activity of human GDF15, and discloses that these antibodies can be used to treat weight loss associated with overexpression of human GDF15, including cachexia.
  • WO2015144855A1 relates to a monoclonal antibody directed against human GDF15 and its antigen-binding portion. The antibody or antigen-binding portion is capable of inhibiting cancer cachexia and/or cancer growth and is used to treat cancer-induced weight loss and/or cancer. Cachexia and cancer.
  • an isolated anti-GDF15 antibody comprising a heavy chain variable domain (V H ), the V H comprising: heavy chain complementarity determining region (HC-CDR) 1 comprising X 1 YYMX 2 ( SEQ ID NO : 35), wherein HC-CDR3 comprising VVYAGWTYPLGI (SEQ ID NO: 13); and light chain variable domain ( VL ) comprising: light chain complementarity determining region (LC-CDR) 1 comprising QASQSISSVLS (SEQ ID NO:18); LC - CDR2 , which contains EASX 1 ID NO:30).
  • an isolated anti-GDF15 antibody comprising a V H comprising: HC- CDR1 comprising the amino acid sequence shown in any one of SEQ ID NOs: 1-2 or a variant thereof HC-CDR2, which includes the amino acid sequence shown in any one of SEQ ID NOs: 7-8 or a variant thereof, which includes up to about 3 amino acid substitutions; Substitution of amino acids; and HC-CDR3 comprising the amino acid sequence shown in SEQ ID NO: 13 or a variant thereof, the variant comprising substitutions of up to about 3 amino acids; and VL , the VL comprising: LC -CDR1, which includes the amino acid sequence shown in SEQ ID NO: 18 or a variant thereof, which variant includes substitutions of up to about 3 amino acids; LC-CDR2, which includes any one of SEQ ID NOs: 23-25 The amino acid sequence shown in SEQ ID NO: 30 or a variant thereof, the variant comprising up to about 3 amino acid substitutions; and LC-CDR3 comprising the
  • an isolated anti-GDF15 antibody comprising: V H comprising HC- CDR1 comprised by V H as shown in any one of the amino acid sequences of SEQ ID NOs: 38-47, HC-CDR2 and HC-CDR3, and VL comprising LC-CDR1, LC- CDR2 and LC-CDR3 comprised by VL as shown in any of the amino acid sequences of SEQ ID NOs: 52-59.
  • an isolated anti-GDF15 antibody comprising: (i) a V H comprising HC-CDR1, HC-CDR2 and HC as shown in the amino acid sequence of SEQ ID NO:38 -CDR3; and VL , which comprises LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in the amino acid sequence SEQ ID NO: 52; (ii) VH , which comprises the amino acid sequence SEQ ID NO V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 as shown in: 39; and V L comprising LC-CDR1, LC-CDR2 and V L as shown in amino acid sequence SEQ ID NO: 53 LC-CDR3; (iii) VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by VH as shown in the amino acid sequence SEQ ID NO:40; and VL comprising the amino acid sequence SEQ ID LC
  • an isolated anti-GDF15 antibody comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2 comprising and V L ,
  • the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 18, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 23, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 30, or Variants of the V L , including substitutions of up to about 5 amino acids in its LC-CDRs;
  • V H the V H includes: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 1, HC- CDR2, which comprises the amino acid sequence SEQ ID NO: 7, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 13, or a variant of the V H whose HC-CDRs comprise substitutions of up to about 5 amino acids; and VL , said VL comprising: LC-CDR1, which includes the amino acid sequence
  • HC-CDR2 which includes the amino acid sequence SEQ ID NO: 7, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 13, or a variant of the V H , which HC-CDRs include up to about 5 substitution of amino acids; and VL , said VL comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 18, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 25, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO :30, or a variant of the VL , comprising at most about 5 amino acid substitutions in its LC-CDRs; (iv) VH , the VH comprising: HC-CDR1, comprising the amino acid sequence SEQ ID NO: 2.
  • HC-CDR2 which includes the amino acid sequence SEQ ID NO: 7, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 13, or a variant of the V H , whose HC-CDRs include up to about 5 Substitutions of amino acids; and V L comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO: 18, LC-CDR2 comprising the amino acid sequence SEQ ID NO: 25 , and LC-CDR3 comprising the amino acid sequence SEQ ID NO: 25 Sequence SEQ ID NO: 30, or a variant of the V L containing up to about 5 amino acid substitutions in its LC-CDRs; (v) V H comprising: HC- CDR1 comprising 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 a variant of the V H whose HC-CDRs contain Substitutions of up to about 5 amino
  • any of the isolated anti-GDF15 antibodies as described above includes: VH , which includes the amino acid sequence shown in any one of SEQ ID NOs: 38-47 or a variant thereof, the variant Having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 38-47; and V L comprising the amino acid sequence set forth in any one of SEQ ID NOs: 52-59 or a variant thereof , the variant has at least about 80% sequence identity with the amino acid sequence shown in any one of SEQ ID NOs: 52-59.
  • an isolated anti-GDF15 antibody comprising: (i) a V H comprising the amino acid sequence SEQ ID NO: 38 or a variant thereof that is at least identical to the amino acid sequence SEQ ID NO: 38 about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 52 or a variant thereof that has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 52; (ii) V H comprising the amino acid sequence SEQ ID NO:39 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:39; and VL comprising the amino acid sequence SEQ ID NO:53 or a variant thereof, which has at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 53; (iii) V H comprising the amino acid sequence SEQ ID NO: 40 or a variant thereof, the variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:40; and VL comprising the amino acid sequence SEQ ID NO:53 or a
  • V H comprising the amino acid sequence SEQ ID NO: 44 or a variant thereof that has at least about 80% sequence identity to 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, which variant has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:53;
  • VH which comprises the amino acid sequence SEQ ID NO:39 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:39; and V L comprising the amino acid sequence SEQ ID NO:54 or a variant thereof having the amino acid sequence SEQ ID NO:54 or a variant thereof having an amino acid sequence identity with the amino acid sequence SEQ ID NO:39
  • the sequence SEQ ID NO:54 has at least about 80% sequence identity;
  • V H comprising the amino acid sequence SEQ ID NO:40 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:40 80% sequence identity;
  • V H comprising the amino acid sequence SEQ ID NO: 43 or a variant thereof that has at least about 80% sequence identity to 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, which variant has at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 54;
  • V H comprising the amino acid sequence SEQ ID NO: 44 or a variant thereof, which variant has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:44; and VL , which comprises the amino acid sequence SEQ ID NO:54 or a variant thereof, which variant has the amino acid sequence SEQ ID NO:54
  • the sequence SEQ ID NO:54 has at least about 80% sequence identity;
  • V H comprising the amino acid sequence SEQ ID NO:39 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:39 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:54
  • V H comprising the amino acid sequence SEQ ID NO: 42 or a variant thereof that has at least about 80% sequence identity to 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, which variant has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:55;
  • VH which comprises the amino acid sequence SEQ ID NO:43 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 43; and V L comprising the amino acid sequence SEQ ID NO: 55 or a variant thereof, which variant has at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 55;
  • V H comprising the amino acid sequence SEQ ID NO: 44 or a variant thereof , the variant having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:44; and V L , comprising the amino acid sequence SEQ ID NO:55 or a variant thereof, the variant
  • an isolated anti-GDF15 antibody comprising: (i) a VH comprising HC-CDR1, HC-CDR2 and HC as shown in the amino acid sequence of SEQ ID NO:48 -CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in the amino acid sequence SEQ ID NO:60.
  • an isolated anti-GDF15 antibody comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 3, HC-CDR2 comprising and V L ,
  • the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 19, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 26, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 31, or
  • the V L variant contains at most about 5 amino acid substitutions in its LC-CDRs.
  • any of the isolated anti-GDF15 antibodies described above includes: VH , which includes the amino acid sequence shown in SEQ ID NO: 48 or a variant thereof, which variant is consistent with SEQ ID NO: The amino acid sequence shown in 48 has at least about 80% sequence identity; and VL , which includes the amino acid sequence shown in SEQ ID NO:60 or a variant thereof that is identical to the amino acid sequence shown in SEQ ID NO:60 The sequences have at least about 80% sequence identity.
  • an isolated anti-GDF15 antibody comprising: (i) a V H comprising HC-CDR1, HC-CDR2 and HC as shown in the amino acid sequence of SEQ ID NO:49 -CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in the amino acid sequence SEQ ID NO:61.
  • an isolated anti-GDF15 antibody comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 4, HC-CDR2 comprising and V L ,
  • the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO:20, LC-CDR2, which includes the amino acid sequence SEQ ID NO:27, and LC-CDR3, which includes the amino acid sequence SEQ ID NO:32, or
  • the V L variant contains at most about 5 amino acid substitutions in its LC-CDRs.
  • any of the isolated anti-GDF15 antibodies as described above includes: VH , which includes the amino acid sequence shown in SEQ ID NO: 49 or a variant thereof, which variant is consistent with SEQ ID NO: The amino acid sequence shown in 49 has at least about 80% sequence identity; and VL , which includes the amino acid sequence shown in SEQ ID NO:61 or a variant thereof that is identical to the amino acid sequence shown in SEQ ID NO:61 The sequences have at least about 80% sequence identity.
  • an isolated anti-GDF15 antibody comprising: (i) a V H comprising HC-CDR1, HC-CDR2 and HC as shown in the amino acid sequence of SEQ ID NO:50 -CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in the amino acid sequence SEQ ID NO:62.
  • an isolated anti-GDF15 antibody comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 5, HC-CDR2 comprising and V L ,
  • the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 21, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 28, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 33, or
  • the V L variant contains at most about 5 amino acid substitutions in its LC-CDRs.
  • any of the isolated anti-GDF15 antibodies described above includes: VH , which includes the amino acid sequence shown in SEQ ID NO: 50 or a variant thereof, which variant is consistent with SEQ ID NO: The amino acid sequence shown in 50 has at least about 80% sequence identity; and VL , which includes the amino acid sequence shown in SEQ ID NO:62 or a variant thereof that is identical to the amino acid sequence shown in SEQ ID NO:62 The sequences have at least about 80% sequence identity.
  • an isolated anti-GDF15 antibody comprising a heavy chain variable domain ( VH ), the VH comprising: heavy chain complementarity determining region (HC-CDR) 1 comprising SYDMT (SEQ ID NO: 6) ; HC-CDR2 comprising IIX 1 X 2 SGX 3 TYYASWAKG (SEQ ID NO: 79), wherein and HC-CDR3, which includes GILVYADYGDHNL (SEQ ID NO:17); and light chain variable domain ( VL ), which includes: light chain complementarity determining region (LC-CDR) 1, which includes QASEDIYTNLA (SEQ ID NO:22); LC-CDR2, which contains AASTLAS (SEQ ID NO:29); and LC-CDR3, which contains LGVYTYISAX 1 GA (SEQ ID NO:81), where X 1 is D or E.
  • HC-CDR heavy chain complementarity determining region
  • HC-CDR2 comprising IIX 1 X 2 SGX 3 TYY
  • an isolated anti-GDF15 antibody which includes VH , and the VH includes: HC-CDR1, which includes the amino acid sequence shown in SEQ ID NO: 6 or a variant thereof, the variant The body comprises a substitution of up to about 3 amino acids; HC-CDR2, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 12, 75-78 or a variant thereof, the variant comprises a substitution of up to about 3 amino acids.
  • HC-CDR3 which comprises the amino acid sequence shown in SEQ ID NO: 17 or a variant thereof, said variant comprising a substitution of up to about 3 amino acids; and VL , said VL comprising: LC-CDR1, It includes the amino acid sequence shown in SEQ ID NO:22 or a variant thereof, which variant includes a substitution of up to about 3 amino acids; LC-CDR2, which includes the amino acid sequence shown in SEQ ID NO:29 or a variant thereof , the variant includes substitutions of up to about 3 amino acids; and LC-CDR3, which includes the amino acid sequence shown in any one of SEQ ID NOs: 34, 80 or a variant thereof, the variant includes up to about 3 Amino acid substitutions.
  • an isolated anti-GDF15 antibody comprising: V H comprising a V H comprising HC- as shown in any of the amino acid sequences of SEQ ID NOs: 51, 82-89 CDR1, HC-CDR2 and HC-CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC comprised by VL as shown in any of the amino acid sequences of SEQ ID NOs: 63, 90-91 -CDR3.
  • an isolated anti-GDF15 antibody comprising: (i) a V H comprising HC-CDR1, HC-CDR2 and HC as shown in the amino acid sequence of SEQ ID NO:51 -CDR3; and VL , which comprises LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in the amino acid sequence SEQ ID NO: 63; (ii) VH , which comprises the amino acid sequence SEQ ID NO V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 as shown in: 82; and V L comprising LC-CDR1, LC-CDR2 and V L as shown in amino acid sequence SEQ ID NO: 90 LC-CDR3; (iii) VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by VH as shown in the amino acid sequence SEQ ID NO:83; and VL comprising the amino acid sequence SEQ ID
  • an isolated anti-GDF15 antibody comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 6, HC-CDR2 comprising and V L ,
  • the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 22, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 29, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 34, or Variants of the V L , including substitutions of up to about 5 amino acids in its LC-CDRs;
  • V H the V H includes: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 6, HC- CDR2, which comprises the amino acid sequence SEQ ID NO: 75, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 17, or a variant of the V H whose HC-CDRs comprise substitutions of up to about 5 amino acids; and VL , said VL comprising:
  • HC-CDR2 which includes the amino acid sequence SEQ ID NO: 76, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 17, or a variant of the V H , which includes up to about 5 HC-CDRs.
  • V L comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO: 22, LC-CDR2 comprising the amino acid sequence SEQ ID NO: 29, and LC-CDR3 comprising the amino acid sequence SEQ ID NO: 29
  • Sequence SEQ ID NO: 80 or a variant of the V L containing up to about 5 amino acid substitutions in its LC-CDRs;
  • V H comprising: HC- CDR1 comprising 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 a variant of the V H whose HC-CDRs contain Substitutions of up to
  • any of the isolated anti-GDF15 antibodies as described above includes: VH , which includes the amino acid sequence shown in any one of SEQ ID NOs: 51, 82-89 or a variant thereof, said A variant having at least about 80% sequence identity with the amino acid sequence set forth in any of SEQ ID NOs: 51, 82-89; and V L comprising The amino acid sequence shown in any one of SEQ ID NOs: 63, 90-91 or a variant thereof, which variant has at least about 80% sequence with the amino acid sequence shown in any one of SEQ ID NOs: 63, 90-91 Identity.
  • any of the isolated anti-GDF15 antibodies as described above which includes: (i) VH , which includes the amino acid sequence shown in SEQ ID NO: 51 or a variant thereof, which variant is identical to SEQ ID NO:51
  • the amino acid sequence shown in ID NO:51 has at least about 80% sequence identity
  • VL which includes the amino acid sequence shown in SEQ ID NO:63 or a variant thereof, which variant is identical to the amino acid sequence shown in SEQ ID NO:63
  • the amino acid sequence shown has at least about 80% sequence identity
  • (ii) VH which comprises the amino acid sequence SEQ ID NO:82 or a variant thereof, which variant has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:82 Sequence identity
  • VL which comprises the amino acid sequence SEQ ID NO:90 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:90
  • VH which comprising the amino acid sequence SEQ ID NO:83 or a variant
  • V H comprising the amino acid sequence SEQ ID NO: 84 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 84; and V L comprising the amino acid sequence SEQ ID NO:90 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:90;
  • VH comprising the amino acid sequence SEQ ID NO:85 or a variant thereof, The variant has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:85; and a VL comprising the amino acid sequence SEQ ID NO:90 or a variant thereof that is identical to the amino acid sequence SEQ ID NO: 90 having at least about 80% sequence identity;
  • V H comprising the amino acid sequence SEQ ID NO: 86 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 86 ; and V L , comprising the amino acid sequence SEQ ID NO: 91 or a variant thereof having at least about 80% sequence identity with the amino acid
  • the isolated anti-GDF15 antibody binds to human GDF15 with a Kd value of 0.1 pM to about 10 nM.
  • 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.
  • any of the isolated anti-GDF15 antibodies described above, the isolated anti-GDF15 antibody comprises an Fc fragment.
  • the isolated anti-GDF15 antibody is a full-length IgG antibody.
  • the isolated anti-GDF15 antibody is a full-length IgGl, IgG2, IgG3 or IgG4 antibody.
  • the isolated anti-GDF15 antibody is a chimeric, fully human, or humanized antibody.
  • the isolated anti-GDF15 antibody is an antigen-binding fragment selected from the group consisting of Fab, Fab', F(ab)' 2 , Fab'-SH, single chain Fv (scFv), Fv Fragments, dAbs, Fds, nanobodies, diabodies and linear antibodies.
  • an isolated nucleic acid molecule encoding any of the anti-GDF15 antibodies described above is provided.
  • a vector is provided comprising any of the nucleic acid molecules described above.
  • a host cell is provided, the host cell comprising any one of the anti-GDF15 antibodies described above, any one of the nucleic acid molecules described above, or any one of the vectors described above.
  • a method for preparing an anti-GDF15 antibody is provided, which includes: a) culturing any of the above host cells under conditions that can effectively express the anti-GDF15 antibody; and b) obtaining the expressed anti-GDF15 antibody from the host cell. GDF15 antibody.
  • a method of treating a disease or condition in a desired individual comprising administering to the individual an effective amount of any of the anti-GDF15 antibodies described above.
  • provided is the use of any of the anti-GDF15 antibodies described above in the preparation of a pharmaceutical composition for treating a disease or condition in a desired individual.
  • the use of any anti-GDF15 antibody or a pharmaceutical composition comprising an anti-GDF15 antibody as described above in the preparation of a medicament for treating a disease or condition is provided.
  • the disease or disorder is related to the GDF15 signaling pathway, including cancer, cachexia, metabolic disease or disorder.
  • the disease or disorder 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 lymphoma, non-Hodgkin lymphoma, bladder cancer, cervical cancer, uterine cancer, testicular cancer, thyroid cancer, kidney cancer, gallbladder cancer, multiple myeloma, nasopharyngeal cancer, laryngeal cancer, pharyngeal cancer cancer, esophageal cancer, etc.), cachexia, cachexia-related weight loss, anorexia nervosa, metabolic diseases (such as imbalances in fat and energy metabolism, appetite regulation, weight regulation).
  • cancer such as brain cancer, melanoma, lung cancer, gastrointestinal tumors, colon cancer, pancreatic cancer, prostate cancer, breast cancer, oral cancer, liver cancer, leukemia , Hodgkin lymphoma, non-Hodgkin lympho
  • compositions, kits and manufactured products containing any of the anti-GDF15 antibodies mentioned above are also provided.
  • Figure 1 shows the effect of an exemplary lead anti-GDF15 antibody GDF-R37-rabIg1 on changes in mouse body weight in the HT1080 animal model of tumor cachexia.
  • Figures 2A-2C show the binding affinity of the humanized anti-GDF15 antibody derived from the lead antibody GDF-R37-rabIg1 to human GDF15 analyzed by ELISA.
  • Figures 3A-3C show the neutralizing effect of the humanized anti-GDF15 antibody derived from the lead antibody GDF-R37-rabIg1 on the binding of GDF15 and GFRAL analyzed by ELISA.
  • Figures 4A-4D show the in vitro biological activity of the humanized anti-GDF15 antibody derived from the lead antibody GDF-R37-rabIg1 in inhibiting GFRAL and RET downstream signaling activation analyzed in reporter cells.
  • Figure 5 shows the effects of exemplary anti-GDF15 antibodies Hum-R37-2, Hum-R37-5 and Hum-R37-8 on changes in mouse body weight in a mouse model of rapid weight loss.
  • the present application provides anti-GDF15 antibody molecules.
  • anti-GDF15 antibody molecules Through a combination of constructed 293T cell display library screening, antibody humanization, affinity maturation, and appropriately designed biochemical and biological experiments, highly efficient antibody molecules capable of binding to human GDF15 and inhibiting the interaction of human GDF15 with its receptor GFRAL have been identified.
  • the results presented here show that compared to the known anti-GDF15 antibody HuO1G06-127 (AVEO), the antibody in the application is even more effective than or equivalent to HuO1G06-127 in various biological experiments.
  • AVEO anti-GDF15 antibody
  • Anti-GDF15 antibodies provided by the present application include, for example, full-length anti-GDF15 antibodies, anti-GDF15 single chain antibodies (scFvs), anti-GDF15Fc fusion proteins, multispecific (such as bispecific) anti-GDF15 antibodies, and anti-GDF15 immunoconjugates. things and the like.
  • the application provides an anti-GDF15 antibody, the anti-GDF15 antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1, comprising X 1 YYMX 2 (SEQ ID NO:35), where X 1 is D or N, and X 2 is S or T; HC-CDR2, which contains MISFSGTTX 1 ATWAKG (SEQ ID NO: 36), where and HC-CDR3 comprising VVYAGWTYPLGI (SEQ ID NO: 13); and light chain variable domain (V L ) comprising: light chain complementarity determining region (LC-CDR) 1 comprising QASQSISSVLS (SEQ ID NO: 18 ) ; LC-CDR2, which contains EASX 1 (SEQ ID NO:30).
  • VH heavy chain variable domain
  • HC-CDR heavy chain complementarity determining region
  • LC-CDR2 heavy chain complementarity determining region
  • the application provides an anti-GDF15 antibody, the anti-GDF15 antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 comprising 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 domain (V L ) , the V L includes: light chain complementarity determining region (LC-CDR) 1, which includes QASQSISSYLA (SEQ ID NO: 19); LC-CDR2, which includes KASTLAS (SEQ ID NO: 26); and LC-CDR3, It contains RCIYGDSYGAA (SEQ ID NO:31).
  • the application provides an anti-GDF15 antibody, the anti-GDF15 antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 comprising 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 includes: light chain complementarity determining region (LC-CDR) 1, which includes QSSKSVVNGDWLA (SEQ ID NO: 20); LC-CDR2, which includes DATLAS (SEQ ID NO: 27); and LC-CDR3, It contains AGVYNNDSDNG (SEQ ID NO:32).
  • VH heavy chain variable domain
  • HC-CDR heavy chain complementarity determining region
  • the application provides an anti-GDF15 antibody, the anti-GDF15 antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 comprising 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 domain (V L ) , the V L includes: light chain complementarity determining region (LC-CDR) 1, which includes QASEYIYSSLA (SEQ ID NO: 21); LC-CDR2, which includes DASDLAS (SEQ ID NO: 28); and LC-CDR3, It contains QCTDLSSAGNT (SEQ ID NO:33).
  • VH heavy chain variable domain
  • HC-CDR heavy chain complementarity determining region
  • TYWMS SEQ ID NO:5
  • HC-CDR2 which
  • the application provides an anti-GDF15 antibody, the anti-GDF15 antibody comprising: a heavy chain variable domain ( VH ), the VH comprising: a heavy chain complementarity determining region (HC-CDR) 1 comprising SYDMT ( SEQ ID NO:6); HC-CDR2 comprising IIX 1 X 2 SGX 3 TYYASWAKG (SEQ ID NO: 79 ), where or S; and HC-CDR3, which comprises GILVYADYGDHNL (SEQ ID NO: 17); and a light chain variable domain (V L ), which V L comprises: light chain complementarity determining region (LC-CDR) 1, which Contains QASEDIYTNLA (SEQ ID NO:22); LC-CDR2, which contains AASTLAS (SEQ ID NO:29); and LC-CDR3, which contains LGVYTYISAX 1 GA (SEQ ID NO:81), where X 1 is D or E .
  • VH heavy chain variable domain
  • HC-CDR heavy chain complement
  • nucleic acids encoding anti-GDF15 antibodies are also provided.
  • compositions containing anti-GDF15 antibodies are also provided.
  • treatment is a method of obtaining beneficial or desired results, including clinical results.
  • said beneficial or desired clinical results Including but not limited to one or more of the following: alleviating one or more symptoms caused by the disease, reducing the severity of the disease, stabilizing the disease (e.g., preventing or delaying the progression of the disease), preventing or delaying the spread of the disease (e.g., metastasis) , prevent or delay disease recurrence, delay or slow disease progression, improve disease status, alleviate disease (partial or complete), reduce the dose of one or more other drugs required to treat the disease, delay disease progression, improve or improve quality of life , increase in body weight, and/or prolong survival.
  • treatment also includes the reduction of pathological consequences of the disease
  • antibody includes full-length antibodies and antigen-binding fragments thereof.
  • Full-length antibodies include two heavy chains and two light chains.
  • the variable regions of the light and heavy chains are responsible for antigen binding.
  • the variable regions in the two chains usually include three hypervariable loops, called 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).
  • CDRs complementarity determining regions
  • the CDR boundaries of the antibodies or antigen-binding fragments disclosed herein may be defined or identified by the Kabat, Chothia or Al-Lazikani convention (Al-Lazikani 1997; Chothia 1985; Chothia 1987; Chothia 1989; Kabat 1987; Kabat 1991).
  • the three CDR regions of the heavy or light chain are inserted between flanking segments called framework regions (FRs), which are more conserved than the CDR regions and form a scaffold supporting the hypervariable loops.
  • FRs flanking segments
  • heavy chain and light chain The constant region is not involved in antigen binding but exhibits a variety of effector functions.
  • Antibodies are classified based on the amino acid sequence of their heavy chain constant region.
  • the five major classes or isotypes of antibodies are IgA, IgD, IgE, IgG, and IgM, characterized by heavy chains of the alpha, delta, epsilon, gamma, and mu types, respectively.
  • major antibody classes are divided into subclasses, such as IgG1 ( ⁇ 1 heavy chain), IgG2 ( ⁇ 2 heavy chain), IgG3 ( ⁇ 3 heavy chain), IgG4 ( ⁇ 4 heavy chain), IgA1 ( ⁇ 1 heavy chain), or IgA2 ( ⁇ 2 heavy chain).
  • antigen-binding fragment includes antibody fragments, e.g., diabodies, Fab, Fab', F(ab') 2 , Fv fragments, disulfide-stabilized Fv fragments (dsFv), (dsFv) 2.
  • Bispecific dsFv (dsFv-dsFv'), disulfide bond-stabilized diabody (ds diabody), single-chain Fv (scFv), scFv dimer (bivalent diabody), Multispecific antibodies consisting of antibody fragments containing one or more CDRs, single domain antibodies, nanobodies, domain antibodies, bivalent 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 to the same antigen as the parent antibody or parent antibody fragment (eg, parent scFv).
  • Antigen-binding fragments also include fusion proteins containing the above-described antibody fragments.
  • the antigen-binding fragment may include one or more CDRs from a specific human antibody grafted to framework regions from one or more different human antibodies.
  • epitope refers to a specific group of atoms or amino acids on an antigen to which an antibody or antibody portion binds. If two antibodies or antibody portions exhibit competitive binding to an antigen, they may bind to the same epitope on the antigen.
  • a first antibody inhibits binding of a second antibody to the GDF15 target by at least 50% (e.g., at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%) at equimolar concentrations. , 95%, 98% or 99%), the first antibody "competes" with the second antibody for binding to the GDF15 target, and vice versa.
  • PCT publication WO03/48731 describes a cross-competition based high-throughput antibody "epitope classification" approach.
  • the terms “specifically bind,” “specifically recognize,” or “specific for” refer to a measurable and reproducible interaction, e.g., binding of an antibody to a target can The presence of the target in a heterogeneous population of molecules, including biomolecules, is determined.
  • the ability of an antibody to specifically recognize a target means that the antibody binds to the target with higher affinity, avidity, easier and/or longer duration than to other targets.
  • an antibody that specifically recognizes an antigen reacts with one or more epitopes of the antigen with a binding affinity that is at least 10 times greater than its binding affinity to other targets.
  • 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 from the same source, and (3) is produced from a different species Expressed by cells of the genus, or (4) does not exist in nature.
  • isolated nucleic acid refers to nucleic acids of genomic, cDNA or synthetic origin, or combinations thereof. Depending on its source, the “isolated nucleic acid” refers to (1) not related to all or part of the polynucleotides in the "isolated nucleic acid” found in nature, (2) may not be related to polynucleotides that are not associated with it in the natural state. The nucleotides are operably linked, or (3) do not occur in nature as part of a longer sequence.
  • CDR or “complementarity determining region” means the non-contiguous antigen binding sites found within the variable domains of heavy and light chain polypeptides.
  • CDR or “complementarity determining region” means the non-contiguous antigen binding sites found within the variable domains of heavy and light chain polypeptides.
  • 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., J. Mol. Biol., 273: 927-948 (1997); MacCallum et al., J. Mol. Biol.
  • chimeric antibody means that a portion of the heavy chain and/or light chain is identical or homologous to the corresponding sequence in an antibody from a specific species or belonging to a specific antibody class or subclass, and this chain(s) Antibodies whose remainder are identical to or homologous to corresponding sequences in antibodies from another genus or belonging to other antibody classes or subclasses, as well as fragments of such antibodies, as long as they have the biological activity in this application ( See U.S. Patent No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)).
  • Fv is the smallest antibody fragment that contains complete antigen recognition and binding sites. This fragment is a dimer formed by a heavy chain variable domain and a light chain variable domain tightly non-covalently linked. The folding of these two domains results in 6 hypervariable loops (3 loops each in the light and heavy chains) that provide the antibody with a mechanism for binding the antigen. Amino acid residues that confer specificity for the antibody to bind to the antigen. However, even a single variable domain (or half of an Fv fragment, which contains only the 3 CDRs specific for the antigen) has the ability to recognize and bind the antigen, albeit with lower affinity than the complete binding site.
  • the scFv polypeptide further includes a linker polypeptide between the VH and VL domains that allows the scFv to form an ideal structure for antigen binding.
  • diabody is a small antibody fragment prepared by using a short linker (for example, 5 to 10 residues) between the V H and V L domains to construct an scFv fragment (see the previous paragraph). This allows the variable domains to pair inter-chain rather than intra-chain, resulting in a bivalent fragment, that is, a fragment with two antigen-binding sites.
  • Bispecific diabodies are heterodimers of two "cross-over" scFv fragments, in which the VH and VL domains of the two antibodies are located on different polypeptide chains.
  • Diabodies are fully described in EP 404,097; WO 93/11161; Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993).
  • Humanized forms of non-human (eg, rodent) antibodies are chimeric antibodies, which include minimal sequence from the non-human antibody.
  • humanized antibodies are human immunoglobulins (recipient antibodies) in which the hypervariable region (HVR) residues of the receptor antibody are modified from a non-human species such as mouse, rat, rabbit or Replacement of hypervariable region residues that are non-human mammalian and possess the desired antibody specificity, affinity and performance (donor antibody).
  • HVR hypervariable region residues of the receptor antibody
  • donor antibody residues in the human immunoglobulin framework region are replaced with corresponding non-human residues.
  • humanized antibodies may include residues that are not present in either the recipient antibody or the donor antibody. These modifications can further improve antibody performance.
  • a humanized antibody will contain substantially all, at least one, and usually two variable domains in which all or substantially all of the hypervariable loops correspond to hypervariable loops of a non-human immunoglobulin, and all or Essentially all framework regions are human immunoglobulin sequences.
  • the human antibody optionally also includes at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.
  • Fc immunoglobulin constant region
  • Percent amino acid sequence identity or “homology” of the polypeptide and antibody sequences identified herein is defined as follows: Sequence comparisons are made where conservative substitutions are considered part of the sequence identity, and the candidate sequence is compared with the candidate sequence to be Compares the percentage of identical amino acid residues in a polypeptide sequence. Percent amino acid sequence identity can be determined by a variety of alignment methods within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, Megalign (DNASTAR), or MUSCLE software. One skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms required to maximize alignment over the full length of the sequences being compared.
  • Fc receptor or "FcR” is used to describe a receptor that binds to the Fc region of an antibody.
  • the FcR described herein is an FcR that binds an IgG antibody, a gamma receptor, including receptors of the Fc ⁇ RI, Fc ⁇ RII, and Fc ⁇ RIII subclasses, including allelic variants and agonist variants of these receptors. Change splicing form.
  • Fc ⁇ RII receptors include Fc ⁇ RIIA (“activating receptor”) and Fc ⁇ RIIB (“inhibitory receptor”), which have similar amino acid sequences and differ mainly in the cytoplasmic domain.
  • the cytoplasmic domain of activating receptor Fc ⁇ RIIA contains an immunoreceptor tyrosine activation motif (ITAM).
  • the cytoplasmic domain of the inhibitory receptor Fc ⁇ RIIB contains an immunoreceptor tyrosine inhibitory motif (ITIM) (see M.in Annu. Rev. Immunol. 15:203-234 (1997)).
  • ITAM immunoreceptor tyrosine activation motif
  • ITIM immunoreceptor tyrosine inhibitory motif
  • FcR in this application covers other types of FcRs, including FcRs identified in the future.
  • FcR also includes the neonatal receptor FcRn, which is responsible for the transfer of maternal IgGs to the neonate (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994) )).
  • FcRn refers to the neonatal Fc receptor (FcRn).
  • FcRn is structurally similar to the major histocompatibility complex (MHC) and consists of an ⁇ chain non-covalently bound to ⁇ 2 microglobulin.
  • MHC major histocompatibility complex
  • FcRn plays an important role in the passive transport of immunoglobulin IgGs from mother to newborn and in regulating serum IgG levels.
  • FcRn serves as a rescue receptor that binds and transports endocytosed IgG in an intact form within and between cells and protects them from default degradation pathways.
  • the "CH1 domain" of the human IgG heavy chain constant region generally extends from amino acid 118 to amino acid 215 (EU numbering system).
  • the "hinge region” is generally defined as extending from position Glu 216 to position Pro 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 after the same position as IgG1, the hinge regions of other IgG isotypes can be aligned with the IgG1 sequence.
  • the "CH2 domain" of the human IgG Fc region usually extends from amino acid 231 to amino acid 340.
  • the unique feature of the CH2 domain is that it does not pair closely with another region, but instead has two N-terminal linked branched sugar chains inserted between the two CH2 domains of the intact natural IgG molecule. It is speculated that sugars may serve as a surrogate for domain-to-domain pairing, helping to keep the CH2 domain stable.
  • the "CH3" domain includes the region extending from the C-terminal residues within the Fc region to the CH2 domain (from amino acid 341 to the C-terminus of the antibody sequence, usually amino acid residue 446 or 447 of IgG).
  • a “functional Fc fragment” has the "effector function” possessed by a native Fc region sequence.
  • exemplary “effector functions” include Clq binding; complement-dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors ( Such as B cell receptor; BCR) wait.
  • effector functions typically require the binding of an Fc region to a binding domain (eg, an antibody variable region) and can be assessed using a variety of experimental methods well known in the art.
  • Antibodies with IgG Fc variants that have "altered" FcR binding affinity or ADCC activity have increased or decreased FcR binding activity and/or ADCC activity compared to the parent polypeptide or a polypeptide comprising a native Fc sequence.
  • An Fc variant that exhibits "enhanced binding" to an FcR has a higher binding affinity (e.g., a lower apparent Kd or IC50 value) to at least one FcR compared to the parent polypeptide or a polypeptide comprising a native IgG Fc sequence. ).
  • the binding capacity is enhanced 3-fold, such as 5, 10, 25, 50, 60, 100, 150, 200, even up to 500-fold or a 25% to 1000% increase in binding capacity compared to the parent polypeptide.
  • An Fc variant exhibits "reduced binding" to an FcR, having a lower affinity (eg, a higher apparent Kd or IC50 value) for at least one FcR compared to the parent polypeptide. Its binding capacity is reduced by 40% or more compared to the parent polypeptide.
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • cytotoxic cells e.g., natural killer cells (NK), neutrophils
  • FcRs Fc receptors
  • Antibodies “arm” cytotoxic cells and are required for this killing.
  • NK cells only express Fc ⁇ RIII
  • monocytes express Fc ⁇ RI, Fc ⁇ RII, and Fc ⁇ RIII.
  • FcR FcR on hematopoietic cells
  • Table 3 The expression of FcR on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991).
  • an in vitro ADCC assay can be performed, as described in U.S. Patent No. 5,500,362 or 5,821,337. Effector cells suitable for such experiments include peripheral blood mononuclear cells (PBMC) and natural killer cells (NK).
  • PBMC peripheral blood mononuclear cells
  • NK natural killer cells
  • the ADCC activity of the target molecule can also be assessed in vivo, for example in an animal model as disclosed in Clynes et al. PNAS (USA) 95:652-656 (1998).
  • the antibody polypeptide is essentially the same in quantity as the wild-type IgG Fc polypeptide (or parent polypeptide) during the experiment, it can more effectively mediate ADCC both in vitro and in vivo.
  • Such variants are generally identified using any in vitro ADCC assay known in the art, such as assays or methods for identifying ADCC activity, such as in animal models and the like. In some embodiments, such variants mediate ADCC 5- to 100-fold, for example, 25- to 50-fold more efficiently than wild-type Fc (or the parent polypeptide).
  • “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 antibodies (subclasses with appropriate structures) that bind cognate antigens.
  • C1q the first component of the complement system
  • CDC experiments can be performed as described in Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996). Polypeptide variants with altered Fc region amino acid sequences and increased or decreased Clq binding capacity are described in US Patent No. 6,194,551 Bl and WO99/51642. The contents of these patent publications are expressly incorporated herein by reference. See also Idusogie et al. J. Immunol. 164:4178-4184 (2000).
  • nucleotide sequence encoding an amino acid sequence includes all nucleotide sequences that are degenerates 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 include introns in some forms.
  • operably linked refers to a functional linkage between a regulatory sequence and a heterologous nucleotide sequence, thereby allowing expression of the latter.
  • a first nucleotide sequence is operably linked to a second nucleotide sequence when the first nucleotide sequence is in a functional relationship with the second nucleotide sequence.
  • a promoter is operably linked to a coding sequence if it affects the transcription or expression of the coding sequence.
  • operably linked DNA sequences are contiguous and, if necessary, two protein-coding regions can be joined in the same reading frame.
  • “Homology” refers to sequence similarity or sequence identity between two polypeptides or between two nucleic acid molecules. If the same position of two compared sequences contains the same base or amino acid monomer subunit, for example, the same position of two DNA molecules both contains adenine, then the two DNA molecules are homologous at that position.
  • the percent homology between two sequences is a function of the number of matching or homologous positions shared by the two sequences divided by the total number of positions multiplied by 100. For example, if 6 out of 10 positions in two sequences match or are homologous, the two sequences are 60% homologous. For example, the DNA sequences ATTGCC and TATGGC have 50% homology. Generally speaking, when comparing two sequences, the comparison is performed with the purpose of obtaining maximum homology.
  • an “effective amount” of an anti-GDF15 antibody or composition disclosed herein is an amount sufficient to achieve a specified purpose.
  • An “effective amount” can be determined empirically and by methods known to be relevant to the stated purpose.
  • a therapeutically effective amount refers to an amount of an anti-GDF15 antibody or composition thereof disclosed herein that is effective in treating a disease or condition in an individual.
  • a therapeutically effective amount of an anti-GDF15 antibody or composition thereof is one capable of reducing the number of cancer cells; reducing the size or weight of the tumor; inhibiting (i.e., slowing or preferably stopping to a certain extent) the impact of tumor cells on surrounding cells. Invasion of organs; inhibition (i.e., slowing down or preferably stopping to a certain extent) tumor metastasis; inhibiting tumor growth to a certain extent, and/or alleviating one or more symptoms associated with cancer to a certain extent.
  • a therapeutically effective amount of an anti-GDF15 antibody or composition thereof is one that inhibits (i.e., slows or preferably stops to a certain extent) the loss of muscle mass; inhibits (i.e., to a certain extent) the loss of muscle mass; One that slows or preferably stops) loss of fat mass; restores to some extent involuntary weight loss, inhibits to some extent loss of organ mass, and/or alleviates to some extent underlying conditions associated with cachexia or multiple symptoms.
  • the anti-GDF15 antibodies or compositions thereof disclosed herein are capable of preventing and/or killing existing tumor cells to the extent that they may be cytostatic or cytotoxic.
  • a therapeutically effective amount refers to an amount capable of prolonging the survival of a patient.
  • a therapeutically effective amount refers to an amount capable of improving progression-free survival of a patient.
  • pharmaceutically acceptable refers to a material that has no biological activity or other undesirable properties, e.g., the material can be incorporated into a pharmaceutical composition administered to a patient, and Does not cause significant adverse biological reactions or interact in a deleterious manner with any other components contained in the composition.
  • Pharmaceutically acceptable carriers or excipients preferably meet 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.
  • Embodiments of the application described herein should be understood to include embodiments “consisting of” and/or “consisting essentially of.”
  • references herein to "about” a value or parameter include (and describe) variations on the value or parameter itself. For example, descriptions referring to “about X” include descriptions of "X”.
  • reference to "not" a value or parameter generally means and describes “other than” a value or parameter.
  • the method cannot be used to treat type X cancer, meaning the method is typically used to treat other types of cancer besides type X cancer.
  • the application provides anti-human, rhesus monkey and/or mouse GDF15 antibodies that specifically bind GDF15.
  • 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.
  • the application provides isolated antibodies that bind GDF15.
  • Contemplated anti-GDF15 antibodies include, for example, full-length anti-GDF15 antibodies (e.g., full-length IgG1 or IgG4), anti-GDF15 single chain antibodies, anti-GDF15 Fc fusion proteins, multispecific (e.g., bispecific) anti-GDF15 antibodies, anti-GDF15 immunization conjugates, and whatnot.
  • the anti-GDF15 antibody is a full-length antibody (eg, full-length IgG1 or IgG4) or an antigen-binding fragment thereof that specifically binds GDF15.
  • the anti-GDF15 antibody is Fab, Fab', F(ab)' 2 , Fab'-SH, single chain Fv (scFv), Fv fragment, dAb, Fd, nanobody, diabody (diabody) or linear antibody.
  • an antibody that specifically binds to GDF15 refers to an antibody that has an affinity for binding to GDF15 that is at least 10 times greater than the affinity for non-target binding (including, for example, 10, 10 2 , 10 3 , 10 4 , 10 5 , 10 6 , or 10 7 times).
  • 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 analysis (RIA).
  • the Kd value can be determined by methods known in the art, such as surface plasmon resonance (SPR) technology or biolayer interference (BLI) technology.
  • non-human anti-GDF15 antibodies comprising human sequences are discussed broadly herein (eg, human heavy and light chain variable domains comprising human CDR sequences), non-human anti-GDF15 antibodies are also contemplated.
  • non-human anti-GDF15 antibodies include the human CDR sequences and non-human framework sequences of the anti-GDF15 antibodies described herein.
  • the non-human framework sequences include any for use as described herein.
  • non-human anti-GDF15 antibodies include anti-GDF15 antibodies generated by grafting one or more human CDR sequences described herein into non-human framework regions (eg, murine or chicken framework region sequences).
  • the complete amino acid sequence of an exemplary human GDF15 includes or consists of the amino acid sequence shown in SEQ ID NO: 68.
  • the mature amino acid sequence of an exemplary human GDF15 includes or consists of the amino acid sequence set forth in SEQ ID NO: 69.
  • the anti-GDF15 antibodies described herein specifically recognize an epitope in human GDF15. In some embodiments, the anti-GDF15 antibody cross-reacts with GDF15 from species other than human. In some embodiments, the anti-GDF15 antibody is fully specific for human GDF15 and does not cross-react with other non-human species.
  • the anti-GDF15 antibody cross-reacts with at least one allelic variant of the GDF15 protein (or fragment thereof).
  • the allelic variant has up to 30 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) compared to the naturally occurring GDF15 protein (or fragment thereof). , 15, 20, 25 or 30) amino acid substitutions (eg, conservative substitutions).
  • the anti-GDF15 antibody does not cross-react with any allelic variant of the GDF15 protein (or fragment thereof).
  • the anti-GDF15 antibody cross-reacts with at least one interspecies variant of GDF15 protein.
  • the GDF15 protein (or fragment thereof) is human GDF15
  • the interspecies variant of the GDF15 protein (or fragment thereof) is a variant in rhesus monkeys.
  • the anti-GDF15 antibody does not cross-react with any interspecies variant of GDF15 protein.
  • the anti-GDF15 antibody comprises an antibody heavy chain constant region and an antibody light chain constant region.
  • the anti-GDF15 antibody comprises an IgGl type heavy chain constant region.
  • the anti-GDF15 antibody comprises an IgG2 type heavy chain constant region.
  • the anti-GDF15 antibody comprises an IgG3 type heavy chain constant region.
  • the anti-GDF15 antibody comprises an IgG4 type heavy chain constant region.
  • the heavy chain constant region comprises (including consists of or consists essentially of) the amino acid sequence SEQ ID NO: 64.
  • the heavy chain constant region comprises (including consists of or consists essentially of) the amino acid sequence SEQ ID NO: 65.
  • the anti-GDF15 antibody comprises a kappa light chain constant region.
  • the light chain constant region comprises (including consists of or consists essentially of) the amino acid sequence SEQ ID NO: 66.
  • the anti-GDF15 antibody comprises a lambda light chain constant region.
  • the light chain constant region comprises (including consists of or consists essentially of) the amino acid sequence SEQ ID NO: 67.
  • the anti-GDF15 antibody comprises an antibody heavy chain variable domain and an antibody light chain variable domain.
  • the anti-GDF15 antibody includes a heavy chain variable domain ( VH ), and the VH includes: heavy chain complementarity determining region (HC-CDR) 1, which includes X 1 YYMX 2 (SEQ ID NO : 35 ) , wherein , which includes VVYAGWTYPLGI (SEQ ID NO: 13); and a light chain variable domain (V L ), which includes: light chain complementarity determining region (LC-CDR) 1, which includes QASQSISSVLS ( SEQ ID NO: 18 ) ; LC- CDR2 , which contains EASX 1 30).
  • VH heavy chain complementarity determining region
  • HC-CDR heavy chain complementarity determining region
  • V L light chain variable domain
  • the anti-GDF15 antibody comprises VH , and the VH comprises: HC-CDR1, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 1-2 or a variant thereof, the variant The body comprises the substitution of up to about 3 (for example, 1, 2 or 3) amino acids; HC-CDR2, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 7-8 or a variant thereof, the variant comprising Substitutions of up to about 3 (eg, 1, 2, or 3) amino acids; and HC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13 or a variant thereof, the variant comprising up to about 3 (eg, 1, 2, or 3) amino acids; 1, 2 or 3) amino acid substitutions.
  • HC-CDR1 comprises the amino acid sequence shown in any one of SEQ ID NOs: 1-2 or a variant thereof
  • the body comprises the substitution of up to about 3 (for example, 1, 2 or 3) amino acids
  • HC-CDR2 which comprises the amino acid sequence
  • the anti-GDF15 antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence shown in any one of SEQ ID NOs: 1-2, HC-CDR2 comprising SEQ The amino acid sequence shown in any one of ID NOs: 7-8, HC-CDR3, includes the amino acid sequence shown in SEQ ID NO: 13.
  • the anti-GDF15 antibody comprises a V L comprising: LC- CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 18 or a variant thereof, the variant comprising up to about 3 Substitutions of (e.g. 1, 2 or 3) amino acids; LC-CDR2, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 23-25 or a variant thereof, the variant comprising up to about 3 ( for example, 1, 2, or 3) amino acid substitutions; and LC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 30 or a variant thereof, the variant comprising up to about 3 (for example, 1, 2, or 3 ) amino acid substitutions.
  • LC- CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 18 or a variant thereof, the variant comprising up to about 3 Substitutions of (e.g. 1, 2 or 3) amino acids
  • LC-CDR2 which comprises the amino acid sequence shown in any one of SEQ ID NOs: 23-25 or a
  • the anti-GDF15 antibody comprises a VL comprising: LC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 18, LC-CDR2 comprising SEQ ID NOs: 23-
  • the amino acid sequence shown in any one of 25, LC-CDR3 includes the amino acid sequence shown in SEQ ID NO: 30.
  • the anti-GDF15 antibody comprises VH , and the VH comprises: HC-CDR1, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 1-2 or a variant thereof, the variant The body comprises the substitution of up to about 3 (for example, 1, 2 or 3) amino acids; HC-CDR2, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 7-8 or a variant thereof, the variant comprising Substitutions of up to about 3 (eg, 1, 2, or 3) amino acids; and HC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13 or a variant thereof, the variant comprising up to about 3 (eg, 1, 2, or 3) amino acids; 1, 2 or 3) amino acid substitutions; and VL , the VL comprising: LC-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 18 or a variant thereof, the variant comprising up to about 3 Substitutions of (e.g.
  • LC-CDR2 which comprises the amino acid sequence shown in any one of SEQ ID NOs: 23-25 or a variant thereof, the variant comprising up to about 3 ( for example, 1, 2, or 3) amino acid substitutions
  • LC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 30 or a variant thereof, the variant comprising up to about 3 (for example, 1, 2, or 3 ) amino acid substitutions.
  • the anti-GDF15 antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence shown in any one of SEQ ID NOs: 1-2, HC-CDR2 comprising SEQ The amino acid sequence shown in any one of ID NOs: 7-8, and HC-CDR3, which includes the amino acid sequence shown in SEQ ID NO: 13; and V L , which V L includes: LC-CDR1, which includes SEQ The amino acid sequence shown in ID NO: 18, LC-CDR2, which includes the amino acid sequence shown in any one of SEQ ID NOs: 23-25, and LC-CDR3, which includes the amino acid sequence shown in SEQ ID NO: 30.
  • the anti-GDF15 antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 7, HC -CDR3, which comprises the amino acid sequence SEQ ID NO: 13, or a variant of said VH , comprising up to about 5 amino acid substitutions in its HC-CDRs; and VL , said VL comprising: LC-CDR1, It comprises the amino acid sequence SEQ ID NO: 18, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 23, LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 30, or a variant of said V L , whose LC- The CDRs contain substitutions of up to about 5 amino acids.
  • the anti-GDF15 antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 7, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 13; and VL, which VL comprises : LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 18, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 23, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:30.
  • the anti-GDF15 antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 7, HC -CDR3, which comprises the amino acid sequence SEQ ID NO: 13, or a variant of said VH , comprising up to about 5 amino acid substitutions in its HC-CDRs; and VL , said VL comprising: LC-CDR1, It comprises the amino acid sequence SEQ ID NO: 18, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 24, LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 30, or a variant of said V L , whose LC- The CDRs contain substitutions of up to about 5 amino acids.
  • the anti-GDF15 antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 7, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 13; and VL, which VL comprises : LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 18, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 24, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:30.
  • the anti-GDF15 antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 7, HC -CDR3, which comprises the amino acid sequence SEQ ID NO: 13, or a variant of said VH , comprising up to about 5 amino acid substitutions in its HC-CDRs; and VL , said VL comprising: LC-CDR1, It comprises the amino acid sequence SEQ ID NO: 18, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 25, LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 30, or a variant of said V L , whose LC- The CDRs contain substitutions of up to about 5 amino acids.
  • the anti-GDF15 antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 7, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 13; and VL, which VL comprises : LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 18, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 25, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:30.
  • the anti-GDF15 antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 7, HC -CDR3, which comprises the amino acid sequence SEQ ID NO: 13, or a variant of said VH , comprising up to about 5 amino acid substitutions in its HC-CDRs; and VL , said VL comprising: LC-CDR1, It comprises the amino acid sequence SEQ ID NO: 18, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 25, LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 30, or a variant of said V L , whose LC- The CDRs contain substitutions of up to about 5 amino acids.
  • the anti-GDF15 antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 7, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 13; and VL, which VL comprises : LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 18, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 25, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:30.
  • the anti-GDF15 antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 8, HC -CDR3, which comprises the amino acid sequence SEQ ID NO: 13, or a variant of said VH , comprising up to about 5 amino acid substitutions in its HC-CDRs; and VL , said VL comprising: LC-CDR1, It comprises the amino acid sequence SEQ ID NO: 18, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 25, LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 30, or a variant of said V L , whose LC- The CDRs contain substitutions of up to about 5 amino acids.
  • the anti-GDF15 antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 8, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 13; and VL, which VL comprises : LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 18, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 25, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:30.
  • the anti-GDF15 antibody comprises a V H comprising HC-CDR1, HC-CDR2 and HC- CDR3; and VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in any one of the amino acid sequences of SEQ ID NOs: 52-59.
  • the anti-GDF15 antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:38; and a VL comprising VL as shown in the amino acid sequence SEQ ID NO: 52 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-GDF15 antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:39; and a VL comprising VL as shown in the amino acid sequence SEQ ID NO: 53 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-GDF15 antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:40; and a VL comprising VL as shown in the amino acid sequence SEQ ID NO: 53 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-GDF15 antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:41; and a VL comprising VL as shown in the amino acid sequence SEQ ID NO: 53 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-GDF15 antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:42; and a VL comprising VL as shown in the amino acid sequence SEQ ID NO: 53 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-GDF15 antibody comprises a VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:43; and a VL comprising VL as shown in the amino acid sequence SEQ ID NO: 53 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-GDF15 antibody comprises a VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:44; and a VL comprising VL as shown in the amino acid sequence SEQ ID NO: 53 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-GDF15 antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:39; and a VL comprising VL as shown in the amino acid sequence SEQ ID NO: 54 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-GDF15 antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:40; and a VL comprising VL as shown in the amino acid sequence SEQ ID NO: 54 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-GDF15 antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:41; and a VL comprising VL as shown in the amino acid sequence SEQ ID NO: 54 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-GDF15 antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:42; and a VL comprising VL as shown in the amino acid sequence SEQ ID NO: 54 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-GDF15 antibody comprises a VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:43; and a VL comprising VL as shown in the amino acid sequence SEQ ID NO: 54 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-GDF15 antibody comprises a VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:44; and a VL comprising VL as shown in the amino acid sequence SEQ ID NO: 54 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-GDF15 antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:39; and a VL comprising VL contains LC-CDR1, LC-CDR2 and LC-CDR3 as shown in the amino acid sequence SEQ ID NO:55.
  • the anti-GDF15 antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:40; and a VL comprising VL contains LC-CDR1, LC-CDR2 and LC-CDR3 as shown in the amino acid sequence SEQ ID NO:55.
  • the anti-GDF15 antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:41; and a VL comprising VL contains LC-CDR1, LC-CDR2 and LC-CDR3 as shown in the amino acid sequence SEQ ID NO:55.
  • the anti-GDF15 antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:42; and a VL comprising VL contains LC-CDR1, LC-CDR2 and LC-CDR3 as shown in the amino acid sequence SEQ ID NO:55.
  • the anti-GDF15 antibody comprises a VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:43; and a VL comprising VL contains LC-CDR1, LC-CDR2 and LC-CDR3 as shown in the amino acid sequence SEQ ID NO:55.
  • the anti-GDF15 antibody comprises a VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:44; and a VL comprising VL contains LC-CDR1, LC-CDR2 and LC-CDR3 as shown in the amino acid sequence SEQ ID NO:55.
  • the anti-GDF15 antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:45; and a VL comprising VL as shown in the amino acid sequence SEQ ID NO: 56 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-GDF15 antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:45; and a VL comprising VL as shown in the amino acid sequence SEQ ID NO: 57 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-GDF15 antibody comprises a VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:46; and a VL comprising VL as shown in the amino acid sequence SEQ ID NO: 58 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-GDF15 antibody comprises a VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:47; and a VL comprising VL as shown in the amino acid sequence SEQ ID NO: 59 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-GDF15 antibody comprises: VH , the VH comprises the amino acid sequence shown in any one of SEQ ID NOs: 38-47 or a variant thereof, the variant is the same as SEQ ID NOs:
  • the amino acid sequence shown in any one of 38-47 has at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity;
  • VL the VL comprises the amino acid sequence shown in any one of SEQ ID NOs: 52-59 or a variant thereof, and the variant has at least about 80% similarity with the amino acid sequence shown in any one of SEQ ID NOs: 52-59.
  • the anti-GDF15 antibody comprises a V H comprising the amino acid sequence set forth in any one of SEQ ID NOs: 38-47, and a V L comprising SEQ ID NOs: 52 The amino acid sequence shown in any one of -59.
  • the anti-GDF15 antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 38 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 38 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 52 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 52.
  • the anti-GDF15 antibody comprises a VH comprising the amino acid sequence SEQ ID NO:38, and a VL comprising the amino acid sequence SEQ ID NO:52.
  • the anti-GDF15 antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 39 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 39 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 53 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 53.
  • the anti-GDF15 antibody comprises VH comprising the amino acid sequence SEQ ID NO:39, and VL comprising the amino acid sequence SEQ ID NO:53.
  • the anti-GDF15 antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 40 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 40 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 53 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 53.
  • the anti-GDF15 antibody comprises a VH comprising the amino acid sequence SEQ ID NO:40, and a VL comprising the amino acid sequence SEQ ID NO:53.
  • the anti-GDF15 antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 41 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 41 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 53 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 53.
  • the anti-GDF15 antibody comprises a VH comprising the amino acid sequence SEQ ID NO:41, and a VL comprising the amino acid sequence SEQ ID NO:53.
  • the anti-GDF15 antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 42 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 42 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 53 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 53.
  • the anti-GDF15 antibody comprises a VH comprising the amino acid sequence SEQ ID NO:42, and a VL comprising the amino acid sequence SEQ ID NO:53.
  • the anti-GDF15 antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 43 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 43 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 53 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 53.
  • the anti-GDF15 antibody comprises a VH comprising the amino acid sequence SEQ ID NO:43, and a VL comprising the amino acid sequence SEQ ID NO:53.
  • the anti-GDF15 antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 44 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 44 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 53 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 53.
  • the anti-GDF15 antibody comprises a VH comprising the amino acid sequence SEQ ID NO:44, and a VL comprising the amino acid sequence SEQ ID NO:53.
  • the anti-GDF15 antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 39 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 39 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 54 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 54.
  • the anti-GDF15 antibody comprises a VH comprising the amino acid sequence SEQ ID NO:39, and a VL comprising the amino acid sequence SEQ ID NO:54.
  • the anti-GDF15 antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 40 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 40 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 54 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 54.
  • the anti-GDF15 antibody comprises VH comprising the amino acid sequence SEQ ID NO:40, and VL comprising the amino acid sequence SEQ ID NO:54.
  • the anti-GDF15 antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 41 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 41 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 54 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 54.
  • the anti-GDF15 antibody comprises a VH comprising the amino acid sequence SEQ ID NO:41, and a VL comprising the amino acid sequence SEQ ID NO:54.
  • the anti-GDF15 antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 42 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 42 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 54 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 54.
  • the anti-GDF15 antibody comprises a VH comprising the amino acid sequence SEQ ID NO:42, and a VL comprising the amino acid sequence SEQ ID NO:54.
  • the anti-GDF15 antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 43 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 43 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 54 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 54.
  • the anti-GDF15 antibody comprises a VH comprising the amino acid sequence SEQ ID NO:43, and a VL comprising the amino acid sequence SEQ ID NO:54.
  • the anti-GDF15 antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 44 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 44 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 54 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 54.
  • the anti-GDF15 antibody comprises a VH comprising the amino acid sequence SEQ ID NO:44, and a VL comprising the amino acid sequence SEQ ID NO:54.
  • the anti-GDF15 antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 39 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 39 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 55 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 55.
  • the anti-GDF15 antibody comprises a VH comprising the amino acid sequence SEQ ID NO:39, and a VL comprising the amino acid sequence SEQ ID NO:55.
  • the anti-GDF15 antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 40 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 40 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 55 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 55.
  • the anti-GDF15 antibody comprises a VH comprising the amino acid sequence SEQ ID NO:40, and a VL comprising the amino acid sequence SEQ ID NO:55.
  • the anti-GDF15 antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 41 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 41 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 55 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 55.
  • the anti-GDF15 antibody comprises a VH comprising the amino acid sequence SEQ ID NO:41, and a VL comprising the amino acid sequence SEQ ID NO:55.
  • the anti-GDF15 antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 42 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 42 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 55 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 55.
  • the anti-GDF15 antibody comprises VH comprising the amino acid sequence SEQ ID NO:42, and VL comprising the amino acid sequence SEQ ID NO:55.
  • the anti-GDF15 antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 43 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 43 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 55 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 55.
  • the anti-GDF15 antibody comprises a VH comprising the amino acid sequence SEQ ID NO:43, and a VL comprising the amino acid sequence SEQ ID NO:55.
  • the anti-GDF15 antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 44 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 44 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 55 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 55.
  • the anti-GDF15 antibody comprises a VH comprising the amino acid sequence SEQ ID NO:44, and a VL comprising the amino acid sequence SEQ ID NO:55.
  • the anti-GDF15 antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 45 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 45 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 56 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 56.
  • the anti-GDF15 antibody comprises a VH comprising the amino acid sequence SEQ ID NO:45, and a VL comprising the amino acid sequence SEQ ID NO:56.
  • the anti-GDF15 antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 45 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 45 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 57 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 57.
  • the anti-GDF15 antibody comprises a VH comprising the amino acid sequence SEQ ID NO:45, and a VL comprising the amino acid sequence SEQ ID NO:57.
  • the anti-GDF15 antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 46 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 46 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 58 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 58.
  • the anti-GDF15 antibody comprises a VH comprising the amino acid sequence SEQ ID NO:46, and a VL comprising the amino acid sequence SEQ ID NO:58.
  • the anti-GDF15 antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 47 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 47 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 59 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 59.
  • the anti-GDF15 antibody comprises a VH comprising the amino acid sequence SEQ ID NO:47, and a VL comprising the amino acid sequence SEQ ID NO:59.
  • the anti-GDF15 antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 9, HC -CDR3, which comprises the amino acid sequence SEQ ID NO: 14, or a variant of said VH , comprising up to about 5 amino acid substitutions in its HC-CDRs; and VL , said VL comprising: LC-CDR1, It comprises the amino acid sequence SEQ ID NO: 19, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 26, LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 31, or a variant of said V L , whose LC- The CDRs contain substitutions of up to about 5 amino acids.
  • the anti-GDF15 antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 9, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO:14; and VL , which VL comprises: LC-CDR1, which comprises the amino acid sequence SEQ ID NO:19, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 26, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:31.
  • the anti-GDF15 antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:48; and a VL comprising VL as shown in the amino acid sequence SEQ ID NO: 60 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-GDF15 antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 48 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 48 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 60 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 60.
  • the anti-GDF15 antibody comprises a VH comprising the amino acid sequence SEQ ID NO:48, and a VL comprising the amino acid sequence SEQ ID NO:60.
  • the anti-GDF15 antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 4, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 10, HC -CDR3, which comprises the amino acid sequence SEQ ID NO: 15, or a variant of said VH , comprising up to about 5 amino acid substitutions in its HC-CDRs; and VL , said VL comprising: LC-CDR1, It comprises the amino acid sequence SEQ ID NO: 20, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 27, LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 32, or a variant of said V L , whose LC- The CDRs contain substitutions of up to about 5 amino acids.
  • the anti-GDF15 antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 4, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 10, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 15; and V L , which V L comprises: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 20, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 27, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:32.
  • the anti-GDF15 antibody comprises a VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:49; and a VL comprising VL as shown in the amino acid sequence SEQ ID NO: 61 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-GDF15 antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 49 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 49 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 61 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 61.
  • the anti-GDF15 antibody comprises a VH comprising the amino acid sequence SEQ ID NO:49, and a VL comprising the amino acid sequence SEQ ID NO:61.
  • the anti-GDF15 antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 5, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 11, HC -CDR3, which comprises the amino acid sequence SEQ ID NO: 16, or a variant of said VH , comprising up to about 5 amino acid substitutions in its HC-CDRs; and VL , said VL comprising: LC-CDR1, It comprises the amino acid sequence SEQ ID NO: 21, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 28, LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 33, or a variant of said V L , whose LC- The CDRs contain substitutions of up to about 5 amino acids.
  • the anti-GDF15 antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 5, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 11, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 16; and V L , which V L comprises: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 21, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 28, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:33.
  • the anti-GDF15 antibody comprises a VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:50; and a VL comprising VL as shown in the amino acid sequence SEQ ID NO: 62 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-GDF15 antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 50 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 50 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 62 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 62.
  • the anti-GDF15 antibody comprises a VH comprising the amino acid sequence SEQ ID NO:50, and a VL comprising the amino acid sequence SEQ ID NO:62.
  • the anti-GDF15 antibody includes a heavy chain variable domain ( VH ), and the VH includes: heavy chain complementarity determining region (HC-CDR) 1, which includes SYDMT (SEQ ID NO: 6) ; HC - CDR2 comprising IIX 1 -CDR3 comprising GILVYADYGDHNL (SEQ ID NO: 17); and light chain variable domain ( VL ) comprising: light chain complementarity determining region (LC-CDR) 1 comprising QASEDIYTNLA (SEQ ID NO:22); LC-CDR2, which contains AASTLAS (SEQ ID NO:29); and LC-CDR3, which contains LGVYTYISAX 1 GA (SEQ ID NO:81), where X 1 is D or E.
  • HC-CDR heavy chain complementarity determining region
  • HC - CDR2 comprising IIX 1 -CDR3
  • the anti-GDF15 antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 6 or a variant thereof, the variant comprising up to about 3 Substitution of three (e.g., 1, 2 or 3) amino acids; HC-CDR2, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 12, 75-78 or a variant thereof, said variant comprising up to about 3 Substitutions of at most (e.g., 1, 2, or 3) amino acids; and HC-CDR3 comprising the amino acid sequence shown in SEQ ID NO: 17 or a variant thereof, the variant comprising at most about 3 (e.g., 1, 2 or 3) amino acid substitutions.
  • HC-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 6 or a variant thereof, the variant comprising up to about 3 Substitution of three (e.g., 1, 2 or 3) amino acids
  • HC-CDR2 which comprises the amino acid sequence shown in any one of
  • the anti-GDF15 antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 6, HC-CDR2 comprising SEQ ID NOs: 12, The amino acid sequence shown in any one of 75-78, HC-CDR3, includes the amino acid sequence shown in SEQ ID NO: 17.
  • the anti-GDF15 antibody comprises a V L comprising: LC- CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 22 or a variant thereof, the variant comprising up to about 3 Substitutions of at most (e.g., 1, 2, or 3) amino acids; LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO: 29 or a variant thereof, the variant comprising at most about 3 (e.g., 1, 2, or 3) amino acid substitutions; and LC-CDR3, which Comprises the amino acid sequence shown in any one of SEQ ID NOs: 34 or 80, or a variant thereof, the variant comprising a substitution of up to about 3 (eg, 1, 2, or 3) amino acids.
  • the anti-GDF15 antibody includes VL , and the VL includes: LC-CDR1, which includes the amino acid sequence shown in SEQ ID NO:22, and LC-CDR2, which includes the amino acid sequence shown in SEQ ID NO:29.
  • the amino acid sequence shown is LC-CDR3, which includes the amino acid sequence shown in any one of SEQ ID NOs: 34 or 80.
  • the anti-GDF15 antibody comprises VH , and the VH comprises: HC-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 6 or a variant thereof, the variant comprising up to about 3 Substitution of three (e.g., 1, 2 or 3) amino acids; HC-CDR2, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 12, 75-78 or a variant thereof, said variant comprising up to about 3 Substitutions of at most (e.g., 1, 2, or 3) amino acids; and HC-CDR3 comprising the amino acid sequence shown in SEQ ID NO: 17 or a variant thereof, the variant comprising at most about 3 (e.g., 1, 2 or 3) amino acid substitutions; and VL , the VL comprising: LC-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 22 or a variant thereof, the variant comprising up to about 3 (e.g.
  • LC-CDR2 which comprises the amino acid sequence shown in SEQ ID NO: 29 or a variant thereof, the variant comprising up to about 3 (for example, 1, 2 or 3) Substitution of amino acids; and LC-CDR3 comprising the amino acid sequence shown in any one of SEQ ID NOs: 34 or 80, or a variant thereof, the variant comprising up to about 3 (e.g., 1, 2, or 3) amino acids replacement.
  • the anti-GDF15 antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 6, HC-CDR2 comprising SEQ ID NOs: 12, The amino acid sequence shown in any one of 75-78, and HC-CDR3, which includes the amino acid sequence shown in SEQ ID NO:17; and VL , which VL includes: LC-CDR1, which includes SEQ ID NO: The amino acid sequence shown in 22, LC-CDR2, which includes the amino acid sequence shown in SEQ ID NO:29, and LC-CDR3, which includes the amino acid sequence shown in any one of SEQ ID NOs: 34 or 80.
  • the anti-GDF15 antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 12, HC -CDR3, which comprises the amino acid sequence SEQ ID NO: 17, or a variant of said VH , comprising up to about 5 amino acid substitutions in its HC-CDRs; and VL , said VL comprising: LC-CDR1, It comprises the amino acid sequence SEQ ID NO: 22, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 29, LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 34, or a variant of said V L , whose LC- The CDRs contain substitutions of up to about 5 amino acids.
  • the anti-GDF15 antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 12, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 17; and V L , which V L comprises: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 22, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 29, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:34.
  • the anti-GDF15 antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 75, HC - CDR3, which comprises the amino acid sequence SEQ ID NO: 17, or a variant of said VH , comprising up to about 5 amino acid substitutions in its HC-CDRs; and VL , said VL comprising: LC-CDR1, which Comprising the amino acid sequence SEQ ID NO: 22, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 29, LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 80, or a variant of said V L , its LC-CDRs Contains substitutions of up to about 5 amino acids.
  • the anti-GDF15 antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 75, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 17; and V L , which V L comprises: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 22, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 29, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:80.
  • the anti-GDF15 antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 76, HC -CDR3, which comprises the amino acid sequence SEQ ID NO: 17, or a variant of said VH , comprising up to about 5 amino acid substitutions in its HC-CDRs; and VL , said VL comprising: LC-CDR1, It comprises the amino acid sequence SEQ ID NO: 22, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 29, LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 80, or a variant of said V L , whose LC- The CDRs contain substitutions of up to about 5 amino acids.
  • the anti-GDF15 antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 76, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 17; and V L , which V L comprises: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 22, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 29, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:80.
  • the anti-GDF15 antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 77, HC -CDR3, which comprises the amino acid sequence SEQ ID NO: 17, or a variant of said VH , comprising up to about 5 amino acid substitutions in its HC-CDRs; and VL , said VL comprising: LC-CDR1, It comprises the amino acid sequence SEQ ID NO: 22, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 29, LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 80, or a variant of said V L , whose LC- The CDRs contain substitutions of up to about 5 amino acids.
  • the anti-GDF15 antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 77, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 17; and V L , which V L comprises: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 22, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 29, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:80.
  • the anti-GDF15 antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 78, HC - CDR3, which comprises the amino acid sequence SEQ ID NO: 17, or a variant of said VH , comprising up to about 5 amino acid substitutions in its HC-CDRs; and VL , said VL comprising: LC-CDR1, which Comprising the amino acid sequence SEQ ID NO: 22, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 29, LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 80, or a variant of said V L , its LC-CDRs Contains substitutions of up to about 5 amino acids.
  • the anti-GDF15 antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 78, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 17; and V L , which V L comprises: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 22, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 29, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:80.
  • the anti-GDF15 antibody comprises a VH comprising HC-CDR1, HC-CDR2 and a VH as shown in any one of the amino acid sequences of SEQ ID NOs: 51, 82-89.
  • the anti-GDF15 antibody comprises a VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:51; and a VL comprising VL as shown in the amino acid sequence SEQ ID NO: 63 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-GDF15 antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:82; and a VL comprising VL as shown in the amino acid sequence SEQ ID NO:90 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-GDF15 antibody comprises a VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:83; and a VL comprising VL as shown in the amino acid sequence SEQ ID NO:90 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-GDF15 antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:84; and a VL comprising VL as shown in the amino acid sequence SEQ ID NO:90 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-GDF15 antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:85; and a VL comprising VL as shown in the amino acid sequence SEQ ID NO:90 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-GDF15 antibody comprises a VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:86; and a VL comprising VL as shown in the amino acid sequence SEQ ID NO:91 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-GDF15 antibody comprises a VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:87; and a VL comprising VL as shown in the amino acid sequence SEQ ID NO:91 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-GDF15 antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:88; and a VL comprising VL as shown in the amino acid sequence SEQ ID NO:91 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-GDF15 antibody comprises a VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:89; and a VL comprising VL as shown in the amino acid sequence SEQ ID NO:91 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-GDF15 antibody comprises: VH , the VH comprises the amino acid sequence shown in any one of SEQ ID NOs: 51, 82-89 or a variant thereof, the variant is identical to SEQ ID NOs: 51, 82-89 or a variant thereof.
  • the amino acid sequence shown in any one of NOs: 51, 82-89 has at least about 80% (such as at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity and VL , the VL comprising the amino acid sequence shown in any one of SEQ ID NOs: 63, 90-91 or a variant thereof, which variant is the same as any one of SEQ ID NOs: 63, 90-91
  • the amino acid sequences shown have at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity.
  • the anti-GDF15 antibody comprises VH comprising the amino acid sequence set forth in any one of SEQ ID NOs: 51, 82-89, and VL comprising SEQ ID NOs : The amino acid sequence shown in any one of 63 and 90-91.
  • the anti-GDF15 antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 51 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 51 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 63 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 63.
  • the anti-GDF15 antibody comprises a VH comprising the amino acid sequence SEQ ID NO:51, and a VL comprising the amino acid sequence SEQ ID NO:63.
  • the anti-GDF15 antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 82 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 82 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 90 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO:90.
  • the anti-GDF15 antibody comprises a VH comprising the amino acid sequence SEQ ID NO:82, and a VL comprising the amino acid sequence SEQ ID NO:90.
  • the anti-GDF15 antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 83 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 83 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 90 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO:90.
  • the anti-GDF15 antibody comprises a VH comprising the amino acid sequence SEQ ID NO:83, and a VL comprising the amino acid sequence SEQ ID NO:90.
  • the anti-GDF15 antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 84 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 84 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 90 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO:90.
  • the anti-GDF15 antibody comprises VH comprising the amino acid sequence SEQ ID NO:84, and VL comprising the amino acid sequence SEQ ID NO:90.
  • the anti-GDF15 antibody comprises: VH comprising the amino acid sequence SEQ ID NO:85 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO:85 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 90 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO:90.
  • the anti-GDF15 antibody comprises a VH comprising the amino acid sequence SEQ ID NO:85, and a VL comprising the amino acid sequence SEQ ID NO:90.
  • the anti-GDF15 antibody comprises: VH comprising the amino acid sequence SEQ ID NO:86 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO:86 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 91 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 91.
  • the anti-GDF15 antibody comprises a VH comprising the amino acid sequence SEQ ID NO:86, and a VL comprising the amino acid sequence SEQ ID NO:91.
  • the anti-GDF15 antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 87 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 87 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 91 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 91.
  • the anti-GDF15 antibody comprises a VH comprising the amino acid sequence SEQ ID NO:87, and a VL comprising the amino acid sequence SEQ ID NO:91.
  • the anti-GDF15 antibody comprises: VH comprising the amino acid sequence SEQ ID NO:88 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO:88 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 91 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO:91.
  • the anti-GDF15 antibody comprises VH comprising the amino acid sequence SEQ ID NO:88, and VL comprising the amino acid sequence SEQ ID NO:91.
  • the anti-GDF15 antibody comprises: VH comprising the amino acid sequence SEQ ID NO:89 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO:89 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 91 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO:91.
  • the anti-GDF15 antibody comprises a VH comprising the amino acid sequence SEQ ID NO:89, and a VL comprising the amino acid sequence SEQ ID NO:91.
  • amino acid substitutions are limited to the "exemplary substitutions” set forth in Table 4 herein. In some embodiments, amino acid substitutions are limited to the "preferred substitutions” set forth in Table 4 herein.
  • functional epitopes can be resolved by combined alanine scanning methods.
  • combinatorial alanine scanning techniques can be used to identify amino acids in the GDF15 protein that are necessary for interaction with anti-GDF15 antibodies.
  • the epitope is conformational and the crystal structure of an anti-GDF15 antibody bound to the GDF15 protein can be used to identify the epitope.
  • the application provides antibodies that competitively bind GDF15 with any of the anti-GDF15 antibodies described herein.
  • antibodies are provided that are capable of binding to an epitope on GDF15 competitively with any of the anti-GDF15 antibodies described herein.
  • an anti-GDF15 antibody is provided that binds to the same epitope as an anti-GDF15 antibody molecule comprising V H and V L , wherein the V H comprises any of SEQ ID NOs: 38-51, 82-89 The amino acid sequence shown, and the VL includes the amino acid sequence shown in any one of SEQ ID NOs: 52-63, 90-91.
  • an anti-GDF15 antibody that competitively binds GDF15 with an anti-GDF15 antibody comprising V H and V L , wherein the V H comprises any one of SEQ ID NOs: 38-51, 82-89
  • the amino acid sequence shown is, and the V L includes the amino acid sequence shown in any one of SEQ ID NOs: 52-63, 90-91.
  • competition experiments can be used to identify monoclonal antibodies that compete with the anti-GDF15 antibodies described herein for binding to GDF15. Competition experiments can determine whether two antibodies bind the same epitope by identifying the same or spatially overlapping epitope or by one antibody competitively inhibiting the binding of another antibody to the antigen. In certain embodiments, such competing antibodies bind the same epitope as the antibodies described herein.
  • Some exemplary competition experiments include, but are not limited to, conventional experiments as mentioned in Harlow and Lane (1988) Antibodies: A Laboratory Manual ch.14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.).
  • each antibody is said to bind the same epitope if it blocks 50% or more of the binding of the other antibody.
  • the antibody that competes with an anti-GDF15 antibody described herein is a chimeric antibody, a humanized antibody, or a fully human antibody.
  • Exemplary anti-GDF15 antibody sequences are shown in Table 2-2A and Table 3-3A, where CDR numbering is performed according to the Kabat definition.
  • CDR numbering is performed according to the Kabat definition.
  • Those skilled in the art will recognize that there are a variety of known algorithms for predicting the location of CDRs and defining Antibody light and heavy chain variable regions.
  • Antibodies containing the CDRs, VH and/or VL sequences of antibodies as described herein, but based on prediction algorithms other than those exemplified in the table below are also within the scope of the present application.
  • GDF15 Growth differentiation factor-15
  • TGF- ⁇ transforming growth factor beta
  • BMP bone morphogenetic proteins
  • GDFs belong to the activin/myostatin subclass.
  • the maturation of human GDF15 undergoes a series of post-translational modification processes.
  • the post-translational unprocessed GDF15 protein (pre-pro-GDF15) has 308 amino acids, including signal peptide sequence (29aa), propeptide (167aa) and mature protein (112aa).
  • the synthesized precursor form of pro-GDF15 protein forms a pro-GDF15 homodimer through cysteine residues; it is then cleaved at the RXXR site, releasing the mature dimeric GDF15 protein and a pro- Peptides (Wang X et al., Biochem Pharmacol, 2013).
  • Glial cell-derived neurotrophic factor (GDNF) receptor alpha-like protein GFRAL as a brainstem-restricted receptor for GDF15 protein, is mainly expressed in the central nervous system (CNS), especially in mice, rats, monkeys and humans.
  • CNS central nervous system
  • NNS nucleus of the solitary tract
  • AP posterior pole
  • GFRAL mRNA expression was analyzed in various embryonic and adult mouse tissues. Two isoforms of GRAL mRNA have been detected in the central nervous system (CNS) of adult mice.
  • GFRAL mRNA was not detected in the peripheral organs examined, such as the heart, liver, spleen, lungs, kidneys, placenta, skeletal muscle, and small intestine.
  • peripheral organs examined such as the heart, liver, spleen, lungs, kidneys, placenta, skeletal muscle, and small intestine.
  • GFRAL mRNAs are relatively more abundant in certain parts of the brain, such as the substantia nigra, hippocampus, and hindbrain (Li et al., J. Neurochem. 2005.)
  • GFRAL protein is a transmembrane protein anchored to the plasma membrane through glycosylphosphatidylinositol (GPI) distributed in lipid rafts.
  • the receptor protein consists of three cysteine-rich domains.
  • GDF15 can activate GFRAL-expressing neurons specifically distributed in the posterior pole area and nucleus of the solitary tract in mice (Hsu et al., Nature, 2017.).
  • GFRAL's co-receptor tyrosine kinase RET is expressed in the AP and nucleus tractus solitarius (NTS), with additional expression observed in several regions of the hypothalamus (Hsu, et al., 2017).
  • the GDF15 dimer protein binds to two GFRALs and then recruits RET molecules to form a complex, thereby triggering phosphorylation of RET and intracellular signaling, further activating its intracellular kinase domain and initiating multiple signaling pathways through brainstem neurons.
  • GDF15-GFRAL signaling plays an important role in weight control.
  • Recombinant GDF15 induces weight loss in mice fed a high-fat diet and in spontaneously obese non-human primates.
  • germline Gfral knockout mice (Gfral-/-) lost the anorexigenic and metabolic-related effects caused by recombinant GDF15.
  • diet-induced obesity and insulin resistance are exacerbated in GFRAL-deficient mice, suggesting a balancing role for this receptor in metabolism (Mullican, S.E. et al. Nat Med. 2017).
  • the anti-GDF15 antibody is a full-length anti-GDF15 antibody.
  • the full-length anti-GDF15 antibody is IgA, IgD, IgE, IgG, or IgM.
  • the full-length anti-GDF15 antibody comprises an IgG constant region, such as that of IgG1, IgG2, IgG3, IgG4, or a variant thereof.
  • the full-length anti-GDF15 antibody comprises a lambda light chain constant region.
  • the full-length anti-GDF15 antibody comprises a kappa light chain constant region.
  • the full-length anti-GDF15 antibody is a full-length human anti-GDF15 antibody.
  • the full-length anti-GDF15 antibody comprises mouse immunoglobulin Fc sequence.
  • the full-length anti-GDF15 antibody comprises an Fc sequence that has been altered or otherwise altered such that it has enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity. Effector functions of (CDC).
  • a full-length anti-GDF15 antibody comprising an IgGl constant region
  • the anti-GDF15 antibody specifically binding to GDF15.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG2 constant region is provided, the anti-GDF15 antibody specifically binding to GDF15.
  • the IgG2 is human IgG2.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 67.
  • a full-length anti-GDF15 antibody comprising an IgG3 constant region is provided, the anti-GDF15 antibody specifically binding to GDF15.
  • the IgG3 is human IgG3.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region is provided, the anti-GDF15 antibody specifically binding to GDF15.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which comprises the amino acid sequence shown in any one of SEQ ID NOs: 1-6 or a variant thereof, the variant comprising up to about 3 (for example, 1, 2 or 3) amino acid substitutions; HC-CDR2, which Comprising the amino acid sequence shown in any one of SEQ ID NOs: 7-12, 75-78 or a variant thereof, the variant comprising a substitution of up to about 3 (eg 1, 2 or 3) amino acids; and HC- CDR3 comprising the amino acid sequence shown in any one of SEQ ID NOs: 13-17 or a variant thereof, the variant comprising a substitution of up to about 3 (eg 1, 2 or 3) amino acids; and b) light Chain variable domain, the light chain variable domain comprises: LC-CDR1, which comprises the amino acid sequence
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the light chain constant region comprises or consists of an amino acid The amino acid sequence consists of SEQ ID NO: 67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG2 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which comprises the amino acid sequence shown in any one of SEQ ID NOs: 1-6 or a variant thereof, the variant comprising up to about 3 (such as 1, 2 or 3) amino acid substitutions; HC-CDR2, which Comprising the amino acid sequence shown in any one of SEQ ID NOs: 7-12, 75-78 or a variant thereof, the variant comprising a substitution of up to about 3 (e.g., 1, 2 or 3) amino acids; and HC- CDR3, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 13-17 or a variant thereof, the variant comprising up to about 3 (such as 1, 2 or 3) amino acid substitutions; and b) light Chain variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence
  • the IgG2 is human IgG2.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 67.
  • a full-length anti-GDF15 antibody comprising an IgG3 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which comprises the amino acid sequence shown in any one of SEQ ID NOs: 1-6 or a variant thereof, the variant comprising up to about 3 (for example, 1, 2 or 3) amino acid substitutions, HC-CDR2, which Comprising the amino acid sequence shown in any one of SEQ ID NOs: 7-12, 75-78 or a variant thereof, the variant comprising a substitution of up to about 3 (e.g., 1, 2 or 3) amino acids; and HC- CDR3, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 13-17 or a variant thereof, the variant comprising up to about 3 (such as 1, 2 or 3) amino acid substitutions; and b) light Chain variable domain, the light chain variable domain includes: LC-CDR1, which includes the amino acid
  • the IgG3 is human IgG3.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which contains The amino acid sequence shown in any one of SEQ ID NOs: 1-6 or a variant thereof, the variant comprising a substitution of up to about 3 (for example, 1, 2 or 3) amino acids; HC-CDR2, which comprises SEQ ID The amino acid sequence shown in any one of NOs: 7-12, 75-78 or a variant thereof, said variant comprising up to about 3 (eg 1, 2 or 3) amino acid substitutions; and HC-CDR3, which Comprising the amino acid sequence shown in any one of SEQ ID NOs: 13-17 or a variant thereof, the variant comprising a substitution of up to about 3 (eg, 1, 2 or 3) amino acids; and b) a light chain variable Structural domain, the light chain variable domain comprises: LC-CDR
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence shown in any one of SEQ ID NOs: 1-6, HC-CDR2, which includes the amino acid sequence shown in any one of SEQ ID NOs: 7-12, 75-78, and HC-CDR3, It includes the amino acid sequence shown in any one of SEQ ID NOs: 13-17, or a variant of the heavy chain variable domain whose HC-CDR sequence contains up to about 5 (for example, 1, 2, 3, 4 or 5) amino acid substitutions; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence shown in any one of SEQ ID NOs: 18-22 , LC-CDR2, which includes the amino acid sequence shown in any one of SEQ ID NOs: 23-29, and LC-CDR3,
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising a) a heavy chain variable domain comprising: HC-CDR1, which contains The amino acid sequence shown in any one of SEQ ID NOs: 1-6, HC-CDR2, which includes the amino acid sequence shown in any one of SEQ ID NOs: 7-12, 75-78, and HC-CDR3, which includes SEQ The amino acid sequence shown in any one of ID NOs: 13-17, or a variant of the heavy chain variable domain, containing up to about 5 (for example, 1, 2, 3, 4 or 5) in its HC-CDR sequence ) amino acid substitution; and b) light chain variable domain, the light chain variable domain comprising: LC-CDR1, which comprises the amino acid sequence shown in any one of SEQ ID NOs: 18-22, LC- CDR2, comprising the amino acid sequence shown in any one of SEQ ID NOs: 23-29, and LC-CDR3, comprising the
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence shown in any one of SEQ ID NOs: 1-6, HC-CDR2, which includes the amino acid sequence shown in any one of SEQ ID NOs: 7-12, 75-78, and HC-CDR3, It comprises the amino acid sequence shown in any one of SEQ ID NOs: 13-17; and b) a light chain variable domain comprising: LC-CDR1 comprising SEQ ID NOs: 18- The amino acid sequence shown in any one of 22, LC-CDR2, which includes the amino acid sequence shown in any one of SEQ ID NOs: 23-29, and LC-CDR3, which includes any of SEQ ID NOs: 30-34, 80 The amino acid sequence shown in 1.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence shown in any one of SEQ ID NOs: 1-6, HC-CDR2, which includes the amino acid sequence shown in any one of SEQ ID NOs: 7-12, 75-78, and HC-CDR3, It comprises the amino acid sequence shown in any one of SEQ ID NOs: 13-17; and b) a light chain variable domain comprising: LC-CDR1 comprising SEQ ID NOs: 18- The amino acid sequence shown in any one of 22, LC-CDR2, which includes the amino acid sequence shown in any one of SEQ ID NOs: 23-29, and LC-CDR3, which includes any of SEQ ID NOs: 30-34, 80 one The amino acid sequence shown.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 7, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 13; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 18, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 23, and LC-CDR3, which includes the amino acid sequence SEQ ID NO:30.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 7, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 13; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 18, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 24, and LC-CDR3, which includes the amino acid sequence SEQ ID NO:30.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which comprises the amino acid sequence SEQ ID NO: 1, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 7, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 13; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 18, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 18 The sequence SEQ ID NO:25, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:30.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 2, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 7, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 13; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 18, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 25, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: :30.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 8, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 13; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 18, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 25, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: :30.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which comprises the amino acid sequence SEQ ID NO: 3, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 9, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 14; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 19, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 19 The sequence SEQ ID NO:26, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:31.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 4, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 10, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 15; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 20, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 27, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: :32.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 5, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 11, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 16; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 21, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 28, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: :33.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which comprises the amino acid sequence SEQ ID NO: 6, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 12, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 17; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 22, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 22 The sequence SEQ ID NO:29, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:34.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 6, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 75, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 17; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 22, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 29, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: :80.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 6, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 76, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 17; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 22, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 29, and LC-CDR3, which includes the amino acid sequence SEQ ID NO:80.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which comprises the amino acid sequence SEQ ID NO: 6, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 77, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 17; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 22, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 22 The sequence SEQ ID NO:29, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:80.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 6, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 78, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 17; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 22, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 29, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: :80.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 7, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 13; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 18, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 23, and LC-CDR3, which includes the amino acid sequence SEQ ID NO:30.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which comprises the amino acid sequence SEQ ID NO: 1, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 7, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 13; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 18, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 18 The sequence SEQ ID NO:24, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:30.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 7, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 13; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 18, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 25, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: :30.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 2, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 7, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 13; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 18, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 25, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: :30.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which comprises the amino acid sequence SEQ ID NO: 1, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 8, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 13; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 18, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 18 The sequence SEQ ID NO:25, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:30.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which comprises the amino acid sequence SEQ ID NO: 3, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 9, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 14; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 19, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 26, and LC-CDR3, which includes the amino acid sequence SEQ ID NO:31.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 4, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 10, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 15; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 20, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 27, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: :32.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which comprises the amino acid sequence SEQ ID NO: 5, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 11, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 16; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 21, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 21 The sequence SEQ ID NO:28, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:33.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 6, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 12, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 17; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 22, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 29, and LC-CDR3, which includes the amino acid sequence SEQ ID NO:34.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 6, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 75, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 17; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 22, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 29, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: :80.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which comprises the amino acid sequence SEQ ID NO: 6, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 76, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 17; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 22, LC-CDR2, which includes the amino acid sequence SEQ ID NO:22 The sequence SEQ ID NO:29, and LC-CDR3, which contains the amino acid sequence SEQ ID NO:80.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 6, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 77, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 17; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 22, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 29, and LC-CDR3, which includes the amino acid sequence SEQ ID NO:80.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 6, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 78, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 17; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 22, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 29, and LC-CDR3, which includes the amino acid sequence SEQ ID NO:80.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region
  • the anti-GDF15 antibody comprises: a heavy chain variable domain ( VH ), the VH comprising SEQ ID NOs: 38-51, The amino acid sequence shown in any one of 82-89 or a variant thereof, which variant has at least about 80% (for example, at least 80%) with the amino acid sequence shown in any one of SEQ ID NOs: 38-51, 82-89 , 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and a light chain variable domain ( VL ) comprising SEQ ID NOs: 52-63, the amino acid sequence shown in any one of 90-91 or a variant thereof, which has at least about 80% ( For example, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG2 constant region
  • the anti-GDF15 antibody comprises: a heavy chain variable domain ( VH ), the VH comprising SEQ ID NOs: 38-51, The amino acid sequence shown in any one of 82-89 or a variant thereof, which variant has at least about 80% (for example, at least 80%) with the amino acid sequence shown in any one of SEQ ID NOs: 38-51, 82-89 , 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and a light chain variable domain (V L ) comprising SEQ ID NOs: 52-63 , the amino acid sequence shown in any one of 90-91 or a variant thereof, the variant has at least about 80% (such as at least 80%) with the amino acid sequence shown in any one of SEQ ID NOs: 52-63, 90-91 %, 85%, 90%, 95%, 96%, 97%, 98% or 99%)
  • the IgG2 is human IgG2.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG3 constant region
  • the anti-GDF15 antibody comprises: a heavy chain variable domain ( VH ), the VH comprising SEQ ID NOs: 38-51, The amino acid sequence shown in any one of 82-89 or a variant thereof, which variant has at least about 80% (for example, at least 80%) with the amino acid sequence shown in any one of SEQ ID NOs: 38-51, 82-89 , 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and a light chain variable domain (V L ) comprising SEQ ID NOs: 52-63 , the amino acid sequence shown in any one of 90-91 or a variant thereof, the variant has at least about 80% (such as at least 80%) with the amino acid sequence shown in any one of SEQ ID NOs: 52-63, 90-91 %, 85%, 90%, 95%, 96%, 97%, 98% or 99%)
  • the IgG3 is human IgG3.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region
  • the anti-GDF15 antibody comprises: a heavy chain variable domain ( VH ), the VH comprising SEQ ID NOs: 38-51, The amino acid sequence shown in any one of 82-89 or a variant thereof, which variant has at least about 80% (for example, at least 80%) with the amino acid sequence shown in any one of SEQ ID NOs: 38-51, 82-89 , 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and a light chain variable domain (V L ) comprising SEQ ID NOs: 52-63 , the amino acid sequence shown in any one of 90-91 or a variant thereof, the variant has at least about 80% (such as at least 80%) with the amino acid sequence shown in any one of SEQ ID NOs: 52-63, 90-91 %, 85%, 90%, 95%, 96%, 97%, 98% or 99%)
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: a heavy chain variable domain ( VH ), said ( VH ) comprising SEQ ID NOs: 38- 51, the amino acid sequence shown in any one of 82-89, and the light chain variable domain (V L ), said (V L ) comprising SEQ ID NOs: 52-63, any one of 90-91 shown Amino acid sequence.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising an IgG4 constant region
  • the anti-GDF15 antibody comprises: a heavy chain variable domain ( VH ), the VH comprising SEQ ID NOs: 38-51, The amino acid sequence shown in any one of SEQ ID NOs: 52-63, 90-91, and the light chain variable domain ( VL ) .
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 38 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:38 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:52 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:52 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprising or consisting of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprising or consisting of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 39 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:39 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:53 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:53 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 40 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:40 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:53 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:53 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 41 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:41 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:53 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:53 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 42 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:42 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:53 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:53 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 43 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:43 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:53 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:53 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 44 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:44 has at least about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO:53 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:53 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 39 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:39 has at least about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO:54 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:54.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 40 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:40 having at least about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO:54 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:54 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 41 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:41 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:54 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:54 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 42 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:42 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:54 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:54 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence Composed of SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 43 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:43 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:54 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:54 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 44 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:44 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:54 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:54 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 39 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:39 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:55 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:55 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprising or consisting of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprising or consisting of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 40 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:40 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:55 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:55 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 41 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:41 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:55 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:55 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 42 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:42 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:55 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:55 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 43 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:43 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:55 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:55 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 44 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:44 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:55 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:55 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 45 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:45 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:56 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:56 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 45 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:45 has at least about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO:57 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:57.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 46 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:46 having at least about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO:58 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:58 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 47 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:47 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:59 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:59 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 48 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:48 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:60 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:60 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence Composed of SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 49 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:49 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:61 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:61 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 50 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:50 having at least about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO:62 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:62 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 51 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:51 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:63 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:63 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprising or consisting of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprising or consisting of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 82 or a variant thereof, the variant having the same amino acid sequence SEQ ID NO:82 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:90 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:90 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 83 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:83 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:90 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:90 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 84 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:84 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:90 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:90 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 85 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:85 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:90 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:90 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 86 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:86 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:91 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:91 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 87 or a variant thereof, the variant having the same amino acid sequence SEQ ID NO:87 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:91 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:91 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 88 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:88 has at least about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO:91 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:91.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG1 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 89 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:89 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:91 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:91 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 38 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:38 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:52 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:52 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 39 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:39 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:53 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:53 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence Composed of SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 40 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:40 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:53 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:53 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 41 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:41 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:53 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:53 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 42 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:42 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:53 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:53 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprising or consisting of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprising or consisting of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 43 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:43 having at least about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO:53 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:53 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 44 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:44 has at least about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO:53 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:53 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 39 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:39 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:54 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:54 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 40 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:40 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:54 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:54 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 41 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:41 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:54 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:54 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 42 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:42 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:54 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:54 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising an IgG4 constant region, wherein the anti-GDF15 antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 43 or a variant thereof, the variant having the same amino acid sequence SEQ ID NO:43 has at least about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO:54 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:54.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 44 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:44 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:54 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:54 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 39 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:39 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:55 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:55 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 40 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:40 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:55 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:55 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence Composed of SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 41 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:41 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:55 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:55 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 42 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:42 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:55 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:55 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 43 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:43 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:55 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:55 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprising or consisting of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprising or consisting of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 44 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:44 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:55 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:55 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 45 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:45 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:56 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:56 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 45 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:45 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:57 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:57 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 46 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:46 having at least about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO:58 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:58 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 47 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:47 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:59 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:59 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 48 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:48 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:60 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:60 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 49 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:49 has at least about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO:61 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:61.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 50 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:50 having at least about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO:62 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:62 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 51 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:51 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:63 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:63 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 82 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:82 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:90 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:90 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence Composed of SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 83 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:83 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:90 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:90 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 84 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:84 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:90 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:90 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 85 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:85 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:90 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:90 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprising or consisting of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprising or consisting of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 86 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:86 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:91 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:91 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 87 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:87 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:91 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:91 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 88 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:88 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:91 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:91 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a full-length anti-GDF15 antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 89 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:89 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:91 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:91 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • Binding affinity is expressed as Kd, Koff, Kon or Ka.
  • Koff refers to the rate constant for the dissociation of an antibody from an antigen/antibody complex, as measured by a kinetic selection device.
  • Kon refers to the binding rate constant at which an antibody binds to an antigen to form an antigen/antibody complex.
  • the equilibrium dissociation constant Kd used in this article refers to the dissociation constant when a specific antibody-antigen interacts. It refers to the antigen concentration required when the antigen occupies half of all antibody binding sites in the antibody molecule solution and reaches equilibrium, which is equal to Koff /Kon. The determination of Kd assumes that all bound molecules are in solution.
  • the corresponding equilibrium dissociation rate constant is expressed as EC 50 , which is a good approximation of Kd.
  • the affinity binding constant Ka is the reciprocal of the dissociation constant Kd.
  • the dissociation constant (Kd) can be used as an indicator of the affinity of the reactive antibody moiety to the antigen.
  • Kd dissociation constant
  • a simple analysis can be performed by the Scatchard method using antibodies labeled with various markers and a Biacore instrument (manufactured by Amersham Biosciences) to analyze interactions between biomolecules by surface plasmon resonance according to the user manual or the included kit. .
  • the Kd value obtained using these methods is expressed in the unit M.
  • Antibodies that specifically bind to a target may have, for example, ⁇ 10-7 M, ⁇ 10-8 M, ⁇ 10-9 M, ⁇ 10-10 M, ⁇ 10-11 M , ⁇ 10-12 M, or ⁇ 10- Kd value of 13 M.
  • the binding specificity of an antibody can be determined experimentally by methods known in the art. These methods include, but are not limited to, Western blots, ELISA-, RIA-, ECL-, IRMA-, EIA-, BIAcore testing, and peptide scanning.
  • the anti-GDF15 antibody specifically binds to the GDF15 target with a Kd value of 10 -7 M to 10 -13 M (e.g., 10 -7 M to 10 -13 M, 10 -8 M to 10 -13 M, 10 -9 M to 10 -13 M or 10 -10 M to 10 -12 M).
  • the Kd value of the binding between the anti-GDF15 antibody and GDF15 is 10 -7 M to 10 -13 M, 1 ⁇ 10 -7 M to 5 ⁇ 10 -13 M, 10 -7 M to 10 -12 M, 10 -7 M to 10 -11 M, 10 -7 M to 10 -10 M, 10 -7 M to 10 -9 M, 10 -8 M to 10 -13 M , 1 ⁇ 10 -8 M to 5 ⁇ 10 -13 M, 10 -8 M to 10 - 12 M, 10 -8 M to 10 -11 M, 10 -8 M to 10 -10 M, 10 -8 M to 10 -9 M, 5 ⁇ 10 -9 M to 1 ⁇ 10 -13 M, 5 ⁇ 10 -9 M to 1 ⁇ 10 -12 M, 5 ⁇ 10 -9 M to 1 ⁇ 10 -11 M, 5 ⁇ 10 -9 M to 1 ⁇ 10 -10 M, 10 -9 M to 10 - 13 M, 10 -9 M to 10 -12 M, 10 -9 M to 10 -11 M, 10 -9 M to 10 -10 M, 5
  • the Kd value for binding between the anti-GDF15 antibody and the non-target is higher than the Kd value for the anti-GDF15 antibody and the target, and in some embodiments cited herein, the Kd value for the anti-GDF15 antibody and the target (e.g., GDF15)
  • the binding affinity is higher than the binding affinity of the anti-GDF15 antibody to the non-target.
  • non-target refers to an antigen other than GDF15.
  • the Kd value of the anti-GDF15 antibody (for GDF15) binding to the non-GDF15 target is at least 10 times different, such as 10-100 times, 100-1000 times, 10 3 -10 4 times, 10 4 -10 5 times, 10 5 -10 6 times, 10 6 -10 7 times, 10 7 -10 8 times, 10 8 -10 9 times , 10 9 -10 10 times, 10 10 -10 11 times, 10 11 -10 12 times .
  • the anti-GDF15 antibody binds to a non-target with a Kd value of 10 -1 M to 10 -6 M (e.g., 10 -1 M to 10 -6 M, 10 -1 M to 10 -5 M, 10 -2 M to 10 -4 M).
  • the non-target refers to an antigen other than GDF15.
  • the Kd value for binding between the anti-GDF15 antibody and the non-GDF15 target is 10 -1 M to 10 -6 M, 1 ⁇ 10 -1 M to 5 ⁇ 10 -6 M, 10 -1 M to 10 -5 M, 1 ⁇ 10 -1 M to 5 ⁇ 10 -5 M, 10 -1 M to 10 -4 M, 1 ⁇ 10 -1 M to 5 ⁇ 10 -4 M , 10 -1 M to 10 -3 M, 1 ⁇ 10 -1 M to 5 ⁇ 10 -3 M, 10 -1 M to 10 -2 M, 10 -2 M to 10 -6 M, 1 ⁇ 10 -2 M to 5 ⁇ 10 -6 M, 10 -2 M to 10 -5 M, 1 ⁇ 10 -2 M to 5 ⁇ 10 -5 M, 10 -2 M to 10 -4 M, 1 ⁇ 10 -2 M to 5 ⁇ 10 -4 M, 10 -2 M to 10 -3 M, 10 -3 M to 10 -6 M, 1 ⁇ 10 -3 M to 5 ⁇ 10 -6 M, 10 -3 M, 10 -3 M to 10 -6 M, 1 ⁇ 10
  • the anti-GDF15 antibody when referring to an anti-GDF15 antibody that specifically recognizes a GDF15 target with high binding affinity and binds to a non-target with low binding affinity, the anti-GDF15 antibody binds to the GDF15 target with a Kd value of 10 -7 M to 10 -13 M (for example, 10 -7 M to 10 -13 M, 10 -8 M to 10 -13 M, 10 -9 M to 10 -13 M, 10 - 10 M to 10 -12 M), and with The Kd value for non-target binding is 10 -1 M to 10 -6 M (eg, 10 -1 M to 10 -6 M, 10 -1 M to 10 -5 M, 10 -2 M to 10 -4 M).
  • the binding affinity of the anti-GDF15 antibody is compared to the binding affinity of a control anti-GDF15 antibody (eg, HuO1G06-127).
  • the Kd value of the binding between the control anti-GDF15 antibody and GDF15 can be at least 2 times, such as 2 times, 3 times, 4 times the Kd value of the binding between the anti-GDF15 antibody and GDF15 described herein. , 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 10-100 times, 100-1000 times, 10 3 -10 4 times.
  • nucleic acid molecules encoding anti-GDF15 antibodies are also considered.
  • a nucleic acid (or set of) nucleic acids encoding a full-length anti-GDF15 antibody is provided, including any of the full-length anti-GDF15 antibodies described herein.
  • the nucleic acid (or set of nucleic acids) of the anti-GDF15 antibody described herein may also include a nucleic acid sequence encoding a polypeptide tag (eg, protein purification tag, His tag, HA tag).
  • isolated host cells comprising an anti-GDF15 antibody, an isolated nucleic acid encoding an anti-GDF15 antibody polypeptide component, or a vector comprising a nucleic acid encoding an anti-GDF15 antibody polypeptide component described herein.
  • variants include nucleotide sequences that hybridize under at least moderately stringent hybridization conditions to a nucleic acid sequence encoding an anti-GDF15 antibody of the present application.
  • the present application also provides a vector into which the nucleic acid sequence of the present application can be inserted.
  • a natural or synthetic nucleic acid encoding an anti-GDF15 antibody is inserted into a suitable expression vector such that the nucleic acid is operably linked to 5' and 3' end regulatory elements, such as a promoter (e.g., lymphocyte-specific promoter) and 3' untranslated region (UTR), which can express anti-GDF15 antibodies (such as full-length anti-GDF15 antibodies).
  • the vector may be suitable for replication and integration in eukaryotic host cells.
  • Typical cloning and expression vectors contain transcriptional and translational terminators, initiation sequences, and promoters that regulate expression of the nucleic acid sequence of interest.
  • nucleic acids described herein can also be used for nucleic acid immunization and gene therapy using standard gene delivery protocols.
  • Nucleic acid delivery methods are known in the art. See, for example, U.S. Pat. Nos. 5,399,346, 5,580,859, 5,589,466, the entire contents of which are incorporated herein by reference.
  • the application also provides gene therapy vectors.
  • Nucleic acids can be cloned into many types of vectors.
  • nucleic acids can be cloned into vectors including, but not limited to, plasmids, phagemids, phage derivatives, animal viruses, and cosmids.
  • Vectors of particular interest include expression vectors, replication vectors, probe generation vectors and sequencing vectors.
  • expression vectors can be provided to cells in the form of viral vectors.
  • Viral vector technology is well known in the art and is described, for example, in Green and Sambrook (2013, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York), and other virology or molecular biology manuals.
  • Viruses that can be used as vectors include, but are not limited to, retroviruses, adenoviruses, adeno-associated viruses, herpesviruses, and lentiviruses.
  • suitable vectors include an origin of replication functional in at least one organism, promoter sequences, convenient restriction enzyme sites, and one or more selectable markers (see, e.g., WO 01/96584; WO 01/29058; and U.S. Pat. No. 6,326,193).
  • retroviruses provide a convenient platform for gene delivery systems.
  • the selected genes can be inserted into vectors and packaged in retroviral particles using techniques known in the art.
  • the recombinant virus is then isolated and delivered to the subject's cells in vivo or in vitro.
  • Many retroviral systems are known in the art.
  • adenoviral vectors are used.
  • Many adenoviral vectors are known in the art.
  • lentivirus is used carrier.
  • Vectors derived from retroviruses, such as lentiviruses are suitable tools for long-term gene transfer because they enable long-term stable integration of the transgene and propagation in progeny cells.
  • Lentiviral vectors have an additional advantage over tumor-derived retroviruses such as murine leukemia virus in that they can transduce non-dividing cells, such as hepatocytes. At the same time, it has the additional advantage of low immunogenicity.
  • promoter elements such as enhancers, regulate the frequency of transcription initiation. Typically they are located 30-110 bp upstream of the start site, although recently many promoters have been found to also contain functional elements downstream of the start site.
  • the spacing between promoter elements is usually flexible, so that promoter function is maintained when elements are interchanged or moved with each other. In the thymidine kinase (tk) promoter, activity does not begin to decrease until the spacing between promoter elements increases to 50 bp.
  • tk thymidine kinase
  • a suitable promoter is the immediate early cytomegalovirus (CMV) promoter sequence. This promoter sequence is a strong constitutive promoter sequence that can drive high-level expression of any polynucleotide sequence operably linked to it.
  • CMV immediate early cytomegalovirus
  • EF-1 ⁇ elongation factor 1 ⁇
  • constitutive promoters may also be used, including, but not limited to, simian virus 40 (SV40) early promoter, mouse mammary tumor virus (MMTV), human immunodeficiency virus long terminal repeat (HIV-LTR) promoter , MoMuLV promoter, avian leukemia virus promoter, Epstein-Barr virus immediate early promoter, Rous sarcoma virus promoter and human gene promoters, such as but not limited to actin promoter, myosin promoter, Hemoglobin promoter and creatine kinase promoter.
  • SV40 simian virus 40
  • MMTV mouse mammary tumor virus
  • HV-LTR human immunodeficiency virus long terminal repeat
  • MoMuLV promoter avian leukemia virus promoter
  • Epstein-Barr virus immediate early promoter Epstein-Barr virus immediate early promoter
  • Rous sarcoma virus promoter Rous sarcoma virus promoter
  • human gene promoters such as but not
  • an inducible promoter provides a molecular switch that turns on the expression of the polynucleotide sequence to which it is operably linked when such expression is desired, and turns off expression when it is not.
  • Inducible promoters include, but are not limited to, metallothionein promoters, glucocorticoid promoters, progesterone promoters, and tetracycline promoters.
  • expression of anti-GDF15 antibodies is inducible.
  • a nucleic acid sequence encoding an anti-GDF15 antibody is operably linked to an inducible promoter, including any of the inducible promoters described herein.
  • an inducible promoter provides a molecular switch that turns on the expression of a polynucleotide sequence operably linked to it when expression is desired, and turns off expression when expression is not needed.
  • exemplary inducible promoters suitable for use in eukaryotic cells include, but are not limited to, hormone regulatory elements (see, for example, Mader, S. and White, JH (1993) Proc. Natl. Acad. Sci. USA 90:5603-5607 ), synthetic ligand regulatory elements (see Spencer, DM et al (1993) Science 262: 1019-1024) and ionizing radiation regulatory elements (see Manome, Y. et al. (1993) Biochemistry 32: 10607-10613; Datta, R .
  • the inducible promoter system used to express anti-GDF15 antibodies is the Tet system. In some embodiments, the inducible promoter system used to express anti-GDF15 antibodies is an E. coli lac repressor system.
  • Tet system An exemplary inducible promoter system used in this application is the Tet system. This system is based on the Tet system described by Gossen et al. (1993).
  • the target polynucleotide is controlled by a promoter containing one or more Tet operator (TetO) sites.
  • TetO Tet operator
  • TetR Tet repressor
  • the activated state for example, in the presence of inducers such as tetracycline (Tc), anhydrotetracycline, doxycycline (Dox) or their active analogs, the inducer causes TetR to be released from TetO, resulting in transcription. .
  • Doxycycline is a member of the tetracycline antibiotic family, its chemical name is 1-dimethylamino-2,4a,5,7-pentahydroxy-11-methyl-4,6-dioxy-1,4a ,11,11a,12,12a-hexahydrotetraene-3-carboxamide.
  • TetR is codon-optimized for expression in mammalian cells, such as mouse or human cells. Due to the degeneracy of the genetic code, most amino acids are encoded by more than one codon, resulting in a large number of variants in the sequence of a given nucleic acid without any change in the sequence of its encoded amino acid. However, many organisms have differences in codon usage, also known as "codon preference" (i.e., the preference for a given amino acid to use a specific codon). Codon preference is often associated with the presence of dominant tRNA species for specific codons, which in turn increases the efficiency of mRNA translation. Coding sequences derived from a specific species (e.g., prokaryotes) can thus be tailored through codon optimization to enhance their expression in different species (e.g., eukaryotes).
  • a specific species e.g., prokaryotes
  • Tet-Off transcription is inactive in the presence of Tc or Dox.
  • tTA tetracycline-regulated transcriptional activator
  • TRE tetracycline-responsive promoter element
  • rtTA is a fusion protein composed of the TetR repressor and the VP16 transcriptional activation domain.
  • a 4-amino acid change in the DNA-binding region of TetR changes the binding properties of rtTA, causing it to only recognize the tetO sequence on the target transgene TRE in the presence of Dox. Therefore, in the Tet-On system, rtTA can activate the transcription of TRE-regulated target genes only in the presence of Dox.
  • lac repressor system of E. coli (see Brown et al., Cell 49:603-612 (1987)).
  • the Lac repressor system functions by regulating the transcription of a target polynucleotide operably linked to a promoter containing the lac operator (lacO).
  • lacO lac operator
  • LacR Lac repressor
  • lacR binds to LacO, thereby preventing the transcription of the target polynucleotide.
  • Expression of the polynucleotide of interest is induced by a suitable inducer, for example, isopropyl- ⁇ -D thiogalactopyranoside (IPTG).
  • IPTG isopropyl- ⁇ -D thiogalactopyranoside
  • the expression vector to be introduced into the cell may also contain a selectable marker gene or a reporter gene or both to facilitate the identification and selection of expressing cells from a population of cells transfected or infected with the viral vector.
  • the selectable marker can be carried on separate DNA fragments and used in co-transfection experiments.
  • Either the selectable marker gene or the reporter gene can be flanked by appropriate regulatory sequences to enable expression in the host cell.
  • Useful selectable markers include, for example, antibiotic resistance genes such as neo and similar genes.
  • Reporter genes can be used to identify potentially transfected cells and evaluate the function of regulatory sequences.
  • a reporter gene is a gene that is not present in or expressed by the recipient organism or tissue and encodes a polypeptide whose expression is manifested by some readily detectable property, such as enzymatic activity. After the DNA is introduced into the recipient cells, the expression of the reporter gene is detected at the appropriate time.
  • Suitable reporter genes may include genes encoding luciferase, ⁇ -galactosidase, chloramphenicol acetyltransferase, secreted alkaline phosphatase, or green fluorescent protein (see, Ui-Tel et al., 2000 FEBS Letters 479 :79-82).
  • Suitable expression systems are well known and can be prepared by known techniques or commercially available.
  • the construct with the smallest 5' flanking region that shows the highest expression level of the reporter gene is considered the promoter.
  • Such promoter regions can be linked to reporter genes and used to assess the ability of certain substances to regulate promoter-driven transcription.
  • nucleic acids encoding any of the full-length anti-GDF15 antibodies described herein are provided.
  • the nucleic acid includes one or more nucleic acid sequences encoding full-length anti-GDF15 antibody heavy and light chains.
  • each of the one or more nucleic acid sequences is contained in a separate vector.
  • at least some of the nucleic acid sequences are included in the same vector.
  • all nucleic acid sequences are contained in the same vector.
  • Vectors may be selected, for example, from mammalian expression vectors and viral vectors (eg, vectors derived from retroviruses, adenoviruses, adeno-associated viruses, herpesviruses and lentiviruses).
  • mammalian expression vectors and viral vectors eg, vectors derived from retroviruses, adenoviruses, adeno-associated viruses, herpesviruses and lentiviruses.
  • the vector can be readily introduced into host cells, such as mammalian cells, bacteria, yeast or insect cells, by any method in the art.
  • the expression vector can be introduced into the host cell by physical, chemical or biological methods.
  • polynucleotides are introduced into the host cell by calcium phosphate transfection.
  • Biological methods for introducing polynucleotides of interest into host cells include the use of DNA and RNA vectors.
  • Viral vectors especially retroviral vectors, have become the most widely used method for inserting genes into mammalian cells, such as human cells.
  • Other viral vectors can be derived from lentivirus, poxvirus, herpes simplex virus type 1, adenovirus, adeno-associated virus, etc. See, for example, U.S. Pat. Nos. 5,350,674 and 5,585,362.
  • colloidal dispersion systems such as polymer complexes, nanocapsules, microspheres, magnetic beads, and lipid-based systems including oil-in-water emulsions, micelles, and mixed gels pellets and liposomes.
  • colloidal dispersion systems such as polymer complexes, nanocapsules, microspheres, magnetic beads, and lipid-based systems including oil-in-water emulsions, micelles, and mixed gels pellets and liposomes.
  • liposomes eg, artificial membrane vesicles.
  • an exemplary delivery vehicle is liposomes.
  • lipid formulations to introduce nucleic acids into host cells (in vitro, ex vivo, or in vivo).
  • the nucleic acid can be associated with lipids.
  • Nucleic acids bound to lipids can be encapsulated into the aqueous interior of liposomes and dispersed within the lipid bilayer of liposomes.
  • Lipid, lipid/DNA or lipid/expression vector related compositions are not limited to any particular structure in solution. For example, they may exist in bilayer structures, in micelles or in "collapsed" structures. They can also simply disperse in solution, possibly forming aggregates that are not uniform in size or shape. Lipids are fatty substances that can be naturally occurring or synthetic lipids.
  • lipids include lipid droplets that occur naturally in the cytoplasm, as well as a class of compounds containing long-chain aliphatic hydrocarbons and their derivatives, such as fatty acids, alcohols, amines, aminoalcohols, and aldehydes.
  • experiments can be performed in order to confirm that the recombinant DNA sequence is present in the host cell.
  • Such experiments include, for example, "molecular biology” experiments well known to those skilled in the art. For example, Southern and Northern blotting, RT-PCR and PCR; "biochemical” experiments, such as detecting the presence or absence of a specific polypeptide, such as by immunological methods (ELISAs and Western blots) or by experiments described in this article All fall within the scope of this application.
  • the anti-GDF15 antibody is a monoclonal antibody or is derived from a monoclonal antibody. In some embodiments, the anti-GDF15 antibody comprises VH and VL from a monoclonal antibody, or a variant thereof. In some embodiments, the anti-GDF15 antibody further includes CH1 and CL regions from a monoclonal antibody, or variants thereof.
  • Monoclonal antibodies can be prepared using, for example, methods known in the art, including hybridoma cell methods, phage display methods, or using recombinant DNA methods. Additionally, exemplary phage display methods are described herein and in the Examples below.
  • an immune agent is usually used to immunize hamsters, mice or other suitable host animals to induce lymphocytes that produce or are capable of producing antibodies that specifically bind to the immune agent.
  • lymphocytes can be immunized in vitro.
  • Immunizing agents may include polypeptides or fusion proteins of the protein of interest.
  • PBLs peripheral blood lymphocytes
  • spleen cells or lymph node cells are used.
  • Lymphocytes are fused to immortalized cell lines using an appropriate fusion agent, such as polyethylene glycol, to form hybridoma cells.
  • Immortal cell lines are typically transformed mammalian cells, particularly myeloma cells of rodent, bovine, and human origin. Typically, rat or mouse myeloma cell lines are used.
  • Hybridoma cells can be cultured in a suitable medium, which preferably contains one or more substances that inhibit the growth or survival of unfused immortal cells. For example, if the parent cells lack the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT or HPRT), the hybridoma cell culture medium usually includes hypoxanthine, aminopterin, and thymidine (HAT medium), which can Prevents the growth of HGPRT-deficient cells.
  • HGPRT hypoxanthine-guanine phosphoribosyltransferase
  • the immortalized cell lines fuse efficiently, ensure high-level and stable expression of the antibody by the selected antibody-producing cells, and are sensitive to certain media, such as HAT media.
  • the immortal cell line is a mouse myeloma cell line and can be obtained from, for example, the Salk Cell Collection in San Diego, California. Heart and American Type Culture Collection in Manassas, Virginia. Also described are human myeloma and mouse-human hybrid myeloma cell lines for the preparation of human monoclonal antibodies.
  • the culture medium in which the hybridoma cells are cultured can then be assayed for the presence of monoclonal antibodies directed against the polypeptide.
  • the binding specificity of monoclonal antibodies produced by hybridoma cells can be determined by immunoprecipitation or in vitro binding experiments, such as radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA). Such techniques or analytical methods are known in the art.
  • the binding affinity of a monoclonal antibody can be determined by Scatchard analysis as described, for example, in Munson and Pollard, Anal. Biochem., 107:220 (1980).
  • hybridoma cells After the desired hybridoma cells are identified, the clones of interest can be subcloned by limiting dilution and cultured by standard methods. Suitable media for this purpose include, for example, modified Eagle's medium (DMEM) and RPMI-1640 medium. Alternatively, hybridoma cells can be grown in mammals in the form of ascites fluid.
  • DMEM modified Eagle's medium
  • RPMI-1640 medium RPMI-1640
  • Monoclonal antibodies secreted by the subclones can be isolated or purified from the culture medium or ascitic fluid by conventional immunoglobulin purification methods, such as protein A-Sepharose, hydroxyapatite chromatography, gel electrophoresis, dialysis, or affinity Chromatography.
  • immunoglobulin purification methods such as protein A-Sepharose, hydroxyapatite chromatography, gel electrophoresis, dialysis, or affinity Chromatography.
  • the anti-GDF15 antibody comprises a sequence selected from a clone of an antibody library (eg, a phage library displaying scFv or Fab fragments).
  • the clones can be identified by screening a combinatorial library of antibody fragments with the desired activity. For example, various methods are known in the art for generating phage display libraries and screening these libraries for antibodies with desired binding properties.
  • phage display methods all components of the V H and V L genes are cloned separately through polymerase chain reaction (PCR), randomly recombined in a phage library, and then screened for phages that can bind the antigen, such as Winter et al. ., Ann. Rev. Immunol., 12:433-455 (1994). Phages typically display antibody fragments as scFv fragments or as Fab fragments. Immunogenically derived library phages provide high-affinity antibodies against immunogens without the need to construct hybridoma cells. Alternatively, natural libraries (e.g.
  • the anti-GDF15 antibody is prepared by phage display screening of anti-GDF15 antibody portions in the library that can specifically bind to the target GDF15.
  • the library may be a human scFv phage display library with at least 1 ⁇ 10 9 (e.g., at least 1 ⁇ 10 9 , 2.5 ⁇ 10 9 , 5 ⁇ 10 9 , 7.5 ⁇ 10 9 , 1 ⁇ 10 10 , 2.5 ⁇ 10 10 , 5 ⁇ 10 10 , 7.5 ⁇ 10 10 or 1 ⁇ 10 11 ) diversity of unique human antibody fragments.
  • the library is a human natural library, constructed from DNA extracted from PMBCs and spleens of healthy subjects, containing all human heavy and light chain subfamilies.
  • the library is a human natural library constructed from DNA extracted from PMBCs isolated from patients with various diseases, such as patients with autoimmune diseases, cancer patients, and patients with infectious diseases.
  • the library is a semi-synthetic human library in which the heavy chain CDR3s are completely random and all amino acids (except cysteine) are present with equal probability at any given position. (See, eg, Hoet, RM et al., Nat. Biotechnol. 23(3):344-348, 2005).
  • the heavy chain CDR3 length of the semi-synthetic human library ranges from 5 to 24 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 , 19, 20, 21, 22, 23 or 24) between amino acids.
  • the library is a fully synthetic phage display library.
  • the library is a non-human phage display library.
  • Phage clones with high affinity to target GDF15 can be screened by iterative binding of phage to target GDF15 bound to a solid support (e.g., beads for solution panning or mammalian cells for cell panning) ), followed by removal of unbound phage and elution of specifically bound phage. Subsequently, bound phage clones are eluted and used to infect suitable host cells, such as E. coli XL1-Blue, for expression and purification. Phage clones that specifically bind GDF15 can be enriched by multiple rounds of panning (eg, 2, 3, 4, 5, 6, or more rounds), such as solution panning, cell panning, or a combination of both. Specific binding of the enriched phage clones to the target GDF15 can be detected by any method known in the art, including, for example, ELISA and FACS.
  • Another way to screen antibody libraries is to display proteins on the surface of yeast cells.
  • Wittrup et al. (US Patents 6,699,658 and 6,696,251) developed a method for displaying libraries in yeast cells.
  • one component includes the yeast lectin protein (Aga1), which is anchored to the yeast cell wall, and the other component includes the second subunit of the lectin protein Aga2, which can pass through disulfide bonds. Binds to the Aga1 protein and is displayed on the surface of yeast cells.
  • Aga1 protein is expressed by integrating the Aga1 gene into the yeast chromosome.
  • a single-chain variable fragment (scFv) library is fused to the Aga2 gene in a yeast display plasmid and, after transformation, is retained in yeast due to the presence of an additional nutritional marker. Both Aga1 and Aga2 proteins are expressed under the control of galactose-inducible promoters.
  • the human antibody V gene library (V H and V K fragments) was obtained by PCR using a set of degenerate primers (Sblattero, D. and Bradbury, A. Immunotechnology 3, 271-278 1998).
  • PCR templates were derived from commercially available RNA or cDNA, including PBMC, spleen, lymph nodes, bone marrow, and tonsils.
  • Independent V H and V K PCR libraries were combined and assembled into scFv formats by overlap extension PCR (Sheets, MD et al, Proc. Natl. Acad. Sci. USA 95, 6157–6162 1998).
  • yeast scFv display library To construct a yeast scFv display library, the resulting scFv PCR product was cloned into a yeast display plasmid in yeast via homologous recombination. (Chao, G, et al, Nat Protoc. 2006; 1(2):755-68. Miller KD, et al. Current Protocols in Cytometry 4.7.1-4.7.30, 2008).
  • Anti-GDF15 antibodies can be screened using a mammalian cell display system, in which the antibody moiety is displayed on the cell surface and antibodies specifically targeting GDF15 are isolated by antigen-directed screening methods (as described in U.S. patent No. 7,732,195B2).
  • a Chinese hamster ovary (CHO) cell library displaying a large number of human IgG antibody genes can be created and used to discover clones expressing high-affinity antibody genes.
  • An alternative display system has been developed that allows the same protein to be simultaneously displayed and secreted on the cell surface through alternative splicing, in which the phenotype of the displayed protein remains correlated with the genotype, allowing for simultaneous biophysical and cell function-based analyses. Characterize the secreted soluble antibodies.
  • This method overcomes many of the limitations of previous mammalian cell displays and enables direct screening and maturation of antibodies in the form of full-length, glycosylated IgGs (Peter M. Bowers, et al, Methods 2014, 65: 44-56) .
  • Transient expression systems are suitable for a single round of antigen selection prior to antibody gene recovery and are therefore most useful for selecting antibodies from smaller libraries.
  • Stable exosome vectors offer an attractive option. Exosome vectors can be efficiently transfected and stably maintained at low copy numbers, allowing for multiple rounds of panning and elucidation of more complex antibody libraries.
  • the IgG library was constructed based on the ligation of germline sequence V gene fragments isolated from a pool of human donors and rearranged (D)J regions. RNA collected from 2000 human blood samples was reverse transcribed into cDNA, VH and VK fragments were amplified using VH and VK specific primers, and purified by gel extraction. The VH and VK fragments were subcloned into display vectors containing IgG1 or K constant regions respectively, and then electroporated or transduced 293T into cells to prepare IgG libraries.
  • V H and V K are ligated to generate scFv, which is then subcloned into a display vector and electroporated or transduced into 293T cells.
  • IgG libraries are constructed based on germline sequence V gene fragments and rearranged (D)J regions isolated from a group of donors, which can be mice, rats, rabbits or monkeys.
  • Monoclonal antibodies can also be prepared by recombinant DNA methods, such as those described in US Patent No. 4,816,567.
  • DNA encoding the monoclonal antibodies described herein can be readily isolated and sequenced by conventional methods (eg, by oligonucleotide probes that specifically bind to genes encoding the light and heavy chains of murine antibodies).
  • Hybridoma cells as described above or the GDF15-specific phage clones of the present application can be used as a source of such DNA.
  • the DNA can be placed into an expression vector, which can then be transfected into host cells, such as simian COS cells, Chinese hamster ovary cancer (CHO) cells, or myeloma cells that do not produce immunoglobulins, to obtain the expression in the recombinant host.
  • host cells such as simian COS cells, Chinese hamster ovary cancer (CHO) cells, or myeloma cells that do not produce immunoglobulins, to obtain the expression in the recombinant host.
  • Monoclonal antibodies synthesized in cells may also be modified, for example by substituting coding sequences for human heavy and light chain constant regions and/or substituting framework regions for homologous non-human sequences (US Patent No. 4,816,567; Morrison et al., supra), or by co-coding sequences.
  • non-immunoglobulin polypeptide is valently linked to the coding sequence for the immunoglobulin.
  • This non-immunoglobulin polypeptide can replace the constant region of the antibody in this application, or can replace an antigen-binding site in the variable domain of the antibody in this application, forming a chimeric bivalent antibody.
  • the antibody may be a monovalent antibody.
  • Methods of preparing monovalent antibodies are known in the art. For example, one involves a recombinant expression method involving an immunoglobulin light chain and a modified heavy chain.
  • the heavy chain is usually truncated at any position in the Fc region to prevent the heavy chains from cross-linking with each other.
  • the relevant cysteine residues are substituted with other amino acid residues or deleted to prevent cross-linking.
  • In vitro methods are also suitable for preparing monovalent antibodies. Digestion of antibodies to produce antibody fragments, particularly Fab fragments, can be accomplished using any method known in the art.
  • Antibody variable domains with the desired binding specificity can be fused to immunoglobulin constant regions. Fusions to the immunoglobulin heavy chain constant region, including at least part of the hinge, CH2 and CH3 regions, are preferred. In some embodiments, the first heavy chain constant region (CH1), which contains the necessary sites for light chain binding, is present in at least one fusion. DNA encoding the immunoglobulin heavy chain fusion, and if desired, DNA encoding the immunoglobulin light chain, is inserted into a separate expression vector and co-transfected into a suitable host organism.
  • the anti-GDF15 antibody (eg, full-length anti-GDF15 antibody) can be a fully human antibody or a humanized antibody.
  • Humanized forms of non-human (e.g., mouse) antibody portions are chimeric immunoglobulins, immunoglobulin chains, or fragments thereof (e.g., Fv, Fab, Fab', F(ab') 2 , scFv, or other fragments of antibodies Antigen binder sequences), which generally include minimal sequences derived from non-human immunoglobulins.
  • Humanized antibodies include human immunoglobulins, immunoglobulin chains or fragments thereof (recipient antibodies) in which the residues of the acceptor CDRs are replaced by non-human (donor antibody) CDRs with the desired specificity, affinity and properties. Residue substitutions, such as mouse, rat or rabbit CDRs. In some embodiments, human immunoglobulin Fv framework residues are replaced with corresponding non-human residues. Humanized antibodies may also contain amino acid residues that neither belong to the recipient antibody nor are in the introduced CDR or framework sequence.
  • a humanized antibody contains at least one, and usually two variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions are common to human immunoglobulins. sequence.
  • humanized antibodies typically contain one or more amino acid residues introduced from a non-human source. Those non-human amino acid residues are often referred to as "implanted” residues, usually from the "imported” variable domain. According to some embodiments, humanization can be performed essentially as described by Winter and colleagues (Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332:323-327 ( 1988); Verhoeyen et al., Science, 239:1534-1536 (1988)), by replacing the corresponding sequences of human antibodies with rodent CDRs or CDR sequences. Thus, this "humanized” antibody portion (U.S. Patent No.
  • a humanized antibody portion is a typical human antibody portion in which some CDR residues and possibly some framework region residues are replaced by residues from similar positions in rodent antibodies.
  • Fully human antibodies are an alternative to humanization.
  • transgenic animals eg, mice
  • transgenic animals eg, mice
  • JH antibody heavy chain junction region
  • transferring human germline immunoglobulin gene arrays into such germline mutant mice can produce human antibodies in response to antigen stimulation, see, for example, akobovits et al., PNAS USA, 90:2551 (1993); Jakobovits et al.
  • Fully human antibodies can be prepared by introducing human immunoglobulin loci into transgenic animals (eg, mice in which the endogenous immunoglobulin genes have been partially or completely silenced). After antigen stimulation, the production of fully human antibodies can be found to be very similar to their production in humans in all aspects, including gene rearrangement, assembly, and antibody libraries. This method is used in US Patent Nos.
  • Fully human antibodies can also be produced by activating B cells in vitro (see U.S. Patents 5,567,610 and 5,229,275) or by using various techniques known in the art, including phage display libraries. Hoogenboom and Winter, J. Mol. Biol., 227: 381 (1991); Marks et al., J. Mol. Biol., 222: 581 (1991).
  • the technology of Cole et al. and Boerner et al. It can also be used to prepare fully human monoclonal antibodies. See Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985) and Boerner et al., J. Immunol., 147(1):86-95 (1991).
  • the amino acid sequences of anti-GDF15 antibody variants are also contemplated.
  • the amino acid sequences of antibody variants can be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody or by peptide synthesis. Such modifications include, for example, deletions and/or insertions and/or substitutions of residues in the antibody amino acid sequence.
  • the final construct can be accomplished by any combination of deletions, insertions, and substitutions of amino acid residues to give it the desired characteristics. For example, antigen binding.
  • anti-GDF15 antibody variants with one or more amino acid substitutions are provided.
  • Target sites for substitution mutations include hypervariable regions (HVRs) and framework regions (FRs).
  • Amino acid substitutions can be introduced into the antibody of interest and the product screened for the desired activity, for example, improved biological activity, maintained/improved antigen binding capacity, reduced immunogenicity, or improved ADCC or CDC.
  • Amino acids are divided into different categories based on the nature of their side chains:
  • Acidic amino acids aspartic acid Asp, glutamic acid Glu;
  • Aromatic amino acids tryptophan Trp, tyrosine Tyr, phenylalanine Phe.
  • Substitutions of non-conservative amino acids involve substitution of one category for another category.
  • An exemplary substitution variant is an affinity matured antibody, which can be conveniently produced using, for example, phage display-based affinity maturation techniques. Briefly, one or more CDR residues are mutated, variant antibody moieties are displayed on phage, and those selected for specific biological activity (e.g., based on GFRAL/RET downstream signaling inhibition assays or binding affinity) Variants. Changes (eg, substitutions) can be made in the HVRs region to obtain improved biological activity based on GFRAL/RET downstream signal inhibition experiments or binding affinity. Alterations can occur in "hot spots" of HVR, i.e., codon-encoded residues that are highly mutated during somatic cell maturation (see, e.g., Chowdhury, Methods Mol.
  • variable genes selected for affinity maturation are introduced into the variable genes selected for affinity maturation by any of a variety of methods, such as error-prone PCR, strand shuffling, or oligonucleotide-directed mutagenesis. .
  • Secondary libraries are then created. The library is screened to identify antibody variants with the desired affinity.
  • Another way to introduce diversity includes the HVR-mediated manner, in which several HVR residues (e.g., 4-6 residues at a time) are randomized. HVR residues involved in antigen binding are specifically recognized, for example, using alanine scanning mutagenesis or modeling. Usually the CDR-H3 and CDR-L3 regions are particularly focused targets.
  • substitutions, insertions, or deletions may occur within one or more HVRs, so long as such changes do not substantially reduce the ability of the antibody to bind the antigen.
  • conservative changes eg, conservative substitutions provided herein
  • HVRs that do not substantially reduce binding affinity. These changes may occur outside the HVR "hot zone" or SDRs area.
  • each HVR is either unchanged or contains no more than 1, 2, or 3 amino acid substitutions.
  • a useful method for identifying amino acid residues or regions of an antibody that can be targeted mutated is called "alanine scanning mutagenesis" as described in Cunningham and Wells (1989) Science, 244:1081-1085 .
  • target residues e.g., charged residues such as arginine, aspartic acid, histidine, lysine, and glutamic acid
  • neutral or negatively charged amino acids e.g., , alanine or glutamic acid
  • Further substitutions can be introduced at amino acid positions to demonstrate functional sensitivity of the position to the initial substitution.
  • the contact sites between the antibody and the antigen are identified through the crystal structure of the antigen-antibody complex. These contact site residues and adjacent residues can be targeted or eliminated as substitution candidates. Screen variants to determine if they have the desired properties.
  • Insertions of amino acid sequences including fusions at the amino and/or carboxyl terminus, ranging in length from 1 residue to polypeptides containing 100 or more residues, and including insertion of 1 or more amino acid residues within the sequence base.
  • terminal insertions include antibodies with a methionyl residue at the N-terminus.
  • Other insertional variants of antibody molecules include fusion of an enzyme (eg, ADEPT) or peptides that increase the serum half-life of the antibody to the N- or C-terminus of the antibody molecule.
  • one or more amino acid modifications are introduced into the Fc region of an antibody described herein (eg, a full-length anti-GDF15 antibody or an anti-GDF15 antibody fusion protein), thereby generating Fc region variants.
  • Fc region variants have enhanced ADCC potency, typically associated with binding to Fc receptors (FcRs).
  • Fc region variants have reduced ADCC efficacy.
  • changes or mutations in the Fc sequence affecting its potency For example, WO 00/42072 and Shields et al. J Biol. Chem. 9(2):6591-6604 (2001) describe enhanced binding to FcRs or Attenuated antibody variants. The contents of these publications are incorporated herein by reference.
  • ADCC Antibody-dependent cell-mediated cytotoxicity
  • NK cells activated by antibodies.
  • NK cells express the Fc receptor CD16. This receptor recognizes and binds to the Fc portion of the antibody molecule bound to the surface of the target cell.
  • the most common Fc receptors on the surface of NK cells are CD16 or Fc ⁇ RIII.
  • Binding of Fc receptors to the Fc region of antibodies results in activation of NK cells, release of cell lytic granules, and subsequent target cell apoptosis.
  • the killing effect of ADCC on tumor cells can be measured through specific experiments of NK-92 cells transfected with high-affinity FcR. The results were compared with wild-type NK-92, which does not express FcR.
  • the application also provides anti-GDF15 antibody variants (e.g., full-length anti-GDF15 antibody variants) that comprise an Fc region with some, but not all, of the effector functions such that they have an extended half-life in vivo, yet specifically
  • the effector function (such as CDC or ADCC) is non-essential or deleterious, making this anti-GDF15 antibody an ideal candidate for this application. Reduction/elimination of CDC and/or ADCC activity is confirmed by performing cytotoxicity assays in vitro and/or in vivo.
  • Fc receptor (FcR) binding assays are used to confirm that the antibody lacks Fc ⁇ R binding ability (and therefore may lack ADCC activity) but still retains FcRn binding ability.
  • NK cells only express Fc ⁇ RIII
  • monocytes express Fc ⁇ RI, Fc ⁇ RII, and Fc ⁇ RIII.
  • Table 3 The expression of FcR on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet Annu. Rev. Immunol. 9:457-492 (1991).
  • Non-limiting examples of in vitro assessment of ADCC activity of target molecules are described in US Pat. No. 5,500,362 (see, e.g., Hellstrom, I.
  • CYTOTOX 96 TM Nonradioactive Cell Toxicity assays (Promega, Madison, Wis.). Effector cells used in these assays include peripheral blood mononuclear cells (PBMC) and natural killer cells (NK).
  • PBMC peripheral blood mononuclear cells
  • NK natural killer cells
  • the ADCC activity of the target molecule is performed in vivo Detection, for example, in animal models, as described in Clynes et al. Proc. Nat'l Acad. Sci. USA 95:652-656 (1998).
  • a C1q binding assay can also be performed to confirm that the antibody cannot bind to C1q , thereby lacking CDC activity.
  • a CDC assay can be performed (see, for example, Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996); Cragg, MS et al., Blood 101:1045-1052 (2003); and Cragg, MS and MJ Glennie, Blood 103:2738-2743 (2004)). Determined using methods known in the art FcRn binding and clearance/half-life in vivo (see, eg, Petkova, SB et al., Int'l. Immunol. 18(12):1759-1769 (2006)).
  • Antibodies with reduced effector function include substitution of one or more residues at residues 238, 265, 269, 270, 297, 327, and 329 of the Fc region (US Pat. No. 6,737,056). These Fc variants include Fc variants with substitutions of two or more residues at positions 265, 269, 270, 297, and 327, including those referred to as Fc variant of "DANA" in which residues 265 and 297 are substituted with alanine (US Pat. No. 7,332,581).
  • an anti-GDF15 antibody (eg, a full-length anti-GDF15 antibody) variant is provided that includes an Fc region variant with one or more amino acid substitutions capable of enhancing ADCC effects.
  • the Fc region variant contains one or more amino substitutions capable of enhancing the ADCC effect at positions 298, 333 and/or 334 (EU residue numbering) of the Fc region.
  • the anti-GDF15 antibody (eg, full-length anti-GDF15 antibody) variant includes amino acid substitutions at positions S298A, E333A, and K334A in the Fc region.
  • changes in the Fc region result in changes (i.e., enhancement or attenuation) of Clq binding and/or complement-dependent cytotoxicity (CDC), see U.S. Pat. No. 6,194,551, WO 99/51642, and Idusogie et al. al., J. Immunol. 164:4178-4184 (2000).
  • changes in the Fc region result in changes (i.e., enhancement or attenuation) of Clq binding and/or complement-dependent cytotoxicity (CDC), see U.S. Pat. No. 6,194,551, WO 99/51642, and Idusogie et al. al., J. Immunol. 164:4178-4184 (2000).
  • an anti-GDF15 antibody e.g., a full-length anti-GDF15 antibody
  • an Fc region variant with one or more amino acid substitutions capable of extending half-life or enhancing interaction with an Fc receptor (FcRn ) combination is provided that includes an Fc region variant with one or more amino acid substitutions capable of extending half-life or enhancing interaction with an Fc receptor (FcRn ) combination.
  • FcRn Fc receptor
  • Fc variants contain 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424 or One or more substitutions in residue 434, for example, substitution of residue 434 in the Fc region (U.S. Pat. No. 7,371,826).
  • anti-GDF15 antibodies eg, full-length anti-GDF15 antibodies
  • Fc variants described herein or combinations thereof.
  • anti-GDF15 antibodies provided herein are altered to increase or decrease the degree of glycosylation of the anti-NGF antibody. Adding or deleting glycosylation sites on the anti-GDF15 antibody can be easily accomplished by changing the amino acid sequence of the anti-NGF antibody or its polypeptide portion to add or remove one or more glycosylation sites.
  • the anti-GDF15 antibody contains an Fc region that can change the sugar attached to it.
  • Natural antibodies produced by mammalian cells typically contain branched biantennary oligosaccharides linked to the Fc region CH2 domain Asn297, often via an N-link, see, e.g., Wright et al., TIBTECH 15:26-32 (1997) .
  • the oligosaccharides may include a variety of sugars, such as mannose, N-acetylglucosamine (GlcNAc), galactose, and sialic acid, as well as Trehalose linked to GlcNAc in the "stem" part of the biantennary oligosaccharide structure.
  • the anti-GDF15 antibodies of the present application can be subjected to oligosaccharide modifications, thereby producing anti-GDF15 antibody variants with certain improved properties.
  • N-glycans linked to the CH2 domain of the Fc region are heterogeneous.
  • Antibodies or Fc fusion proteins produced in CHO cells are fucosylated by fucosyltransferase activity, see Shoji-Hosaka et al., J. Biochem. 2006, 140:777-83.
  • a small proportion of naturally occurring afucosylated IgGs can be detected in human serum.
  • N-glycosylation of the Fc region is important for its binding to Fc ⁇ R; afucosylated N-glycan enhances the binding ability of Fc to Fc ⁇ RIIIa.
  • the enhanced binding ability to FcRIIIa results in enhanced ADCC effect, which is advantageous in certain antibody therapeutic applications that require cytotoxicity.
  • enhanced effector function may be detrimental when Fc-mediated cytotoxicity is not required.
  • the Fc fragment or CH2 domain is non-glycosylated.
  • glycosylation is prevented by mutating the N-glycosylation site in the CH2 domain.
  • anti-GDF15 antibody eg, full-length anti-GDF15 antibody
  • anti-GDF15 antibody variants comprise an Fc region, wherein the carbohydrate structure linked to the Fc region has reduced fucose or lacks fucose, which may Will enhance ADCC function.
  • anti-GDF15 antibodies that have reduced fucose relative to the same anti-GDF15 antibody produced in wild-type CHO cells. That is, they are characterized by having smaller amounts of fucose than antibodies produced by native CHO cells (e.g., CHO cells that produce the native glycosylated form, CHO cells that contain the native FUT8 gene).
  • the N-linked glycan of the anti-GDF15 antibody has less than 50%, 40%, 30%, 20%, 10%, or 5% fucose.
  • the fucose content of the anti-GDF15 antibody may be 1%-80%, 1%-65%, 5%-65%, or 20%-40%.
  • the N-linked glycans of the anti-GDF15 antibody do not comprise fucose, i.e., wherein the anti-GDF15 antibody contains no fucose at all, or is free of fucose or afucosylated.
  • the fucose content is calculated by calculating the average fucose content within the sugar chain attached to Asn297 relative to the total of all sugar structures attached to Asn297 (such as complex, hybrid or mannose structures) measured by MALDI-TOF mass spectrometry. quantity, as described in WO 2008/077546.
  • Asn297 refers to the asparagine residue located at position 297 of the Fc region (EU Fc region residue numbering system). However, due to minor sequence changes in the antibody, Asn297 can also be located ⁇ 3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300. These fucosylation variants may have enhanced ADCC function. See, for example, US Patent Publication Nos.
  • Cell lines capable of producing afucosylated antibodies include Lec13 CHO cells lacking protein fucosylation function (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); US Pat Appl No US 2003 /0157108A1, Presta, L; and WO 2004/056312A1, Adams et al., especially in practice Example 11), and gene knockout cell lines, such as ⁇ -1,6-fucosyltransferase gene, FUT8 gene knockout CHO cells (see Yamane-Ohnuki et al. Biotech. Bioeng. 87:614 ( 2004); Kanda, Y. et al., Biotechnol. Bioeng., 94(4):680-688(2006); and WO2003/085107).
  • Anti-GDF15 antibody (eg, full-length anti-GDF15 antibody) variants further provide bisecting oligosaccharides, eg, wherein the biantennary oligosaccharide linked to the Fc region of the anti-GDF15 antibody is bisected by GlcNAc.
  • Such anti-GDF15 antibody (eg, full-length anti-GDF15 antibody) variants may have reduced fucosylation and/or enhanced ADCC function. Examples of such antibody variants are in WO 2003/011878 (Jean-Mairet et al.); U.S. Pat. No. 6,602,684 (Umana et al.); US 2005/0123546 (Umana et al.), and Ferrara et al.
  • anti-GDF15 antibody eg, full-length anti-GDF15 antibody
  • anti-GDF15 antibody variants that have at least one galactose residue in the oligosaccharide linked to the Fc region.
  • Such anti-GDF15 antibody variants may have enhanced CDC function.
  • Such variants are described, for example, in WO1997/30087 (Patel et al.); WO 1998/58964 (Raju, S.); and WO 1999/22764 (Raju, S.).
  • the anti-GDF15 antibody (eg, full-length anti-GDF15 antibody) variant comprises an Fc region capable of binding Fc ⁇ RIII.
  • the anti-GDF15 antibody (e.g., full-length anti-GDF15 antibody) variant comprising an Fc region has ADCC activity in the presence of human effector cells (e.g., T cells) or is consistent with other variants having a human wild-type IgG1 Fc region. Enhanced ADCC activity in the presence of human effector cells compared to the same anti-GDF15 antibody (eg, full-length anti-GDF15 antibody).
  • cysteine-engineered anti-GDF15 antibody eg, a full-length anti-GDF15 antibody
  • the substitution residue occurs at an accessible site of the anti-GDF15 antibody.
  • reactive sulfhydryl groups are located in accessible sites of the anti-GDF15 antibody and can be used to couple the anti-GDF15 antibody to other moieties, such as a drug moiety or a linker-drug moiety, to prepare anti-GDF15 immunoconjugates as further described herein.
  • Cysteine-engineered anti-GDF15 antibodies eg, full-length anti-GDF15 antibodies
  • anti-GDF15 antibodies eg, full-length anti-GDF15 antibodies
  • anti-GDF15 antibodies can be further modified to include other non-protein moieties known in the art and readily available.
  • Suitable moieties for derivatizing anti-GDF15 antibodies include, but are not limited to, water-soluble polymers.
  • Non-limiting examples of water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), ethylene glycol/propylene glycol copolymer, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1 , 3-dioxopentane, poly-1,3,6-trioxane, ethylene/maleic anhydride copolymer, polyamino acid (homopolymer or random copolymer), dextran or poly(n- vinylpyrrolidone) polyethylene glycol, propylene glycol homopolymer, propylene oxide/ethylene oxide copolymer, polyoxyethylated polyols (such as glycerol), polyvinyl alcohol, and mixtures thereof.
  • PEG polyethylene glycol
  • ethylene glycol/propylene glycol copolymer carboxymethylcellulose
  • dextran polyvinyl alcohol
  • polyvinylpyrrolidone poly-1 , 3-diox
  • Polyethylene glycol propionaldehyde offers advantages in manufacturing due to its stability in water.
  • the polymers can be of any molecular weight and can be branched or unbranched.
  • Polymer attached to anti-GDF15 antibody The number can vary, and if more than one polymer is linked, they can be the same or different molecules.
  • the amount and/or type of polymer used for derivatization can be determined based on considerations including, but not limited to, the need to improve the properties or functionality of the anti-GDF15 antibody, whether the anti-GDF15 antibody derivative is useful under specific conditions. Treatment etc.
  • compositions comprising any of the anti-GDF15 antibodies (e.g., full-length anti-GDF15 antibodies), nucleic acids encoding the antibodies, vectors comprising nucleic acids encoding the antibodies, or host cells comprising the nucleic acids or vectors described herein. substances, also referred to here as preparations).
  • a pharmaceutical composition comprising any anti-GDF15 antibody described herein and a pharmaceutically acceptable carrier.
  • a suitable anti-GDF15 antibody can be obtained by mixing an anti-GDF15 antibody of the desired purity with an optional pharmaceutically acceptable carrier, excipient or stabilizer (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980))
  • Antibody preparations are prepared in the form of lyophilized preparations or liquid preparations.
  • Acceptable carriers, excipients or stabilizers are non-toxic to the recipient at the doses and concentrations used and include buffers such as phosphates, citric acid and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (e.g.
  • Octadecyldimethylbenzyl ammonium chloride hexamethylammonium chloride; benzalkonium chloride; benzethonium chloride; phenol; butanol or benzyl alcohol; alkyl parabens, such as p-hydroxybenzoate Methyl formate or propyl parahydroxybenzoate; catechol; resorcinol; cyclohexanol; 3-pentanol and m-cresol); low molecular weight (less than 10 residues) peptides; proteins, e.g.
  • hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates, including glucose, mannose or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes such as zinc-protein complex); and/or non-ionic surfactants such as TWEEN TM , PLURONICS TM or polyethylene glycol (PEG); exemplary formulations are as described in WO98/56418, expressly incorporated herein by reference.
  • Lyophilized formulations suitable for subcutaneous administration are described in WO97/04801. Such lyophilized formulations can be reconstituted with appropriate diluents into high protein concentration formulations, and the reconstituted formulations can be administered subcutaneously to the individuals to be treated herein. Cationic liposomes or liposomes can be used to deliver the anti-GDF15 antibodies of the present application to cells.
  • the formulations described herein may also contain one or more other active substances necessary for the treatment of specific conditions, preferably substances with complementary activities and no adverse reactions to each other.
  • the anti-GDF15 antibody it may be desirable to further include anticancer agents, immunostimulants, chemotherapeutic agents, inhibitors of activin A or the activin A receptor ActRIIB (such as anti-activin A antibodies or antigen-binding fragments thereof , anti-ActRIIB antibodies or antigen-binding fragments, small molecule inhibitors of activin A, small molecule inhibitors of ActRIIB, and decoy receptors for ActRIIB such as soluble ActRIIB receptors, fusions of soluble ActRIIB receptors and Fc molecules), IL -6 or inhibitors of IL-6 receptor IL-6R (such as anti-IL-6 antibodies or antigen-binding fragments thereof, anti-IL-6R antibodies or antigen
  • the anti-GDF15 antibody (e.g., full-length anti-GDF15 antibody) can also be embedded in microcapsules prepared, for example, by coacervation techniques and interfacial polymerization, such as in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, respectively). , microemulsions, nanoparticles and nanocapsules) or in macroemulsions - microcapsules and poly(methyl methacrylate) microcapsules. Sustained release formulations can be prepared.
  • sustained release formulations of anti-GDF15 antibodies can be prepared.
  • suitable examples of sustained release formulations include solid hydrophobic polymeric semipermeable matrices containing the antibodies (or fragments thereof) in the form of shaped articles, for example, films or microcapsules.
  • sustained-release matrices include polyester, hydrogel (eg, poly(2-hydroxyethyl methacrylate) or poly(vinyl alcohol)), polylactic acid (U.S. Pat. No.
  • L-glutamine Acid and L-glutamic acid ethyl ester copolymer non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymer such as LUPRON DEPOTTM (a biodegradable product composed of lactic acid-glycolic acid copolymer and leuprolide acetate) injection microspheres) and poly-D(-)-3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and lactic-glycolic acid can release molecules over 100 days, certain hydrogels can release proteins in much shorter time periods.
  • encapsulated antibodies When encapsulated antibodies stay in the body for a long time, they will denature or aggregate due to exposure to a humid environment at 37°C, which may lead to loss of biological activity or changes in immunogenicity.
  • Reasonable strategies can be designed to stabilize anti-GDF15 antibodies based on the corresponding mechanisms. For example, if the aggregation mechanism is found to be through thiodisulfide exchange to form intermolecular S-S bonds, this can be achieved by modifying sulfhydryl residues, lyophilizing in acidic solutions, controlling water content, using appropriate additives, and developing specific polymers. matrix composition to achieve stabilization.
  • the anti-GDF15 antibody (eg, full-length anti-GDF15 antibody) is formulated with citrate, sodium chloride, acetate, succinate, glycine, polysorbate 80 (Tween 80), or in any combination of the above buffers.
  • Preparations for in vivo administration must be sterile. This can be easily accomplished, for example, by applying sterile filtration membrane filtration.
  • Anti-GDF15 antibodies may be administered to an individual (e.g., a mammal, such as a human) to treat diseases and/or conditions resulting from dysregulation of the GDF15 signaling pathway (e.g., cancer, cachexia, metabolic disease), which include, but are not limited to, cancer (e.g., brain cancer, melanoma, lung cancer, gastrointestinal tumors, colon cancer, pancreatic cancer, prostate cancer, breast cancer, oral Cancer, liver cancer, leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, bladder cancer, cervical cancer, uterine body cancer, testicle cancer, thyroid cancer, kidney cancer, gallbladder cancer, multiple myeloma, nasopharyngeal cancer, laryngeal cancer, pharyngeal cancer, esophageal cancer, etc.), cachexia, renal failure, sepsis, AIDS, chronic adada, nasopharyngeal cancer, laryngeal cancer
  • the present application provides a method for treating diseases and/or conditions (e.g., cancer, cachexia, metabolic diseases) caused by dysregulation of the GDF15 signaling pathway, comprising administering to an individual an effective amount of an anti-inflammatory drug.
  • a composition e.g., a pharmaceutical composition
  • a GDF15 antibody e.g., a full-length anti-GDF15 antibody
  • the individual is a human being.
  • a method for treating an individual with a disease associated with the GDF15 signaling pathway comprising administering to the individual an effective amount of a drug containing a specific Pharmaceutical compositions of GDF15 antibodies (e.g., full-length anti-GDF15 antibodies) that bind to an epitope on human GDF15, wherein the epitope comprises the amino acid residues of human GDF15.
  • the anti-GDF15 antibody is a full-length antibody.
  • the full-length anti-GDF15 antibody is an IgGl or IgG4 antibody.
  • the disease or disorder 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 lymphoma, non-Hodgkin lymphoma, bladder cancer, cervical cancer, uterine cancer, testicular cancer, thyroid cancer, kidney cancer, gallbladder cancer, multiple myeloma, nasopharyngeal cancer, laryngeal cancer, pharyngeal cancer cancer, esophageal cancer, etc.), cachexia, cachexia caused by renal failure, sepsis, AIDS, chronic obstructive pulmonary disease, cachexia-related weight loss, nausea and vomiting caused by radiotherapy and chemotherapy, advanced chronic intertubular Qualitative nephritis, morning sickness, liver cirrhosis, sarcopenia, metabolic diseases (such as fat and energy metabolism imbalance, appetite regulation, weight regulation).
  • cancer such as brain cancer,
  • a method for treating an individual with a disease associated with the GDF15 signaling pathway comprising administering to the individual an effective amount of an anti- Pharmaceutical compositions of GDF15 antibodies (e.g., full-length anti-GDF15 antibodies), heavy chain variable domains (V H ), the V H comprising: heavy chain complementarity determining region (HC-CDR) 1 comprising X 1 YYMX 2 ( SEQ ID NO : 35), wherein HC-CDR3 comprising VVYAGWTYPLGI (SEQ ID NO: 13); and light chain variable domain (V L ) comprising: light chain complementarity determining region (LC-CDR) 1 comprising QASQSISSVLS (SEQ ID NO:18); LC - CDR2 , which contains EASX 1 ID NO:30).
  • GDF15 antibodies e.g., full-length anti-GDF15 antibodies
  • V H comprising: heavy chain complementarity determining region (HC-CDR) 1 comprising X 1 YYMX 2 ( S
  • the anti-GDF15 antibody is a full-length antibody.
  • the full-length anti-GDF15 antibody is an IgGl or IgG4 antibody.
  • the disease or disorder 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 lymphoma, non-Hodgkin lymphoma, bladder cancer, cervical cancer, uterine cancer, testicular cancer, thyroid cancer, kidney cancer, gallbladder cancer, multiple myeloma, nasopharyngeal cancer, laryngeal cancer, pharyngeal cancer cancer, esophageal cancer, etc.), cachexia, renal failure, Cachexia caused by sepsis, AIDS, chronic obstructive pulmonary disease, cachexia-related weight loss, nausea and vomiting caused by radiotherapy and chemotherapy, advanced chronic tubulo
  • cancer such as brain cancer, mel
  • a method for treating an individual with a disease associated with the GDF15 signaling pathway comprising administering to the individual an effective amount of an anti-GDF15 antibody.
  • a method for treating an individual with a disease associated with the GDF15 signaling pathway comprising administering to the individual an effective amount of an anti-GDF15 antibody.
  • VL which VL includes Have at least about 80% sequence identity with the amino acid sequence shown in any of SEQ ID NOs: 52-59.
  • an anti-GDF15 antibody described herein is a full-length anti-GDF15 antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 64.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 67.
  • a method for treating an individual with a disease associated with the GDF15 signaling pathway comprising administering to the individual an effective amount of an anti-GDF15 antibody.
  • the CDRs contain substitutions of up to about
  • the anti-GDF15 antibodies described herein comprise: VH comprising the amino acid sequence SEQ ID NO:38 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO:38. % sequence identity; and VL comprising the amino acid sequence SEQ ID NO:52 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:52.
  • an anti-GDF15 antibody described herein is a full-length anti-GDF15 antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the anti-GDF15 antibodies described herein comprise: V H comprising the amino acid sequence SEQ ID NO: 39 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 39 % sequence identity; and VL comprising the amino acid sequence SEQ ID NO:53 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:53.
  • an anti-GDF15 antibody described herein is a full-length anti-GDF15 antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the anti-GDF15 antibodies described herein comprise: V H comprising the amino acid sequence SEQ ID NO: 40 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 40 % sequence identity; and VL comprising the amino acid sequence SEQ ID NO:53 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:53.
  • an anti-GDF15 antibody described herein is a full-length anti-GDF15 antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the anti-GDF15 antibodies described herein comprise: VH comprising the amino acid sequence SEQ ID NO:41 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO:41 % sequence identity; and VL comprising the amino acid sequence SEQ ID NO:53 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:53.
  • an anti-GDF15 antibody described herein is a full-length anti-GDF15 antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain The constant region comprises or consists of the amino acid sequence SEQ ID NO:64. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the anti-GDF15 antibodies described herein comprise: V H comprising the amino acid sequence SEQ ID NO: 42 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 42 % sequence identity; and VL comprising the amino acid sequence SEQ ID NO:53 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:53.
  • an anti-GDF15 antibody described herein is a full-length anti-GDF15 antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the anti-GDF15 antibodies described herein comprise: VH comprising the amino acid sequence SEQ ID NO:43 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO:43. % sequence identity; and VL comprising the amino acid sequence SEQ ID NO:53 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:53.
  • an anti-GDF15 antibody described herein is a full-length anti-GDF15 antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the anti-GDF15 antibodies described herein comprise: VH comprising the amino acid sequence SEQ ID NO:44 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO:44. % sequence identity; and VL comprising the amino acid sequence SEQ ID NO:53 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:53.
  • an anti-GDF15 antibody described herein is a full-length anti-GDF15 antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the anti-GDF15 antibodies described herein comprise: V H comprising the amino acid sequence SEQ ID NO: 39 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 39 %sequence Identity; and VL comprising the amino acid sequence SEQ ID NO:54 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:54.
  • an anti-GDF15 antibody described herein is a full-length anti-GDF15 antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the anti-GDF15 antibodies described herein comprise: V H comprising the amino acid sequence SEQ ID NO: 40 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 40 % sequence identity; and V L comprising the amino acid sequence SEQ ID NO:54 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:54.
  • an anti-GDF15 antibody described herein is a full-length anti-GDF15 antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the anti-GDF15 antibodies described herein comprise: VH comprising the amino acid sequence SEQ ID NO:41 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO:41 % sequence identity; and V L comprising the amino acid sequence SEQ ID NO:54 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:54.
  • an anti-GDF15 antibody described herein is a full-length anti-GDF15 antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the anti-GDF15 antibodies described herein comprise: V H comprising the amino acid sequence SEQ ID NO: 42 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 42 % sequence identity; and V L comprising the amino acid sequence SEQ ID NO:54 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:54.
  • an anti-GDF15 antibody described herein is a full-length anti-GDF15 antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or consists of amino acids The sequence consists of SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the anti-GDF15 antibodies described herein comprise: VH comprising the amino acid sequence SEQ ID NO:43 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO:43. % sequence identity; and VL comprising the amino acid sequence SEQ ID NO:54 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:54 .
  • an anti-GDF15 antibody described herein is a full-length anti-GDF15 antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the anti-GDF15 antibodies described herein comprise: VH comprising the amino acid sequence SEQ ID NO:44 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO:44. % sequence identity; and VL comprising the amino acid sequence SEQ ID NO:54 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:54.
  • an anti-GDF15 antibody described herein is a full-length anti-GDF15 antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the anti-GDF15 antibodies described herein comprise: V H comprising the amino acid sequence SEQ ID NO: 39 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 39 % sequence identity; and VL comprising the amino acid sequence SEQ ID NO:55 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:55 .
  • an anti-GDF15 antibody described herein is a full-length anti-GDF15 antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the anti-GDF15 antibodies described herein comprise: VH comprising the amino acid sequence SEQ ID NO:40 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO:40 % sequence identity; and VL comprising the amino acid sequence SEQ ID NO:55 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:55 .
  • the anti- GDF15 antibodies are full-length anti-GDF15 antibodies containing IgG1 or IgG4 constant regions.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the anti-GDF15 antibodies described herein comprise: VH comprising the amino acid sequence SEQ ID NO:41 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO:41 % sequence identity; and VL comprising the amino acid sequence SEQ ID NO:55 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:55 .
  • an anti-GDF15 antibody described herein is a full-length anti-GDF15 antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the anti-GDF15 antibodies described herein comprise: VH comprising the amino acid sequence SEQ ID NO:42 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO:42. % sequence identity; and VL comprising the amino acid sequence SEQ ID NO:55 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:55 .
  • an anti-GDF15 antibody described herein is a full-length anti-GDF15 antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the anti-GDF15 antibodies described herein comprise: VH comprising the amino acid sequence SEQ ID NO:43 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO:43. % sequence identity; and VL comprising the amino acid sequence SEQ ID NO:55 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:55 .
  • an anti-GDF15 antibody described herein is a full-length anti-GDF15 antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the anti-GDF15 antibodies described herein comprise: VH comprising the amino acid sequence SEQ ID NO:44 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO:44. % sequence identity; and VL comprising the amino acid sequence SEQ ID NO:55 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:55 .
  • an anti-GDF15 antibody described herein is a full-length anti-GDF15 antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a method for treating an individual with a disease associated with the GDF15 signaling pathway comprising administering to the individual an effective amount of an anti-GDF15 antibody.
  • the anti-GDF15 antibodies described herein comprise: VH comprising the amino acid sequence SEQ ID NO:45 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO:45. % sequence identity; and VL comprising the amino acid sequence SEQ ID NO:56 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:56.
  • an anti-GDF15 antibody described herein is a full-length anti-GDF15 antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a method for treating an individual with a disease associated with the GDF15 signaling pathway comprising administering to the individual an effective amount of an anti-GDF15 antibody.
  • the anti-GDF15 antibodies described herein comprise: VH comprising the amino acid sequence SEQ ID NO:45 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO:45. % sequence identity; and VL comprising the amino acid sequence SEQ ID NO:57 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:57.
  • an anti-GDF15 antibody described herein is a full-length anti-GDF15 antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a method for treating an individual with a disease associated with the GDF15 signaling pathway comprising administering to the individual an effective amount of an anti-GDF15 antibody.
  • the anti-GDF15 antibodies described herein comprise: V H comprising the amino acid sequence SEQ ID NO: 46 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 46 % sequence identity; and VL comprising the amino acid sequence SEQ ID NO:58 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:58 .
  • an anti-GDF15 antibody described herein is a full-length anti-GDF15 antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a method for treating an individual with a disease associated with the GDF15 signaling pathway comprising administering to the individual an effective amount of an anti-GDF15 antibody.
  • the anti-GDF15 antibodies described herein comprise: V H comprising the amino acid sequence SEQ ID NO: 47 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 47 % sequence identity; and VL comprising the amino acid sequence SEQ ID NO:59 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:59.
  • an anti-GDF15 antibody described herein is a full-length anti-GDF15 antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a method for treating an individual with a disease associated with the GDF15 signaling pathway comprising administering to the individual an effective amount of an anti- Pharmaceutical compositions of GDF15 antibodies (e.g., full-length anti-GDF15 antibodies), heavy chain variable domains (V H ), the V H comprising: HC-CDR1, comprising the amino acid sequence SEQ ID NO: 3, HC-CDR2 , which comprises the amino acid sequence SEQ ID NO: 9, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 14, or a variant of said V H , whose HC-CDRs comprise substitutions of up to about 5 amino acids; and A light chain variable domain ( VL ) comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO: 19, LC-CDR2 comprising the amino acid sequence SEQ ID NO: 26, and LC-CDR3, It comprises the amino acid sequence SEQ ID NO: 31, or
  • the anti-GDF15 antibody is a full-length antibody.
  • the full-length anti-GDF15 antibody is an IgGl or IgG4 antibody.
  • the disease or disorder 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 lymphoma, non-Hodgkin lymphoma, bladder cancer, cervical cancer, uterine cancer, testicular cancer, thyroid cancer, kidney cancer, gallbladder cancer, multiple myeloma, nasopharyngeal cancer, laryngeal cancer, pharyngeal cancer cancer, esophageal cancer, etc.), cachexia, cachexia caused by renal failure, sepsis, AIDS, chronic obstructive pulmonary disease, cachexia-related weight loss, nausea and vomiting caused by radiotherapy and chemotherapy, advanced chronic intertubular Quali
  • a method for treating an individual with a disease associated with the GDF15 signaling pathway comprising administering to the individual an effective amount of an anti-GDF15 antibody.
  • the composition wherein the antibody comprises: V H , the V H comprises the amino acid sequence shown in SEQ ID NO: 48 or a variant thereof, the variant has at least the same amino acid sequence as shown in SEQ ID NO: 48 about 80% Sequence identity; and VL , the VL comprising the amino acid sequence set forth in SEQ ID NO:60 or a variant thereof, which variant has at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO:60 sex.
  • an anti-GDF15 antibody described herein is a full-length anti-GDF15 antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 64.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 67.
  • a method for treating an individual with a disease associated with the GDF15 signaling pathway comprising administering to the individual an effective amount of an anti- Pharmaceutical compositions of GDF15 antibodies (e.g., full-length anti-GDF15 antibodies), heavy chain variable domains ( VH ), the VH comprising: HC-CDR1, comprising the amino acid sequence SEQ ID NO: 4, HC-CDR2 , which comprises the amino acid sequence SEQ ID NO: 10, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 15, or a variant of said V H , whose HC-CDRs comprise substitutions of up to about 5 amino acids; and A light chain variable domain (V L ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 20, LC-CDR2 comprising the amino acid sequence SEQ ID NO: 27, and LC-CDR3, It comprises the amino acid sequence SEQ ID NO: 32,
  • the anti-GDF15 antibody is a full-length antibody.
  • the full-length anti-GDF15 antibody is an IgGl or IgG4 antibody.
  • the disease or disorder 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 lymphoma, non-Hodgkin lymphoma, bladder cancer, cervical cancer, uterine cancer, testicular cancer, thyroid cancer, kidney cancer, gallbladder cancer, multiple myeloma, nasopharyngeal cancer, laryngeal cancer, pharyngeal cancer cancer, esophageal cancer, etc.), cachexia, cachexia caused by renal failure, sepsis, AIDS, chronic obstructive pulmonary disease, cachexia-related weight loss, nausea and vomiting caused by radiotherapy and chemotherapy, advanced chronic intertubular Quali
  • a method for treating an individual with a disease associated with the GDF15 signaling pathway comprising administering to the individual an effective amount of an anti-GDF15 antibody.
  • the composition wherein the antibody comprises: V H , the V H comprises the amino acid sequence shown in SEQ ID NO: 49 or a variant thereof, the variant has at least the same amino acid sequence as the amino acid sequence shown in SEQ ID NO: 49. About 80% sequence identity; and VL , the VL comprising the amino acid sequence shown in SEQ ID NO:61 or a variant thereof, which has at least about 80% similarity with the amino acid sequence shown in SEQ ID NO:61 % sequence identity.
  • an anti-GDF15 antibody described herein is a full-length anti-GDF15 antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a method for treating an individual with a disease associated with the GDF15 signaling pathway comprising administering to the individual an effective amount of an anti- Pharmaceutical compositions of GDF15 antibodies (e.g., full-length anti-GDF15 antibodies), heavy chain variable domains ( VH ), the VH comprising: HC-CDR1, comprising the amino acid sequence SEQ ID NO: 5, HC-CDR2 , which comprises the amino acid sequence SEQ ID NO: 11, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 16, or a variant of said V H , whose HC-CDRs comprise substitutions of up to about 5 amino acids; and A light chain variable domain ( VL ) comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO: 21, LC-CDR2 comprising the amino acid sequence SEQ ID NO: 28, and LC-CDR3, It comprises the amino acid sequence SEQ ID NO: 33,
  • the anti-GDF15 antibody is a full-length antibody.
  • the full-length anti-GDF15 antibody is an IgGl or IgG4 antibody.
  • the disease or disorder 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 lymphoma, non-Hodgkin lymphoma, bladder cancer, cervical cancer, uterine cancer, testicular cancer, thyroid cancer, kidney cancer, gallbladder cancer, multiple myeloma, nasopharyngeal cancer, laryngeal cancer, pharyngeal cancer cancer, esophageal cancer, etc.), cachexia, cachexia caused by renal failure, sepsis, AIDS, chronic obstructive pulmonary disease, cachexia-related weight loss, nausea and vomiting caused by radiotherapy and chemotherapy, advanced chronic intertubular Quali
  • a method for treating an individual with a disease associated with the GDF15 signaling pathway comprising administering to the individual an effective amount of an anti-GDF15 antibody.
  • the composition wherein the antibody comprises: V H , the V H comprises the amino acid sequence shown in SEQ ID NO: 50 or a variant thereof, the variant has at least the same amino acid sequence as shown in SEQ ID NO: 50 About 80% sequence identity; and VL , the VL comprising the amino acid sequence shown in SEQ ID NO:62 or a variant thereof, which has at least about 80% similarity with the amino acid sequence shown in SEQ ID NO:62 % sequence identity.
  • an anti-GDF15 antibody described herein is a full-length anti-GDF15 antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 64.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 67.
  • a method for treating an individual with a disease associated with the GDF15 signaling pathway comprising administering to the individual an effective amount of an anti- A pharmaceutical composition of a GDF15 antibody (e.g., a full-length anti-GDF15 antibody), a heavy chain variable domain (V H ), the V H comprising: heavy chain complementarity determining region (HC-CDR) 1 comprising SYDMT (SEQ ID NO : 6) ; HC - CDR2 , which contains IIX 1 and HC-CDR3, which includes GILVYADYGDHNL (SEQ ID NO: 17); and light chain variable domain (V L ), which includes: light chain complementarity determining region (LC-CDR) 1, which includes QASEDIYTNLA ( SEQ ID NO:22); LC-CDR2, which contains AASTLAS (SEQ ID NO:29); and LC-CDR3, which contains LGVYTYISAX 1
  • HC-CDR heavy chain complementarity determining region
  • LC-CDR light chain
  • the anti-GDF15 antibody is a full-length antibody.
  • the full-length anti-GDF15 antibody is an IgGl or IgG4 antibody.
  • the disease or disorder 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 lymphoma, non-Hodgkin lymphoma, bladder cancer, cervical cancer, uterine cancer, testicular cancer, thyroid cancer, kidney cancer, gallbladder cancer, multiple myeloma, nasopharyngeal cancer, laryngeal cancer, pharyngeal cancer cancer, esophageal cancer, etc.), cachexia, cachexia caused by renal failure, sepsis, AIDS, chronic obstructive pulmonary disease, cachexia-related weight loss, nausea and vomiting caused by radiotherapy and chemotherapy, advanced chronic intertubular Quali
  • a method for treating an individual with a disease associated with the GDF15 signaling pathway comprising administering to the individual an effective amount of an anti-GDF15 antibody.
  • a method for treating an individual with a disease associated with the GDF15 signaling pathway comprising administering to the individual an effective amount of an anti-GDF15 antibody.
  • the composition wherein the antibody comprises: VH , the VH comprises the amino acid sequence shown in any one of SEQ ID NOs: 51, 82-89 or a variant thereof, the variant is the same as SEQ ID NOs: 51 , the amino acid sequence shown in any one of 82-89 has at least about 80% sequence identity; and VL , the VL comprises the amino acid sequence shown in any one of SEQ ID NOs: 63, 90-91 or a variant thereof A variant having at least about 80% sequence identity with the amino acid sequence shown in any one of SEQ ID NOs: 63, 90-91.
  • an anti-GDF15 antibody described herein is a full-length anti-GDF15 antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a method for treating an individual with a disease associated with the GDF15 signaling pathway comprising administering to the individual an effective amount of an anti-GDF15 antibody.
  • an anti-GDF15 antibody e.g., a full-length anti-GDF15 antibody
  • a heavy chain variable domain V H
  • the V H comprising: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 6, HC-CDR2, which Comprising the amino acid sequence SEQ ID NO: 12, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 17, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs
  • a light chain Variable domain V L
  • said V L comprising: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 22, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 29, and LC-CDR3, which comprises The amino acid sequence SEQ ID NO: 34
  • the anti-GDF15 antibodies described herein comprise: V H comprising the amino acid sequence SEQ ID NO: 51 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 51 % sequence identity; and VL comprising the amino acid sequence SEQ ID NO:63 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:63.
  • an anti-GDF15 antibody described herein is a full-length anti-GDF15 antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a method for treating an individual with a disease associated with the GDF15 signaling pathway comprising administering to the individual an effective amount of an anti-GDF15 antibody.
  • the anti-GDF15 antibodies described herein comprise: VH comprising the amino acid sequence SEQ ID NO:82 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO:82 % sequence identity; and VL comprising the amino acid sequence SEQ ID NO:90 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:90 .
  • an anti-GDF15 antibody described herein is a full-length anti-GDF15 antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64. In some embodiments, the heavy chain constant region comprises Or consisting of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a method for treating an individual with a disease associated with the GDF15 signaling pathway comprising administering to the individual an effective amount of an anti-GDF15 antibody.
  • the CDRs contain substitutions of
  • the anti-GDF15 antibodies described herein comprise: VH comprising the amino acid sequence SEQ ID NO:83 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO:83 % sequence identity; and V L comprising the amino acid sequence SEQ ID NO:90 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:90.
  • an anti-GDF15 antibody described herein is a full-length anti-GDF15 antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a method for treating an individual with a disease associated with the GDF15 signaling pathway comprising administering to the individual an effective amount of an anti-GDF15 antibody.
  • the anti-GDF15 antibodies described herein comprise: VH comprising the amino acid sequence SEQ ID NO:84 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO:84. % sequence identity; and VL comprising the amino acid sequence SEQ ID NO:90 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:90 .
  • an anti-GDF15 antibody described herein is a full-length anti-GDF15 antibody comprising an IgGl or IgG4 constant region.
  • the The IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • a method for treating an individual with a disease associated with the GDF15 signaling pathway comprising administering to the individual an effective amount of an anti-GDF15 antibody.
  • the CDRs contain substitutions of
  • the anti-GDF15 antibodies described herein comprise: VH comprising the amino acid sequence SEQ ID NO:85 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO:85. % sequence identity; and V L comprising the amino acid sequence SEQ ID NO:90 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:90.
  • an anti-GDF15 antibody described herein is a full-length anti-GDF15 antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the anti-GDF15 antibodies described herein comprise: VH comprising the amino acid sequence SEQ ID NO:86 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO:86 % sequence identity; and VL comprising the amino acid sequence SEQ ID NO:91 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:91.
  • an anti-GDF15 antibody described herein is a full-length anti-GDF15 antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the anti-GDF15 antibodies described herein comprise: VH comprising the amino acid sequence SEQ ID NO:87 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO:87 %sequence Identity; and VL comprising the amino acid sequence SEQ ID NO:91 or a variant thereof that has at least about 80 % sequence identity with the amino acid sequence SEQ ID NO:91.
  • an anti-GDF15 antibody described herein is a full-length anti-GDF15 antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the anti-GDF15 antibodies described herein comprise: VH comprising the amino acid sequence SEQ ID NO:88 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO:88. % sequence identity; and VL comprising the amino acid sequence SEQ ID NO:91 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:91.
  • an anti-GDF15 antibody described herein is a full-length anti-GDF15 antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the anti-GDF15 antibodies described herein comprise: VH comprising the amino acid sequence SEQ ID NO:89 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO:89 % sequence identity; and VL comprising the amino acid sequence SEQ ID NO:91 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:91.
  • an anti-GDF15 antibody described herein is a full-length anti-GDF15 antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:64. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:65. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:66. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:67.
  • the subject is a mammal (eg, human, non-human primate, rat, mouse, cow, horse, porcine, sheep, goat, dog, cat, etc.).
  • the individual is a human.
  • the individual is a clinical patient, clinical trial volunteer, experimental animal, etc.
  • the individual is less than 60 years old (including, for example, less than 50, 40, 30, 25, 20, 15, or 10 years old).
  • the individual is older than 60 years old (including, for example, older than 70, 80, 90, or 100 years old).
  • the individual is diagnosed with or genetically predisposed to one or more diseases or conditions described herein (eg, cancer, cachexia, metabolic disease).
  • the individual has one or more risk factors associated with one or more diseases or conditions described herein.
  • the application provides a method of delivering an anti-GDF15 antibody (e.g., any of the anti-GDF15 antibodies described herein, e.g., an isolated anti-GDF15 antibody) to cells in an individual that express GDF15 on their surface, said The method includes administering to the individual a composition comprising an anti-GDF15 antibody.
  • an anti-GDF15 antibody e.g., any of the anti-GDF15 antibodies described herein, e.g., an isolated anti-GDF15 antibody
  • the anti-GDF15 antibodies e.g., full-length anti-GDF15 antibodies
  • compositions described herein are combined with a second, third, or fourth agent (including, for example, an anti-cancer agent, an immunostimulant, a chemotherapeutic agent).
  • a second, third, or fourth agent including, for example, an anti-cancer agent, an immunostimulant, a chemotherapeutic agent.
  • inhibitors of activin A or activin A receptor ActRIIB such as anti-activin A antibodies or antigen-binding fragments thereof, anti-ActRIIB antibodies or antigen-binding fragments, small molecule inhibitors of activin A, small molecule inhibitors of ActRIIB , as well as ActRIIB decoy receptors such as soluble ActRIIB receptors, fusions of soluble ActRIIB receptors and Fc molecules
  • inhibitors of IL-6 or IL-6 receptor IL-6R such as anti-IL-6 antibodies or their antigens Binding fragments, anti-IL-6R antibodies or antigen-binding fragments thereof, small molecule inhibitors of IL-6, small molecule inhibitors of IL-6R, and decoy receptors of IL-6R such as soluble IL-6R receptor, soluble IL-6R receptor and Fc molecule fusion
  • inhibitors of TNF ⁇ or IL-1 such as anti-TNF ⁇ antibodies or antigen-binding fragments thereof, anti-IL-1
  • Cancer treatments are evaluated using, for example, tumor regression, reduction in tumor weight or size, time to progression, survival, progression-free survival, overall response rate, duration of response, quality of life, protein expression levels and/or activity.
  • Methods of determining the effectiveness of treatment may be employed, including, for example, detection of response by radiographic imaging.
  • the effect of treatment is evaluated as percent tumor growth inhibition (%TGI), calculated using the equation 100 - (T/C ⁇ 100), where T is the relative mean tumor volume of the treated tumor and C is Relative mean tumor volume of untreated tumors.
  • %TGI percent tumor growth inhibition
  • the %TGI is about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95 % or more than 95%.
  • Treatments of cancer-related cachexia are evaluated using, for example, inhibition of muscle mass loss, inhibition of fat mass loss, restoration of involuntary weight loss, inhibition of organ mass loss.
  • Methods of determining the effectiveness of treatment may be employed, including, for example, detection of response by radiographic imaging.
  • therapeutic efficacy is assessed by the level of weight reversal in cachexia patients, calculated as the rate of initial weight change compared to before administration of the antibody.
  • the involuntary weight loss is restored by at least about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, or 35%.
  • therapeutic efficacy is assessed by the level of inhibition of fat mass loss in cachexia patients.
  • fat mass loss is inhibited by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94% , 95% or more than 95%.
  • therapeutic efficacy is assessed by the level of inhibition of muscle mass loss in cachexia patients.
  • fat mass loss is inhibited by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94% , 95% or more than 95%.
  • the dosage of an anti-GDF15 antibody (eg, isolated anti-GDF15 antibody) composition administered to an individual may vary depending on the particular composition, the mode of administration, and the type of disease being treated.
  • the amount of the composition eg, a composition comprising an anti-GDF15 antibody
  • an objective response eg, a partial response or a complete response
  • the amount of anti-GDF15 antibody composition is sufficient to produce a complete response in an individual.
  • the amount of anti-GDF15 antibody composition is sufficient to produce a partial response in an individual.
  • the anti-GDF15 antibody composition is administered at a dose (e.g., when administered alone) sufficient to produce greater than 20%, 25%, 30%, 35%, or more in a population of individuals treated with the anti-GDF15 antibody composition.
  • An individual's response to the treatment methods described herein can be determined, for example, by the level of weight reversal in cachexia patients.
  • the amount of the composition is sufficient to prolong progression-free survival in an individual. In some embodiments, the amount of the composition is sufficient to prolong the overall survival of the subject. In some embodiments, the amount of the composition (eg, when administered alone) is sufficient to produce greater than 50%, 60%, 70%, or 77% of clinical benefit in a population of individuals treated with an anti-GDF15 antibody composition.
  • the amount of a composition is before treatment or with An amount sufficient to control symptoms and reduce the risk of exacerbation compared to the corresponding activity in other subjects not receiving treatment.
  • the magnitude of this effect can be measured using standard methods, such as in vitro assays of purified enzymes, cell-based assays, animal models, or human trials.
  • the amount of anti-GDF15 antibody (e.g., full-length anti-GDF15 antibody) in the composition is less than the amount that causes a toxic effect (i.e., an amount that is greater than a clinically acceptable level of toxicity) when the composition is administered to an individual. effect), or at a level at which potential side effects can be controlled or tolerated.
  • a toxic effect i.e., an amount that is greater than a clinically acceptable level of toxicity
  • the amount of the composition approximates the maximum tolerated dose (MTD) of the composition. In some embodiments, the amount of the composition is greater than 80%, 90%, 95%, or 98% of the MTD.
  • the amount of anti-GDF15 antibody (eg, full-length anti-GDF15 antibody) in the composition ranges from 0.001 ⁇ g to 1000 ⁇ g.
  • the effective amount of anti-GDF15 antibody eg, full-length anti-GDF15 antibody in the composition ranges from 0.1 ⁇ g/kg to 100 mg/kg based on body weight.
  • Anti-GDF15 antibody compositions can be administered to an individual (e.g., a human) by a variety of routes, including, for example, intravenous injection, intraarterial administration, intraperitoneal injection, intrapulmonary administration, oral administration, inhalation administration, intravascular administration, Intramuscular, intratracheal, subcutaneous, intraocular, intrathecal, mucosal or transdermal administration. In some practical In the examples, a sustained-release formulation of the composition was used.
  • the composition is administered intravenously.
  • the composition is administered intraarterially.
  • the composition is administered intraperitoneally.
  • the composition is administered intrahepatically.
  • the composition is administered by hepatic artery infusion.
  • the composition is administered to a site distal to the first lesion.
  • an article of manufacture comprising a substance that can be used to treat diseases related to the GDF15 signaling pathway (e.g., cancer, cachexia, metabolic diseases), or for delivering an anti-GDF15 antibody (eg, a full-length anti-GDF15 antibody) to cells expressing GDF15 on their surface.
  • the article of manufacture may include a container and a label or package insert on or accompanying the container. Suitable containers include, for example, bottles, vials, syringes, and the like. Containers can be made from a variety of materials, such as glass or plastic.
  • the container contains a composition effective for treating the disease or condition described herein and has a sterile port (eg, the container may be an IV bag or a vial with a hypodermic needle-pierceable cap).
  • a sterile port eg, the container may be an IV bag or a vial with a hypodermic needle-pierceable cap.
  • At least one active substance in the composition is the anti-GDF15 antibody described in this application.
  • the label or package insert identifies the specific condition for which the composition is used to treat.
  • the label or package insert further contains instructions for administering the anti-GDF15 antibody composition to a patient. Articles and kits including combination therapies are considered within the scope of this article.
  • Package insert means the instructions usually included in the commercial packaging of therapeutic products that contain information on indications, usage, dosage, administration, contraindications and/or warnings relevant to the use of these therapeutic products.
  • the package insert indicates that the composition can be used to treat diseases related to the GDF15 signaling pathway (eg, cancer, cachexia, metabolic diseases).
  • the package insert indicates that the composition can be used to treat the following diseases, including cancer (such as brain cancer, melanoma, lung cancer, gastrointestinal tumors, colon cancer, pancreatic cancer, prostate cancer, breast cancer, Oral cancer, liver cancer, leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, bladder cancer, cervical cancer, uterine body cancer, testicular cancer, thyroid cancer, kidney cancer, gallbladder cancer, multiple myeloma, nasopharynx cancer, laryngeal cancer, pharyngeal cancer, esophageal cancer, etc.), cachexia, cachexia caused by renal failure, sepsis, AIDS, chronic obstructive pulmonary disease, cachexia-related weight loss, nausea caused by radiotherapy and chemotherapy Vomiting, advanced chronic tubulointerstitial nephritis, morning sickness, cirrhosis, sarcopenia, metabolic diseases (such as imbalance of fat and energy metabolism, appetite regulation, weight
  • cancer such
  • the article of manufacture may further include a second container containing a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffer, Green's solution, or dextrose solution.
  • a pharmaceutically acceptable buffer such as bacteriostatic water for injection (BWFI), phosphate buffer, Green's solution, or dextrose solution.
  • kits that can be used for various purposes, such as for treating diseases related to the GDF15 signaling pathway (e.g., cancer, cachexia, metabolic diseases), or for delivering anti-GDF15 antibodies (e.g., full-length anti-GDF15 antibodies). ) into cells expressing GDF15 on their surface, optionally in combination with a preparation.
  • Kits of the present application include one or more containers containing an anti-GDF15 antibody composition (or single dose form and/or preparation) and in In some embodiments, another agent (eg, an agent described herein) and/or instructions consistent with any of the methods described herein are further included.
  • the kit may further include instructions for selecting individuals suitable for treatment. Instructions for use accompanying the kit in this application are usually written instructions on the label or package insert (e.g., a sheet of paper included in the kit), machine-readable instructions (e.g., instructions on a magnetic or optical storage disc) Also acceptable.
  • the kit includes a composition comprising an anti-GDF15 antibody (eg, a full-length anti-GDF15 antibody).
  • a kit includes: a) a composition comprising any one of the anti-GDF15 antibodies described herein, and b) an effective amount of at least one other agent capable of enhancing the effects of the anti-GDF15 antibody (e.g., treating effect, detection effect).
  • a kit includes: a) a composition comprising any one of the anti-GDF15 antibodies described herein, and b) administering the anti-GDF15 antibody composition to an individual for treating a disease associated with the GDF15 signaling pathway (e.g., cancer, cachexia, metabolic diseases) instructions for use.
  • a disease associated with the GDF15 signaling pathway e.g., cancer, cachexia, metabolic diseases
  • a kit includes: a) a composition comprising any one of the anti-GDF15 antibodies described herein, and b) an effective amount of at least one other agent capable of enhancing the effects of the anti-GDF15 antibody (e.g., treating effect, detecting effect) and c) instructions for administering to an individual anti-GDF15 antibody compositions and other substances for the treatment of diseases related to the GDF15 signaling pathway (e.g., cancer, cachexia, metabolic diseases).
  • the anti-GDF15 antibody and other substances may be present in separate containers or in the same container.
  • the kit may include one specific composition or two or more compositions, one of which includes an anti-GDF15 antibody and another of which includes another agent.
  • the kit includes a nucleic acid (or a set of nucleic acids) encoding an anti-GDF15 antibody (eg, a full-length anti-GDF15 antibody).
  • the kit comprises: a) a nucleic acid (or set of nucleic acids) encoding an anti-GDF15 antibody (eg, a full-length anti-GDF15 antibody), and b) a host expressing the nucleic acid (or set of nucleic acids) cell.
  • the kit comprises: a) a nucleic acid (or a set of) nucleic acids encoding an anti-GDF15 antibody (e.g., a full-length anti-GDF15 antibody), and b) instructions for: i) in a host cell Expressing an anti-GDF15 antibody, ii) preparing a composition comprising the anti-GDF15 antibody, and iii) administering the composition comprising the anti-GDF15 antibody to an individual to treat a disease associated with the GDF15 signaling pathway (e.g., cancer, cachexia, metabolic disease) .
  • a disease associated with the GDF15 signaling pathway e.g., cancer, cachexia, metabolic disease
  • the kit includes: a) a nucleic acid (or a set of nucleic acids) encoding an anti-GDF15 antibody (eg, a full-length anti-GDF15 antibody), b) a host cell expressing the nucleic acid (or a set of nucleic acids) , and c) instructions for use in: i) expressing an anti-GDF15 antibody in a host cell, ii) preparing a composition comprising an anti-GDF15 antibody, and iii) administering a composition comprising an anti-GDF15 antibody to an individual to treat patients with GDF15 signaling Pathway-related diseases (e.g., cancer, cachexia, metabolic diseases).
  • GDF15 signaling Pathway-related diseases e.g., cancer, cachexia, metabolic diseases.
  • kits described in this application are packaged in a suitable form.
  • suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (eg, sealed mylar or plastic bags), and the like. Kits may optionally provide other components such as buffers and instructions. Accordingly, the present application also provides articles including vials, bottles, jars, flexible packaging (eg, sealed Mylar or plastic bags), and the like.
  • Containers may be unit dose, bulk (e.g., multi-dose packaging) or subunit dosage.
  • a kit is provided that contains a sufficient dose of an anti-GDF15 antibody as described herein (e.g., a full-length anti-GDF15 antibody) to effectively treat an individual over a long period of time, such as one week, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months or longer time.
  • the kit may also contain multiple unit doses of the anti-GDF15 antibody, the pharmaceutical composition and instructions for use, and be packaged in quantities sufficient for storage and use in pharmacies, such as hospital pharmacies and compounding pharmacies.
  • GDF15 Growth and differentiation factor 15
  • GFRAL GDNF family receptor ⁇ -like, GDNF family receptor ⁇ -like protein
  • RET Tyrosine kinase receptor, tyrosine kinase receptor
  • Example 1 Preparation of recombinant GDF15 antigen and screening of anti-GDF15 antibodies
  • the cDNA encoding human, rhesus monkey or mouse GDF15 was constructed into a mammalian cell expression vector by subcloning. Add His tag and/or hFc tag and/or other tags commonly used by those skilled in the art to the above cDNA to construct and express a fusion protein containing human, rhesus monkey or mouse GDF15, such as human GDF15-his (SEQ ID NO: 73), human GDF15-hFc (SEQ ID NO: 70), rhesus monkey GDF15-hFc (SEQ ID NO: 71), mouse GDF15-hFc (SEQ ID NO: 72).
  • human GDF15-his SEQ ID NO: 73
  • human GDF15-hFc SEQ ID NO: 70
  • rhesus monkey GDF15-hFc SEQ ID NO: 71
  • mouse GDF15-hFc SEQ ID NO: 72.
  • GDF15 proteins including human GDF15-his, human GDF15-hFc, rhesus monkey GDF15-hFc or mouse GDF15-hFc. Briefly, the expression vector containing the above fusion protein gene was transfected into 293F cells respectively, and the above cells were cultured at 37°C, 5% CO 2 , and 120 rpm for 5 days, and the cell culture fluids were collected respectively.
  • Ni-NTA 5ml
  • IMAC immobilized metal affinity chromatography
  • Recombinant proteins with hFc tags were purified using MabCap At 4FF prepacked columns according to the manufacturer's instructions.
  • the specific operation is as follows: Use the 5ml MabCap At 4FF prepacked column from Changzhou Tiandi Renren Biotechnology Co., Ltd. for protein purification. After loading the sample, first rinse the column with 10 to 15 column volumes of equilibrium solution (PBS, pH 7.2), and then use 5 to 6 column volumes of eluent (0.1M Gly, 0.15M NaCl, pH 3.2). stripping and collection purpose For protein, add an appropriate amount of 1M Tris to adjust the pH to neutral, and use an ultrafiltration tube with an appropriate molecular weight cutoff to concentrate and change the medium to PBS.
  • PBS equilibrium solution
  • eluent 0.1M Gly, 0.15M NaCl, pH 3.2
  • New Zealand rabbits were immunized using human GDF15-his as antigen together with equal parts (v/v) of adjuvant. Collect rabbit serum after immunization, and detect the total IgG titer in the above serum by ELISA. After several rounds of immunization, rabbit spleens were used to construct a 293T cell display library. Briefly, the rabbit spleen after immunization was taken, B cells were sorted, RNA was extracted, cDNA was obtained through reverse transcription, V H and V K specific primers were used to amplify the V H and V K fragments, and after gel recovery and purification, the cDNA was obtained. VH and VK are connected into the lentiviral shuttle vector to construct a complete antibody and packaged into lentivirus to infect 293T cells to obtain a 293T cell display library.
  • Screen anti-GDF15 antibodies Isolate antibodies that specifically recognize GDF15 from the above-mentioned 293T cell display library. Briefly, flow cytometry was used to sort out positive single cells that bound human GDF15-hFc and culture them in 96-well plates. Coat the human GDF15-his protein on a microplate, add the 293T cell expression supernatant, screen out the positive clones that bind to human GDF15-his, extract the genomic DNA (gDNA) of the positive clones, and use V H and V K specific VH and VK fragments were amplified by PCR with specific primers, and then sequenced to obtain candidate lead antibody sequences. The heavy chain and light chain variable domain sequences of candidate lead antibodies are shown in Tables 2 and 3.
  • the VL and VH of the rabbit anti-GDF15 antibody sequence obtained by sequencing were constructed into the rabbit-derived eukaryotic expression vector pTTal-rab-CLB4 (containing the light chain constant region) and pTTal-rab Ig1-H (containing the IgG1 heavy chain constant region), respectively. area).
  • the extracted plasmids expressing light chain or heavy chain were co-transfected into 293F cells, cultured at 37°C, 8% CO 2 , and 120 rpm for 5 days, and the culture medium was purified using a protein A affinity chromatography column.
  • the Protein A column was first equilibrated with 6 column volumes of 50 mM PBS buffer (containing 0.15 M NaCl, pH 7.2) at a flow rate of 150 cm/h.
  • the culture supernatant (pH adjusted to 7.2) flows through the column at a flow rate of 150cm/h.
  • 50mM sodium citrate buffer (pH 3.5) to elute, collect the eluate, and adjust the pH to neutral.
  • Use a desalting column to replace the IgG solution in PBS buffer, and then concentrate by ultrafiltration to determine the IgG concentration to obtain the full-length anti-GDF15 antibody.
  • ELISA binding test The purified monoclonal antibody is bound to the human GDF15-his protein in a binding test. This test is used to identify the binding activity of the anti-GDF15 antibody. Briefly, the anti-GDF15 antibody to be detected was coated into a 96-well plate (200ng/well), incubated at 37°C for 1 hour, washed with PBST, and blocked with 1% BSA at room temperature for 1 hour. Then, 100 ⁇ l/well of serially diluted human GDF15-his solution (dose range 0-50 ⁇ g/ml) was added, and after incubation, 100 ⁇ l anti-his tag secondary antibody (anti-his-HRP (1:2000), Borsi) was added to each well. , Cat. No.
  • the results are shown in Table 5.
  • the anti-GDF15 antibody can effectively bind to human GDF15, and its binding activity is better than or equivalent to the positive control antibody Hu01G06-127-IgG1.
  • the inhibitory activity of concentration gradient anti-GDF15 antibodies on the binding of GDF15 and GFRAL receptors was tested through ELISA experiments, and the IC 50 value was used as a standard to measure the neutralizing activity of candidate molecules. Briefly, 96-well plates were coated with 100 ng/well GFRAL-his protein (SEQ ID NO: 74), incubated at 37°C for 1 hour, washed with PBST solution and blocked with 1% BSA at 37°C for 1 hour. Then, a gradient dilution of the antibody to be detected (dose range 0-10 ⁇ g/ml) was added to each well, and an equal volume of human GDF15-hFc protein (0.5 ⁇ g/ml) was immediately added.
  • GDF15-GFRAL/RET signaling pathway after the mature GDF15 protein binds to the two GFRAL proteins on the cell surface, it recruits two other co-receptor RET proteins to form a complex, inducing the activation of the RET intracellular signal peptide, further causing Key signaling such as RET-Ras-Erk-SRF.
  • RET-Ras-Erk-SRF Key signaling
  • Overexpressed in 293T cells GFRAL and RET proteins were simultaneously transferred into the reporter gene plasmid of SRE, a key factor downstream of RET protein, to complete cell transfection and monoclonal cell line screening, and evaluate the biological activity of the anti-GDF15 antibody at the cellular level through the reporter gene expression level.
  • the plasmid carrying the human GFRAL/RET protein coding gene and the plasmid pGL4.33[luc2p/SRE/Hygro] (E1340, Promega) carrying the RET downstream protein reporter gene were co-transfected into 293T cells, and the target single clone was obtained by screening.
  • 293T-GFRAL/RET-Luc cells were seeded in a black light-proof 96-well plate. After overnight culture, human GDF15-his protein diluent (15ng/ml, cell culture medium containing 0.1% BSA) was added, and an equal volume was added at the same time.
  • Anti-GDF15 antibody in vivo disease model activity assay
  • HT1080 model An animal model of tumor cachexia (HT1080 model) was selected to verify the in vivo biological activity of the anti-GDF15 antibody. Briefly, NCG mice were subcutaneously injected with HT1080 cells (1 ⁇ 10 6 cells/animal) (ATCC, Cat. No. CCL-121) to model tumors. Grouping was done after significant weight loss. The model group was divided into a drug administration group and a blank control group. The drug group received a single intravenous injection of the candidate antibody GDF-R37-rabIg1 (10 mpk), and the blank control group was injected with PBS or normal saline; the normal mouse group was injected with PBS or normal saline. The biological activity of candidate antibodies was tested by plotting the rate of change in mouse body weight.
  • the results are shown in Figure 1.
  • the exemplary anti-GDF15 antibody GDF-R37-rabIg1 can effectively restore the body weight of mice in the model group.
  • the heavy and light chain variable region sequences were compared with the sequences in the antibody germline database to obtain high homology human race model plate.
  • the CDR regions of the rabbit antibody are grafted onto a selected human germline template to generate humanized variable regions, which are then recombined with the corresponding human IgG constant regions (preferably IgG1 heavy chain (LALA) and kappa light chain).
  • LALA IgG1 heavy chain
  • the lead antibody GDF-R54-rabIg1 was also humanized and risk point modified in the CDR region, thereby obtaining eight humanized molecules hum_R54-1 to hum_R54-8.
  • the variable domain sequences of the heavy and light chains of humanized antibodies are shown in Table 2A and Table 3A.
  • Example 2 The corresponding experimental protocol in Example 2 was used to detect the affinity and biological activity of the humanized anti-GDF15 antibody, including affinity detection, neutralizing activity detection and biological activity detection.
  • the affinity detection scheme described in Example 2 was used to detect the ability of the humanized antibody (human IgG1 form) to bind to the GDF15 protein.
  • the results of the binding activity of humanized molecules derived from the lead antibody GDF-R54-rabIg1 are shown in Table 11.
  • the humanized antibodies (human IgG1 form) hum_R54-1, hum_R54-2, hum_R54-3, and hum_R54-4 , hum_R54-5, hum_R54-6, hum_R54-7, and hum_R54-8 can all effectively bind to GDF15, and their binding activity is comparable to the positive control antibody Hu01G06-127-IgG1.
  • the neutralizing activity detection protocol described in Example 2 was used to detect the ability of the humanized antibody (human IgG1 form) to inhibit the binding of GDF15 and GFRAL.
  • the results of the neutralizing activity of humanized molecules derived from the lead antibody GDF-R54-rabIg1 are shown in Table 8B.
  • the humanized antibodies (human IgG1 form) hum_R54-1, hum_R54-2, hum_R54-3, hum_R54- 4.
  • hum_R54-5, hum_R54-6, hum_R54-7, and hum_R54-8 can all effectively block the binding of GDF15 to its receptor GFRAL, and their neutralizing activity is equivalent to that of the positive control antibody Hu01G06-127-IgG1, or even better than that of the positive control antibody. better.
  • Table 8A Neutralizing activity of anti-GDF15 antibodies after humanization
  • Example 2 The biological activity detection scheme described in Example 2 was used to detect the inhibitory activity of the humanized antibody (human IgG1 form) on the activation of downstream signals of GFRAL and RET.
  • the biological activity results of the humanized molecules derived from the lead antibody GDF-R54-rabIg1 are shown in Table 12.
  • the humanized antibodies (human IgG1 form) hum_R54-1, hum_R54-2, hum_R54-3, hum_R54- 4.
  • hum_R54-5, hum_R54-6, hum_R54-7, and hum_R54-8 can all effectively inhibit the activation of downstream signals of GFRAL and RET, and their inhibitory activity is equivalent to or better than the positive control antibody Hu01G06-127-IgG1.
  • Biacore 8K was used to characterize the affinity of anti-GDF15 antibodies to human GDF15, rhesus monkey GDF15, and mouse GDF15.
  • the anti-GDF15 antibody is fixed on the sensor chip CM5, and the affinity of the antibody at different concentrations to the GDF15 protein of different species is detected.
  • the binding rate and dissociation rate of the antibody are measured using SPR technology, and the binding affinity is determined.
  • the Kon, Koff and Kd values are shown in Table 9.
  • 16 SD rats were randomly divided into four groups, with 4 rats in each group, half male and half female. Rats in each group were intravenously injected with 10 mpk of humanized exemplary anti-GDF15 antibodies Hum-R37-2, Hum-R37-5, and Hum-R37-8. Hu01G06-127-IgG1 antibody was used as a positive control. Blood was first collected before antibody injection, and then at 5 min, 1 h, 5 h, 1 d, 3 d, 7 d, 10 d, 14 d and 17 d after injection. After the blood was centrifuged, the plasma was collected, and the blood drug concentration in each sample was detected by ELISA. use Software version 6.0 determines pharmacokinetic parameters through the noncompartmental model (NCA).
  • NCA noncompartmental model
  • PK parameters including maximum serum concentration (Cmax), time to maximum serum concentration (Tmax), and half-life (T 1/2 ), were determined using the linear trapezoidal rule and linear interpolation method with uniform weighting. , apparent volume of distribution (Vd), clearance (Cl), area under the curve (AUC(0-t)) of measured concentration from the beginning of administration time to the last sampling time point, and blood plasma concentration from the beginning of administration time to infinity time Area under the drug concentration-time curve (AUC(0- ⁇ )), etc.
  • Example 6 In vivo disease model activity detection of anti-GDF15 antibodies
  • GDF15-hFc modeling was used to verify the in vivo biological activity of the anti-GDF15 antibody. Briefly, C57/BL6 mice were subcutaneously injected with human GDF15-hFc protein (the modeling dose was 2 mpk) to create a model. After a significant weight loss compared with normal mice, a single intravenous injection was performed.
  • the results are shown in Figure 5.
  • the exemplary anti-GDF15 antibodies Hum-R37-2, Hum-R37-5 and Hum-R37-8 can effectively restore the body weight of mice in the model group, and their in vivo activity is better than that of the positive control antibody Hu01G06. -127-IgG1, or equivalent.
  • Exemplary anti-GDF15 antibodies hum_R54-3, hum_R54-4, and hum_R54-8 can effectively restore the body weight of mice in the model group, and their in vivo activity is better than or equivalent to the positive control antibody Hu01G06-127-IgG1 (data not shown) ).

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Abstract

一种特异性地识别生长分化因子-15(GDF15)的抗体或抗原结合片段，及其制备方法和用途。

Description

特异性识别GDF15的抗体及其应用
以xml文本文件提交序列表
本申请要求申请号为202210497637.0，申请日为2022.05.09，发明名称为“特异性识别GDF15的抗体及其应用”的中国专利申请的优先权，且该申请的全部内容以引用方式并入本文中。
以xml文件提交序列表
电子序列表的内容通过整体引用并入本文中：(文本名称：GDF15-seq.xml，记录日期：2023.03.16，大小：87KB)。
技术领域
本发明涉及特异性识别GDF15的抗体，及其制备方法和用途，包括用其治疗癌症、恶液质和/或代谢性疾病的方法。
背景技术
生长分化因子-15(GDF15)，又称为巨噬细胞抑制性细胞因子1(MIC-1)，是转化生长因子β(TGF-β)超家族的非典型成员。人类GDF15的成熟经过一系列的翻译后修饰过程。翻译后未加工的GDF15蛋白(pre-pro-GDF15)有308个氨基酸，包括信号肽序列(29aa)，前肽(167aa)和成熟蛋白(112aa)。合成的前体形式的pro-GDF15蛋白，通过半胱氨酸残基形成pro-GDF15同源二聚体；然后在RXXR位点被切割，C端释放成熟的二聚体GDF15蛋白和一段前肽(Wang X等人，Biochem Pharmacol，2013)。
成熟的二聚体GDF15蛋白被分泌到胞外基质，在健康人中的正常循环浓度范围约为0.15-1.15ng/ml。GDF15的浓度随着年龄的增长而增加，但在健康的老年人中没有性别差异。GDF15的浓度与胱抑素C和C反应蛋白的浓度有关(Brown,D.A.et al.Lancet,2002.；Kempf,T.et al.Clin.Chem,2007.)。人类在运动期间和运动后恢复期间，循环中的GDF15会增加。GDF15在大多数组织包括骨骼肌中表达。有研究表明，GDF15在细胞应激或损伤时从肌肉中分泌出来，以自分泌或旁分泌的方式作用于局部(Kleinert,M.et al.Mol.Metab,2018)。GDF15在成人心肌中通常不表达，然而它在损伤或衰竭的心脏中被显著诱导。在心肌损伤期间，GDF15在心肌细胞、脂肪细胞、巨噬细胞、内皮细胞和血管平滑肌细胞中表达(Wollert，K.C.et al.Clin Chem.2017；Planavila,A.et al.Adv.Protein Chem.2017)。总之，在生理条件下，GDF15在大多数组织中的产生是微弱的，但在炎症和组织损伤时被强烈诱导。
GDF15虽然被划分为TGFβ家族成员，但目前的研究并没有确认GDF15直接结合的TGFβ受体。四个不同的研究团队同时确认了GFRAL作为GDF15的受体(Hsu等，Nature,2017；Yang,L.等，Nat Med,2017；Mullican,S.E.等，Nat Med,2017；Emmerson,P.J.等，Nat Med,2017.)。Hsu等人的研究发现GDF15并不结合任何已知的TGFβ受体。通过解析GDF15蛋白的晶体结构，发现该蛋白中存在一个额外的不同于TGFβ家族成员的二硫键，并筛选确认了胶质细胞来源的神经营养因子(GDNF)受体α样蛋白GFRAL作为GDF15蛋白的脑干限制性受体(Hsu等人，Nature,2017)。该受体通过酪氨酸激酶共受体RET介导下游的信号传导。在GDF15-GFRAL信号通路中，GDF15二聚体蛋白结合GFRAL受体，GDF15-GFRAL复合物招募共受体RET，并引起RET的二聚化和磷酸化以及胞内信号AKT，ERK1/2和磷脂酶C(PLCγ)的磷酸化(Shannon E.Mullican&Rangwala,2018；L.Yang,et al.,2017)。尽管GDF15/GFRAL信号通路仍未完全了解，也需要更多的研究将GDF15受体与成熟GDF15的生物活性联系起来，但是可以确认的是，GDF15活性的分子基础是通过GFRAL/RET，而不是通过TGFβ信号转导(Hsu等人，Nature,2017)。
GDF15蛋白与多种疾病例如肥胖、胰岛素抵抗等有关(S.N.Breit et al.,Growth Factors,2011.)。在基因工程小鼠中敲除GDF15导致体重增加；而GDF15过表达导致小鼠的体重和脂肪含量降低，代谢参数改变(L.Maccia等人，PLOS ONE，2012；V.W.Tsai等人，PLOS ONE，2013)。随后在转基因小鼠中的研究进一步确认了体重的降低，证实了这些表型，包括：hGDF15在小鼠中的广泛表达没有减少食物摄入量，但是改善了葡萄糖的耐受性，胰岛素敏感度，以及降低的体重、胰岛素、葡萄糖、血清IGF-1水平、瘦蛋白水平和脂肪组织(Chrysovergis,et al.,2014)。这些发现表明GDF15是作为体重与能量平衡的重要调节因子。
GDF15在癌症恶液质的发生中发挥重要的作用。恶液质是一种由癌症引起的医学症状，通常涉及非主动减重者的体重丢失、肌肉萎缩、乏力、虚弱及严重食欲下降，是艾滋病、慢性阻塞性肺病(COPD)、充血性心力衰竭、多发性硬化症、肺结核和癌症等慢性病晚期发病率和死亡率的主要原因之一。其中恶性肿瘤是诱发难治性恶液质的主要因素，保守估算我国每年新发肿瘤恶液质的人数超过150万(占新发肿瘤病人的36.4％左右)，约20％的癌症病人死于恶液质本身(Murphy KT.等，Expert Opin Emerg Drugs.2009)。很多恶性癌症，特别是侵袭性脑癌、黑素瘤、肺癌、胃肠道肿瘤结肠癌胰腺癌前列腺癌和乳腺癌患者中，其肿瘤以及血清中呈现GDF15水平的显著升高(Huang CY等，Clin Cancer Res.2009.)。L.Lerner等人的研究表明，与没有体重减轻的癌症患者和非癌症患者对照组相比，体重下降的癌症患者的GDF15循环水平明显增加(Lerner L等，J Cachexia Sarcopenia Muscle.2015.)。此外，GDF15水平与癌症患者的体重减轻、降低的脂肪量、肌肉质量、力量、身体表现评分和生存率有关，而瘦体重(LBM)下降是癌症患者的消极和独立的预后因素(Reuben DB,等， Arch Intern Med,1988.)，握力下降与这一人群的生存率降低有关(Gale CR.等，Int J Epidemiol.2007)。
专利申请WO2014100689A1公开了结合人GDF15并且抑制人GDF15的活性的单克隆抗体，并公开了这些抗体可以用来治疗与人GDF15过表达相关的体重损失包括恶液质等。WO2015144855A1涉及一种针对人GDF15的单克隆抗体及其抗原结合部分，该抗体或抗原结合部分能够抑制癌性恶液质和/或癌症的生长，用于治疗癌症引起的体重减轻和/或癌性恶液质以及癌症。
因此，本领域仍然需要有效抑制或以其他方式拮抗GDF15的治疗性抗体，以及治疗通过GDF15介导的疾病或病症的相关方法，例如癌症、癌性恶液质，癌症引起的体重减轻等疾病。
本文提及的所有出版物、专利、专利申请和已公开的专利申请中披露的内容，以引用方式全部并入本文中。
申请概述
在一些实施例中，提供一种分离的抗GDF15抗体，包含重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含X1YYMX2(SEQ ID NO:35)，其中X1为D或N，X2为S或T；HC-CDR2，其包含MISFSGTTX1ATWAKG(SEQ ID NO:36)，其中X1为H或Y；和HC-CDR3，其包含VVYAGWTYPLGI(SEQ ID NO:13)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含QASQSISSVLS(SEQ ID NO:18)；LC-CDR2，其包含EASX1X2AS(SEQ ID NO:37)，其中X1为I或T，X2为L或Q；和LC-CDR3，其包含QANYDVYNYGNP(SEQ ID NO:30)。
在一些实施例中，提供一种分离的抗GDF15抗体，其包含VH，所述VH包含：HC-CDR1，其包含SEQ ID NOs:1-2中任一所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；HC-CDR2，其包含SEQ ID NOs:7-8中任一所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；和HC-CDR3，其包含SEQ ID NO:13所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含SEQ ID NO:18所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；LC-CDR2，其包含SEQ ID NOs:23-25中任一所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；和LC-CDR3，其包含SEQ ID NO:30所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代。
在一些实施例中，提供一种分离的抗GDF15抗体，其包含：VH，所述VH包含如SEQ ID NOs:38-47中任一氨基酸序列所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3，以及VL，所述VL包含如SEQ ID NOs:52-59中任一氨基酸序列所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，提供一种分离的抗GDF15抗体，其包含：(i)VH，其包含如氨基酸序列SEQ ID NO:38所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:52所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；(ii)VH，其包含如氨基酸序列SEQ ID NO:39所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:53所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；(iii)VH，其包含如氨基酸序列SEQ ID NO:40所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:53所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；(iv)VH，其包含如氨基酸序列SEQ ID NO:41所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:53所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；(v)VH，其包含如氨基酸序列SEQ ID NO:42所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:53所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；(vi)VH，其包含如氨基酸序列SEQ ID NO:43所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:53所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；(vii)VH，其包含如氨基酸序列SEQ ID NO:44所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:53所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；(viii)VH，其包含如氨基酸序列SEQ ID NO:39所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:54所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；(ix)VH，其包含如氨基酸序列SEQ ID NO:40所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:54所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；(x)VH，其包含如氨基酸序列SEQ ID NO:41所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:54所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；(xi)VH，其包含如氨基酸序列SEQ ID NO:42所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:54所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；(xii)VH，其包含如氨基酸序列SEQ ID NO:43所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:54所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；(xiii)VH，其包含如氨基酸序列SEQ ID NO:44所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:54所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；(xiv)VH，其包含如氨基酸序列SEQ ID NO:39所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:55所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；(xv)VH，其包含如氨基酸序列SEQ ID NO:40所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ  ID NO:55所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；(xvi)VH，其包含如氨基酸序列SEQ ID NO:41所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:55所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；(xvii)VH，其包含如氨基酸序列SEQ ID NO:42所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:55所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；(xviii)VH，其包含如氨基酸序列SEQ ID NO:43所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:55所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；(xix)VH，其包含如氨基酸序列SEQ ID NO:44所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:55所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；(xx)VH，其包含如氨基酸序列SEQ ID NO:45所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:56所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；(xxi)VH，其包含如氨基酸序列SEQ ID NO:45所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:57所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；(xxii)VH，其包含如氨基酸序列SEQ ID NO:46所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:58所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；(xxiii)VH，其包含如氨基酸序列SEQ ID NO:47所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:59所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，提供一种分离的抗GDF15抗体，其包含：(i)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:7，和HC-CDR3，其包含氨基酸序列SEQ ID NO:13，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:18，LC-CDR2，其包含氨基酸序列SEQ ID NO:23，和LC-CDR3，其包含氨基酸序列SEQ ID NO:30，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(ii)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:7，和HC-CDR3，其包含氨基酸序列SEQ ID NO:13，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:18，LC-CDR2，其包含氨基酸序列SEQ ID NO:24，和LC-CDR3，其包含氨基酸序列SEQ ID NO:30，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(iii)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:7，和HC-CDR3，其包含氨基酸序列SEQ ID NO:13，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代； 以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:18，LC-CDR2，其包含氨基酸序列SEQ ID NO:25，和LC-CDR3，其包含氨基酸序列SEQ ID NO:30，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(iv)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:2，HC-CDR2，其包含氨基酸序列SEQ ID NO:7，和HC-CDR3，其包含氨基酸序列SEQ ID NO:13，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:18，LC-CDR2，其包含氨基酸序列SEQ ID NO:25，和LC-CDR3，其包含氨基酸序列SEQ ID NO:30，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(v)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:8，和HC-CDR3，其包含氨基酸序列SEQ ID NO:13，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:18，LC-CDR2，其包含氨基酸序列SEQ ID NO:25，和LC-CDR3，其包含氨基酸序列SEQ ID NO:30，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，如上所述任一种分离的抗GDF15抗体，其包含：VH，其包含SEQ ID NOs:38-47中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:38-47中任一所示的氨基酸序列具有至少约80％序列同一性；以及VL，其包含SEQ ID NOs:52-59中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:52-59中任一所示的氨基酸序列具有至少约80％序列同一性。
在一些实施例中，提供一种分离的抗GDF15抗体包含：(i)VH，其包含氨基酸序列SEQ ID NO:38或其变体，所述变体与氨基酸序列SEQ ID NO:38具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:52或其变体，所述变体与氨基酸序列SEQ ID NO:52具有至少约80％序列同一性；(ii)VH，其包含氨基酸序列SEQ ID NO:39或其变体，所述变体与氨基酸序列SEQ ID NO:39具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:53或其变体，所述变体与氨基酸序列SEQ ID NO:53具有至少约80％序列同一性；(iii)VH，其包含氨基酸序列SEQ ID NO:40或其变体，所述变体与氨基酸序列SEQ ID NO:40具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:53或其变体，所述变体与氨基酸序列SEQ ID NO:53具有至少约80％序列同一性；(iv)VH，其包含氨基酸序列SEQ ID NO:41或其变体，所述变体与氨基酸序列SEQ ID NO:41具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:53或其变体，所述变体与氨基酸序列SEQ ID NO:53具有至少约80％序列同一性；(v)VH，其包含氨基酸序列SEQ ID NO:42或其变体，所述变体与氨基酸序列SEQ ID NO:42具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:53或其变体，所述变体与氨基酸序列SEQ ID NO:53具有至少约80％序列同一性；(vi)VH，其包含氨基酸序列SEQ ID NO:43或其变体，所述变体与 氨基酸序列SEQ ID NO:43具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:53或其变体，所述变体与氨基酸序列SEQ ID NO:53具有至少约80％序列同一性；(vii)VH，其包含氨基酸序列SEQ ID NO:44或其变体，所述变体与氨基酸序列SEQ ID NO:44具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:53或其变体，所述变体与氨基酸序列SEQ ID NO:53具有至少约80％序列同一性；(viii)VH，其包含氨基酸序列SEQ ID NO:39或其变体，所述变体与氨基酸序列SEQ ID NO:39具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:54或其变体，所述变体与氨基酸序列SEQ ID NO:54具有至少约80％序列同一性；(ix)VH，其包含氨基酸序列SEQ ID NO:40或其变体，所述变体与氨基酸序列SEQ ID NO:40具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:54或其变体，所述变体与氨基酸序列SEQ ID NO:54具有至少约80％序列同一性；(x)VH，其包含氨基酸序列SEQ ID NO:41或其变体，所述变体与氨基酸序列SEQ ID NO:41具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:54或其变体，所述变体与氨基酸序列SEQ ID NO:54具有至少约80％序列同一性；(xi)VH，其包含氨基酸序列SEQ ID NO:42或其变体，所述变体与氨基酸序列SEQ ID NO:42具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:54或其变体，所述变体与氨基酸序列SEQ ID NO:54具有至少约80％序列同一性；(xii)VH，其包含氨基酸序列SEQ ID NO:43或其变体，所述变体与氨基酸序列SEQ ID NO:43具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:54或其变体，所述变体与氨基酸序列SEQ ID NO:54具有至少约80％序列同一性；(xiii)VH，其包含氨基酸序列SEQ ID NO:44或其变体，所述变体与氨基酸序列SEQ ID NO:44具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:54或其变体，所述变体与氨基酸序列SEQ ID NO:54具有至少约80％序列同一性；(xiv)VH，其包含氨基酸序列SEQ ID NO:39或其变体，所述变体与氨基酸序列SEQ ID NO:39具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:55或其变体，所述变体与氨基酸序列SEQ ID NO:55具有至少约80％序列同一性；(xv)VH，其包含氨基酸序列SEQ ID NO:40或其变体，所述变体与氨基酸序列SEQ ID NO:40具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:55或其变体，所述变体与氨基酸序列SEQ ID NO:55具有至少约80％序列同一性；(xvi)VH，其包含氨基酸序列SEQ ID NO:41或其变体，所述变体与氨基酸序列SEQ ID NO:41具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:55或其变体，所述变体与氨基酸序列SEQ ID NO:55具有至少约80％序列同一性；(xvii)VH，其包含氨基酸序列SEQ ID NO:42或其变体，所述变体与氨基酸序列SEQ ID NO:42具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:55或其变体，所述变体与氨基酸序列SEQ ID NO:55具有至少约80％序列同一性；(xviii)VH，其包含氨基酸序列SEQ ID NO:43或其变体，所述变体与氨基酸序列SEQ ID NO:43具有至少约80％序列同一性；以及VL，其包含氨基酸序列 SEQ ID NO:55或其变体，所述变体与氨基酸序列SEQ ID NO:55具有至少约80％序列同一性；(xix)VH，其包含氨基酸序列SEQ ID NO:44或其变体，所述变体与氨基酸序列SEQ ID NO:44具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:55或其变体，所述变体与氨基酸序列SEQ ID NO:55具有至少约80％序列同一性；(xx)VH，其包含氨基酸序列SEQ ID NO:45或其变体，所述变体与氨基酸序列SEQ ID NO:45具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:56或其变体，所述变体与氨基酸序列SEQ ID NO:56具有至少约80％序列同一性；(xxi)VH，其包含氨基酸序列SEQ ID NO:45或其变体，所述变体与氨基酸序列SEQ ID NO:45具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:57或其变体，所述变体与氨基酸序列SEQ ID NO:57具有至少约80％序列同一性；(xxii)VH，其包含氨基酸序列SEQ ID NO:46或其变体，所述变体与氨基酸序列SEQ ID NO:46具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:58或其变体，所述变体与氨基酸序列SEQ ID NO:58具有至少约80％序列同一性；(xxiii)VH，其包含氨基酸序列SEQ ID NO:47或其变体，所述变体与氨基酸序列SEQ ID NO:47具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:59或其变体，所述变体与氨基酸序列SEQ ID NO:59具有至少约80％序列同一性。
在一些实施例中，提供一种分离的抗GDF15抗体，其包含：(i)VH，其包含如氨基酸序列SEQ ID NO:48所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:60所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，提供一种分离的抗GDF15抗体，其包含：(i)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:3，HC-CDR2，其包含氨基酸序列SEQ ID NO:9，和HC-CDR3，其包含氨基酸序列SEQ ID NO:14，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:19，LC-CDR2，其包含氨基酸序列SEQ ID NO:26，和LC-CDR3，其包含氨基酸序列SEQ ID NO:31，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，如上所述任一种分离的抗GDF15抗体，其包含：VH，其包含SEQ ID NO:48所示的氨基酸序列或其变体，所述变体与SEQ ID NO:48所示的氨基酸序列具有至少约80％序列同一性；以及VL，其包含SEQ ID NO:60所示的氨基酸序列或其变体，所述变体与SEQ ID NO:60所示的氨基酸序列具有至少约80％序列同一性。
在一些实施例中，提供一种分离的抗GDF15抗体，其包含：(i)VH，其包含如氨基酸序列SEQ ID NO:49所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:61所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，提供一种分离的抗GDF15抗体，其包含：(i)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:4，HC-CDR2，其包含氨基酸序列SEQ ID NO:10，和HC-CDR3，其包含氨基酸序列SEQ ID NO:15，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:20，LC-CDR2，其包含氨基酸序列SEQ ID NO:27，和LC-CDR3，其包含氨基酸序列SEQ ID NO:32，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，如上所述任一种分离的抗GDF15抗体，其包含：VH，其包含SEQ ID NO:49所示的氨基酸序列或其变体，所述变体与SEQ ID NO:49所示的氨基酸序列具有至少约80％序列同一性；以及VL，其包含SEQ ID NO:61所示的氨基酸序列或其变体，所述变体与SEQ ID NO:61所示的氨基酸序列具有至少约80％序列同一性。
在一些实施例中，提供一种分离的抗GDF15抗体，其包含：(i)VH，其包含如氨基酸序列SEQ ID NO:50所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:62所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，提供一种分离的抗GDF15抗体，其包含：(i)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:5，HC-CDR2，其包含氨基酸序列SEQ ID NO:11，和HC-CDR3，其包含氨基酸序列SEQ ID NO:16，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:21，LC-CDR2，其包含氨基酸序列SEQ ID NO:28，和LC-CDR3，其包含氨基酸序列SEQ ID NO:33，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，如上所述任一种分离的抗GDF15抗体，其包含：VH，其包含SEQ ID NO:50所示的氨基酸序列或其变体，所述变体与SEQ ID NO:50所示的氨基酸序列具有至少约80％序列同一性；以及VL，其包含SEQ ID NO:62所示的氨基酸序列或其变体，所述变体与SEQ ID NO:62所示的氨基酸序列具有至少约80％序列同一性。
在一些实施例中，提供一种分离的抗GDF15抗体，包含重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含SYDMT(SEQ ID NO:6)；HC-CDR2，其包含IIX1X2SGX3TYYASWAKG(SEQ ID NO:79)，其中X1为N或S，X2为G、N或S，X3为N或S；和HC-CDR3，其包含GILVYADYGDHNL(SEQ ID NO:17)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含QASEDIYTNLA(SEQ ID NO:22)；LC-CDR2，其包含AASTLAS(SEQ ID NO:29)；和LC-CDR3，其包含LGVYTYISAX1GA(SEQ ID NO:81)，其中X1为D或E。
在一些实施例中，提供一种分离的抗GDF15抗体，其包含VH，所述VH包含：HC-CDR1，其包含SEQ ID NO:6所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；HC-CDR2，其包含SEQ ID NOs:12，75-78中任一所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；和HC-CDR3，其包含SEQ ID NO:17所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含SEQ ID NO:22所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；LC-CDR2，其包含SEQ ID NO:29所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；和LC-CDR3，其包含SEQ ID NOs:34，80中任一所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代。
在一些实施例中，提供一种分离的抗GDF15抗体，其包含：VH，所述VH包含如SEQ ID NOs:51,82-89中任一氨基酸序列所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，所述VL包含如SEQ ID NOs:63,90-91中任一氨基酸序列所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，提供一种分离的抗GDF15抗体，其包含：(i)VH，其包含如氨基酸序列SEQ ID NO:51所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:63所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；(ii)VH，其包含如氨基酸序列SEQ ID NO:82所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:90所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；(iii)VH，其包含如氨基酸序列SEQ ID NO:83所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:90所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；(iv)VH，其包含如氨基酸序列SEQ ID NO:84所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:90所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；(v)VH，其包含如氨基酸序列SEQ ID NO:85所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:90所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；(vi)VH，其包含如氨基酸序列SEQ ID NO:86所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:91所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；(vii)VH，其包含如氨基酸序列SEQ ID NO:87所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:91所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；(viii)VH，其包含如氨基酸序列SEQ ID NO:88所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:91所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；(ix)VH，其包含如氨基酸序列SEQ ID NO:89所示的VH包含的HC-CDR1、HC-CDR2和 HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:91所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，提供一种分离的抗GDF15抗体，其包含：(i)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:12，和HC-CDR3，其包含氨基酸序列SEQ ID NO:17，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:22，LC-CDR2，其包含氨基酸序列SEQ ID NO:29，和LC-CDR3，其包含氨基酸序列SEQ ID NO:34，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(ii)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:75，和HC-CDR3，其包含氨基酸序列SEQ ID NO:17，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:22，LC-CDR2，其包含氨基酸序列SEQ ID NO:29，和LC-CDR3，其包含氨基酸序列SEQ ID NO:80，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(iii)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:76，和HC-CDR3，其包含氨基酸序列SEQ ID NO:17，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:22，LC-CDR2，其包含氨基酸序列SEQ ID NO:29，和LC-CDR3，其包含氨基酸序列SEQ ID NO:80，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(iv)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:77，和HC-CDR3，其包含氨基酸序列SEQ ID NO:17，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:22，LC-CDR2，其包含氨基酸序列SEQ ID NO:29，和LC-CDR3，其包含氨基酸序列SEQ ID NO:80，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代；(v)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:78，和HC-CDR3，其包含氨基酸序列SEQ ID NO:17，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:22，LC-CDR2，其包含氨基酸序列SEQ ID NO:29，和LC-CDR3，其包含氨基酸序列SEQ ID NO:80，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，如上所述任一种分离的抗GDF15抗体，其包含：VH，其包含SEQ ID NOs:51,82-89中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:51,82-89中任一所示的氨基酸序列具有至少约80％序列同一性；以及VL，其包含 SEQ ID NOs:63,90-91中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:63,90-91中任一所示的氨基酸序列具有至少约80％序列同一性。
在一些实施例中，如上所述任一种分离的抗GDF15抗体，其包含：(i)VH，其包含SEQ ID NO:51所示的氨基酸序列或其变体，所述变体与SEQ ID NO:51所示的氨基酸序列具有至少约80％序列同一性；以及VL，其包含SEQ ID NO:63所示的氨基酸序列或其变体，所述变体与SEQ ID NO:63所示的氨基酸序列具有至少约80％序列同一性；(ii)VH，其包含氨基酸序列SEQ ID NO:82或其变体，所述变体与氨基酸序列SEQ ID NO:82具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:90或其变体，所述变体与氨基酸序列SEQ ID NO:90具有至少约80％序列同一性；(iii)VH，其包含氨基酸序列SEQ ID NO:83或其变体，所述变体与氨基酸序列SEQ ID NO:83具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:90或其变体，所述变体与氨基酸序列SEQ ID NO:90具有至少约80％序列同一性。(iv)VH，其包含氨基酸序列SEQ ID NO:84或其变体，所述变体与氨基酸序列SEQ ID NO:84具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:90或其变体，所述变体与氨基酸序列SEQ ID NO:90具有至少约80％序列同一性；(v)VH，其包含氨基酸序列SEQ ID NO:85或其变体，所述变体与氨基酸序列SEQ ID NO:85具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:90或其变体，所述变体与氨基酸序列SEQ ID NO:90具有至少约80％序列同一性；(vi)VH，其包含氨基酸序列SEQ ID NO:86或其变体，所述变体与氨基酸序列SEQ ID NO:86具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:91或其变体，所述变体与氨基酸序列SEQ ID NO:91具有至少约80％序列同一性；(vii)VH，其包含氨基酸序列SEQ ID NO:87或其变体，所述变体与氨基酸序列SEQ ID NO:87具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:91或其变体，所述变体与氨基酸序列SEQ ID NO:91具有至少约80％序列同一性；(viii)VH，其包含氨基酸序列SEQ ID NO:88或其变体，所述变体与氨基酸序列SEQ ID NO:88具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:91或其变体，所述变体与氨基酸序列SEQ ID NO:91具有至少约80％序列同一性；(ix)VH，其包含氨基酸序列SEQ ID NO:89或其变体，所述变体与氨基酸序列SEQ ID NO:89具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:91或其变体，所述变体与氨基酸序列SEQ ID NO:91具有至少约80％序列同一性。
在一些实施例中，分离的抗GDF15抗体与人GDF15的结合的Kd值为0.1pM至约10nM。
在一些实施例中，提供一种分离的抗GDF15抗体，其与上述任一种分离的抗GDF15抗体竞争与GDF15的特异性结合。在一些实施例中，提供一种分离的抗GDF15抗体，其与上述任一种分离的抗GDF15抗体特异性地结合相同的表位。
在一些实施例中，如上所述任一种分离的抗GDF15抗体，所述分离的抗GDF15抗体包含Fc片段。在一些实施例中，所述分离的抗GDF15抗体是全长的IgG抗体。在一些实施例中，所述分离的抗GDF15抗体是全长的IgG1、IgG2、IgG3或IgG4抗体。在一些实施例中，所述分离的抗GDF15抗体是嵌合的、全人的或人源化的抗体。在一些实施例中，所述分离的抗GDF15抗体是抗原结合片段，所述抗原结合片段选自Fab、Fab’、F(ab)’2、Fab’-SH、单链Fv(scFv)、Fv片段、dAb、Fd、纳米抗体(nanobody)、双链抗体(diabody)和线性抗体。
在一些实施例中，提供一种分离的核酸分子，所述核酸分子编码如上所述任一种抗GDF15抗体。在一些实施例中，提供一种载体，所述载体包含如上所述任一种核酸分子。在一些实施例中，提供一种宿主细胞，所述宿主细胞包含如上所述任一种抗GDF15抗体、如上所述任一种核酸分子或如上所述任一种载体。在一些实施例中，提供一种制备抗GDF15抗体的方法，其包含：a)在能有效表达抗GDF15抗体的条件下培养上述任一种宿主细胞；和b)从宿主细胞中获得表达的抗GDF15抗体。
在一些实施例中，提供一种治疗所需个体疾病或病症的方法，包括向所述个体施用有效量的如上所述的任一种抗GDF15抗体。在一些实施例中，提供如上所述的任一种抗GDF15抗体在制备用于治疗所需个体疾病或病症的药物组合物中的用途。在一些实施例中，提供如上所述的任一种抗GDF15抗体或包含抗GDF15抗体的药物组合物在制备用于治疗疾病或病症的药物中的用途。在一些实施例中，所述疾病或病症与GDF15信号通路有关，包括癌症，恶液质，代谢性疾病或病症。在一些实施例中，所述疾病或病症选自例如，癌症(如脑癌、黑素瘤、肺癌、胃肠道肿瘤、结肠癌、胰腺癌、前列腺癌、乳腺癌、口腔癌、肝癌、白血病、霍奇金淋巴瘤，非霍奇金淋巴瘤、膀胱癌、子宫颈癌、子宫体癌、睾丸癌，甲状腺癌、肾癌、胆囊癌、多发性骨髓瘤、鼻咽癌、喉癌、咽癌，食道癌等)，恶液质，恶液质相关的体重减少，神经性厌食症，代谢性疾病(如脂肪和能量代谢失衡、调节食欲、调节体重)。
同时还提供包含如上所述的任一种抗GDF15抗体的药物组合物、试剂盒以及生产制品。
附图说明
图1所示为在肿瘤恶液质动物模型HT1080模型中，示例性先导抗GDF15抗体GDF-R37-rabIg1对小鼠体重变化的影响。
图2A-2C所示为ELISA分析的来源于先导抗体GDF-R37-rabIg1的人源化抗GDF15抗体与人GDF15的结合亲和力。
图3A-3C所示为ELISA分析的来源于先导抗体GDF-R37-rabIg1的人源化抗GDF15抗体对GDF15和GFRAL结合的中和作用。
图4A-4D所示为报告细胞分析的来源于先导抗体GDF-R37-rabIg1的人源化抗GDF15抗体抑制GFRAL和RET下游信号激活的体外生物学活性。
图5所示为在小鼠体重快速减轻模型中，示例性抗GDF15抗体Hum-R37-2、Hum-R37-5及Hum-R37-8对小鼠体重变化的影响。
本申请的详细描述
本申请一方面提供抗GDF15抗体分子。通过构建的293T细胞展示库筛选、抗体人源化、亲和力成熟以及适当设计的生物化学及生物学实验的组合，已经鉴定出能够结合人GDF15并抑制人GDF15与其受体GFRAL作用的高效抗体分子。本文给出的结果表明，与已知抗GDF15抗体Hu01G06-127(AVEO)相比，在各种生物学实验中本申请中的抗体甚至比Hu01G06-127更有效或与其相当。
本申请所提供的抗GDF15抗体包括，例如，全长抗GDF15抗体、抗GDF15单链抗体(scFvs)、抗GDF15Fc融合蛋白、多特异性(如双特异性)抗GDF15抗体、抗GDF15免疫偶联物以及诸如此类的。
另一方面，本申请提供抗GDF15抗体，所述抗GDF15抗体包含：重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含X1YYMX2(SEQ ID NO:35)，其中X1为D或N，X2为S或T；HC-CDR2，其包含MISFSGTTX1ATWAKG(SEQ ID NO:36)，其中X1为H或Y；和HC-CDR3，其包含VVYAGWTYPLGI(SEQ ID NO:13)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含QASQSISSVLS(SEQ ID NO:18)；LC-CDR2，其包含EASX1X2AS(SEQ ID NO:37)，其中X1为I或T，X2为L或Q；和LC-CDR3，其包含QANYDVYNYGNP(SEQ ID NO:30)。
另一方面，本申请提供抗GDF15抗体，所述抗GDF15抗体包含：重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含DYYMS(SEQ ID NO:3)；HC-CDR2，其包含DIYGGSGTTDYASWVKG(SEQ ID NO:9)；和HC-CDR3，其包含GITADI(SEQ ID NO:14)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含QASQSISSYLA(SEQ ID NO:19)；LC-CDR2，其包含KASTLAS(SEQ ID NO:26)；和LC-CDR3，其包含RCIYGDSYGAA(SEQ ID NO:31)。
另一方面，本申请提供抗GDF15抗体，所述抗GDF15抗体包含：重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含SHWMS(SEQ ID NO:4)；HC-CDR2，其包含FVSPSGRAYYTSWVNG(SEQ ID NO:10)；和HC-CDR3，其包含GYTSGLDI(SEQ ID NO:15)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含QSSKSVVNGDWLA(SEQ ID NO:20)；LC-CDR2，其包含DAATLAS(SEQ ID NO:27)；和LC-CDR3，其包含AGVYNNDSDNG(SEQ ID NO:32)。
另一方面，本申请提供抗GDF15抗体，所述抗GDF15抗体包含：重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含TYWMS(SEQ ID NO:5)；HC-CDR2，其包含TIYAGSGGTWYASWVKG(SEQ ID NO:11)；和HC-CDR3，其包含GPNYSDAI(SEQ ID NO:16)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含QASEYIYSSLA(SEQ ID NO:21)；LC-CDR2，其包含DASDLAS(SEQ ID NO:28)；和LC-CDR3，其包含QCTDLSSSAGNT(SEQ ID NO:33)。
另一方面，本申请提供抗GDF15抗体，所述抗GDF15抗体包含：重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含SYDMT(SEQ ID NO:6)；HC-CDR2，其包含IIX1X2SGX3TYYASWAKG(SEQ ID NO:79)，其中X1为N或S，X2为G、N或S，X3为N或S；和HC-CDR3，其包含GILVYADYGDHNL(SEQ ID NO:17)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含QASEDIYTNLA(SEQ ID NO:22)；LC-CDR2，其包含AASTLAS(SEQ ID NO:29)；和LC-CDR3，其包含LGVYTYISAX1GA(SEQ ID NO:81)，其中X1为D或E。
同时还提供编码抗GDF15抗体的核酸，包含抗GDF15抗体的组合物，以及制备和使用抗GDF15抗体的方法。
定义
如本文所述，“治疗(treatment)”或“治疗(treating)是一种获得有益的或期望的结果的方法，包括临床结果。鉴于本申请的目的，所述有益的或期望的临床结果，包括但不限于以下一种或多种：缓解由疾病引起的一种或多种症状，减轻疾病程度，稳定疾病(例如，预防或延迟疾病恶化)，预防或延迟疾病的扩散(例如，转移)，预防或延迟疾病复发，延迟或减缓疾病进展，改善疾病状态，缓解疾病(部分或全部)，减少治疗疾病所需的一种或多种其他药物的剂量，延迟疾病进展，改善或提高生活质量，增加体重，和/或延长生存期。同时，“治疗”还包括疾病病理结果的减少
(例如，对癌症而言，肿瘤体积)。本申请的方法考虑了这些治疗的任何一个或多个方面。
术语“抗体”包括全长抗体及其抗原结合片段。全长抗体包括两条重链和两条轻链。轻链和重链的可变区负责抗原的结合。两条链中的可变区通常包括3个高变的环，被称为互补决定区(CDRs)(轻链(LC)CDRs包括LC-CDR1、LC-CDR2和LC-CDR3，重链(HC)CDRs包括HC-CDR1、HC-CDR2和HC-CDR3)。本文所披露的抗体或抗原结合片段的CDR边界可以通过Kabat，Chothia或Al-Lazikani惯例来定义或识别(Al-Lazikani 1997；Chothia 1985；Chothia 1987；Chothia 1989；Kabat 1987；Kabat 1991)。重链或轻链的3个CDR区插入到被称为框架区(FRs)的侧翼区段之间，所述框架区比CDR区具有更高的保守性，并形成支撑高变环的支架。重链和轻链 的恒定区并不参与抗原结合，但展示出多种效应功能。抗体是基于它们重链恒定区的氨基酸序列进行分类的。抗体的五种主要类别或同种型是IgA、IgD、IgE、IgG和IgM，其特征在于分别具有α、δ、ε、γ和μ型重链。几种主要的抗体类别被分为亚类，如IgG1(γ1重链)、IgG2(γ2重链)、IgG3(γ3重链)、IgG4(γ4重链)、IgA1(α1重链)或IgA2(α2重链)。
如本文所述，术语“抗原结合片段”包括抗体片段，例如，双链抗体(diabody)、Fab、Fab’、F(ab’)2、Fv片段、二硫键稳定的Fv片段(dsFv)、(dsFv)2、双特异性dsFv(dsFv-dsFv’)、二硫键稳定的双链抗体(ds双链抗体)、单链Fv(scFv)、scFv二聚体(二价双链抗体)，由包含一个或多个CDRs的抗体片段组成的多特异性抗体、单域抗体、纳米抗体(nanobody)、域抗体、二价域抗体或者能够与抗原结合但不包含完整抗体结构的任何其他抗体片段。抗原结合片段能够与亲本抗体或亲本抗体片段(如亲本scFv)结合相同的抗原。抗原结合片段还包括包含上述抗体片段的融合蛋白。在一些实施例中，抗原结合片段可能包括来自特定人抗体的一个或多个CDRs，该CDRs被移植到来自一个或多个不同人抗体的框架区。
如本文所述，术语“表位”是指抗体或抗体部分结合的抗原上特定的原子或氨基酸组。如果两种抗体或抗体部分表现出与某抗原竞争性结合，则它们可能结合抗原上的相同表位。
如本文所用，当第一抗体在等摩尔浓度下抑制第二抗体与GDF15靶标结合至少50％(例如至少55％、60％、65％、70％、75％、80％、85％、90％、95％、98％或99％)时，第一抗体与第二抗体“竞争”结合GDF15靶标，反之亦然。PCT出版物WO03/48731描述了基于交叉竞争的高通量抗体“表位归类”方法。
如本文所述，术语“特异性地结合”、“特异性地识别”或“对..来说是特异性的”是指可测量的和可再现的相互作用，例如抗体与靶标的结合可以确定在异质分子群，包括生物分子中存在该靶标。例如，抗体能够特异性地识别某靶标(可以是表位)是指，与其它靶标结合相比，该抗体与该靶标的结合具有更高的亲和力，亲合力，更容易和/或更持久。在一些实施例中，特异性地识别抗原的抗体与抗原的一个或多个抗原决定簇反应，其结合亲和力是其与其它靶标结合亲和力的至少10倍。
如本文所述，一种“分离的”抗GDF15抗体是指一种抗GDF15抗体，其(1)与天然存在的蛋白无关，(2)不含相同来源的其他蛋白，(3)由不同种属的细胞所表达，或(4)自然界中不存在。
如本文所述，术语“分离的核酸”，是指基因组、cDNA或合成来源的核酸或其组合。根据其来源，所述“分离的核酸”是指(1)与自然界中发现的“分离的核酸”中的全部或部分多核苷酸无关，(2)可与自然状态下不与之相连的多核苷酸可操作性地连接，或(3)在自然界中不作为较长序列的一部分而存在。
如本文所用，术语“CDR”或“互补决定区”意指重链和轻链多肽的可变结构域内发现的非连续抗原结合位点。在文献Kabat et al.,J.Biol.Chem.252:6609-6616(1977)； Kabat et al.,U.S.Dept.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.,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 M.P.et al.,Dev.Comp.Immunol.,27:55-77(2003)；和Honegger and Plückthun,J.Mol.Biol.,309:657-670(2001)中已经描述这些特殊的区域，其中当彼此之间互相比较时，这些定义包括氨基酸残基的重合或子集。然而，采用任何一种定义方式来指示抗体或移植抗体或其变体的CDR，均包括在本文所定义和使用的术语范围之内。表1中列了由上述引用的各篇参考文献所定义的CDR所包括的氨基酸残基的位置，以示比较。CDR预测的算法和结合界面在本领域是已知的，包括，例如Abhinandan and Martin,Mol.Immunol.,45:3832-3839(2008)；Ehrenmann F.et al.,Nucleic Acids Res.,38:D301-D307(2010)；和Adolf-Bryfogle J.et al.,Nucleic Acids Res.,43:D432-D438(2015)中均有描述。本段中所引用的参考文献的内容以其整体引用并入本文中，以用于本申请和可能包含在本文中的一个或多个权利要求中。
表1:CDR定义
1氨基酸残基编号参照上述Kabat et al.中的命名方法
2氨基酸残基编号参照上述Chothia et al.中的命名方法
3氨基酸残基编号参照上述MacCallum et al.中的命名方法
4氨基酸残基编号参照上述Lefranc et al.中的命名方法
5氨基酸残基编号参照上述Honegger and Plückthun中的命名方法
术语“嵌合抗体”是指，重链和/或轻链的一部分与来自特定种属或属于特定抗体种类或亚类的抗体中的相应序列一致或具有同源性，而这个(些)链的剩余部分与来自另一种属或属于其它抗体种类或亚类的抗体中的相应序列一致或具有同源性的抗体，以及此类抗体的片段，只要其具有本申请中的生物学活性(见U.S.Patent No.4,816,567；and Morrison et al.,Proc.Natl.Acad.Sci.USA,81:6851-6855(1984))。
“Fv”是包含完整抗原识别及结合位点的最小抗体片段。该片段是由一个重链可变结构域和一个轻链可变结构域紧密非共价连接形成的二聚体。通过这两个域的折叠衍生出6个高变环(轻链和重链中各3个环)，所述高变环为抗体提供了用于结合抗原 的氨基酸残基，并且赋予抗体与抗原结合的特异性。然而，即使单个可变结构域(或Fv片段的一半，其仅包含对抗原具有特异性的3个CDRs)也具有识别和结合抗原的能力，尽管其亲和力低于完整的结合位点。
“单链Fv”，也可简写成“sFv”或“scFv”，是包含被连接成单一多肽链的VH和VL抗体域的抗体片段。在一些实施例中，scFv多肽进一步包括VH和VL域之间的连接多肽，该连接多肽使得scFv形成抗原结合的理想结构。关于scFv的概述，见Pluckthun in The Pharmacology of Monoclonal Antibodies,vol.113,Rosenburg and Moore eds.,Springer-Verlag,New York,pp.269-315(1994)。
术语“双链抗体(diabody)”是在VH和VL域之间采用短接头(例如5～10个残基)，构建scFv片段(见上段内容)制备而成的一种小抗体片段，这样就使得可变结构域在链间而不是链内进行配对，产生一个双价片段，即具有两个抗原结合位点的片段。双特异性的双链抗体是两个“交叉”scFv片段的异二聚体，其中两个抗体的VH和VL域位于不同的多肽链上。在EP 404,097；WO 93/11161；Hollinger et al.,Proc.Natl.Acad.Sci.USA,90:6444-6448(1993)中全面描述了双链抗体。
非人源(如啮齿类)抗体的“人源化”形式是嵌合抗体，其包括最少的来自非人源抗体的序列。大多数情况下，人源化抗体是人源免疫球蛋白(受体抗体)，其中受体抗体的高变区(HVR)残基被来自非人源种属例如小鼠、大鼠、兔或非人类哺乳动物的且具有理想的抗体特异性，亲和力和性能的高变区残基所取代(供体抗体)。在某些情况下，人源免疫球蛋白框架区中的残基被相应的非人源残基所取代。另外，人源化抗体可以包括在受体抗体或供体抗体中均不存在的残基。这些修饰能够进一步改善抗体的性能。通常，人源化抗体会包含基本上所有，至少一个，通常两个可变结构域，其中所有或基本上所有的高变环均与非人免疫球蛋白的高变环相对应，以及所有或基本上所有的框架区均是人免疫球蛋白序列。人源抗体任选地也还包括免疫球蛋白恒定区(Fc)的至少一部分，通常是人免疫球蛋白的恒定区。具体细节可以参考Jones et al.,Nature 321:522-525(1986)；Riechmann et al.,Nature 332:323-329(1988)；和Presta,Curr.Op.Struct.Biol.2:593-596(1992)。
本文所鉴定的多肽和抗体序列的“氨基酸序列同一性百分比(％)”或“同源性”被定义：在认为保守性取代属于序列同一性的一部分的情况下进行序列对比，候选序列与待比较多肽序列中相同氨基酸残基所占的百分比。可以通过本领域技术范围内的多种比对方式来确定氨基酸序列同一性百分比，例如，使用如BLAST、BLAST-2、ALIGN、Megalign(DNASTAR)、或MUSCLE软件等可公开获得的计算机软件。本领域技术人员可以确定用于测量比对的合适的参数，包括在所比较序列的全长上实现最大化比对所需的任何算法。然而，为了本文的目的，氨基酸序列同一性百分比数值是使用序列比对电脑程序MUSCLE(Edgar,R.C.,Nucleic Acids Research 32(5):1792-1797,2004；Edgar,R.C.,BMC Bioinformatics 5(1):113,2004)生成的。
术语“Fc受体”或“FcR”用于描述结合抗体Fc区的受体。在一些实施例中，本申请所述的FcR是结合IgG抗体(一种γ受体)的FcR，包括FcγRI、FcγRII和FcγRIII亚类的受体，包括这些受体的等位基因变体和可变剪接形式。FcγRII受体包括FcγRIIA(“激活受体”)和FcγRIIB(“抑制受体”)，它们具有相似的氨基酸序列，主要在细胞质结构域有所不同。激活受体FcγRIIA的胞质结构域中含有免疫受体酪氨酸活化基序(ITAM)。抑制受体FcγRIIB的胞质结构域中含有免疫受体酪氨酸抑制基序(ITIM)(见M.inAnnu.Rev.Immunol.15:203-234(1997))。所述术语还包括同种异型，例如FcγRIIIA同种异型：FcγRIIIA-Phe158、FcγRIIIA-Val158、FcγRIIA-R131和/或FcγRIIA-H131。在Ravetch and Kinet,Annu.Rev.Immunol 9:457-92(1991)和Capel et al.,Immunomethods 4:25-34(1994)；以及de Haas et al.,J.Lab.Clin.Med.126:330-41(1995)中对FcRs进行了描述。本申请中术语FcR涵盖其他类型的FcRs，包括将来鉴定的FcRs。术语FcR同时还包括新生儿受体FcRn，其负责向新生儿转移母体IgGs(Guyer et al.,J.Immunol.117:587(1976)以及Kim et al.,J.Immunol.24:249(1994))。
术语“FcRn”指新生儿Fc受体(FcRn)。FcRn与主要组织相容性复合体(MHC)在结构上相似，由α链非共价结合到β2微球蛋白上组成。新生儿Fc受体FcRn的多种功能在Ghetie and Ward(2000)Annu.Rev.Immunol.18,739-766.中进行了综述。FcRn在免疫球蛋白IgGs从母体向新生儿的被动转运和调控血清IgG水平中起到重要作用。FcRn作为一种救助受体，可以在细胞内和细胞间以完整的形式结合和运输胞吞化的IgG，并使它们免于经受默认的降解途径。
人IgG重链恒定区的“CH1结构域”通常从118位氨基酸延伸到215位氨基酸(EU编号系统)。
“铰链区”通常被定义为从人IgG1的216位Glu延伸到230位Pro(Burton,Molec.Immunol.22:161-206(1985))。通过将形成重链间二硫键的第一个和最后一个半胱氨酸残基置于与IgG1相同位置后，可以使得其他IgG同种型的铰链区与IgG1序列比对。
人IgG Fc区的“CH2结构域”通常从231位氨基酸延伸到340位氨基酸。CH2结构域的独特之处在于，它不会与另一个区域紧密配对，而是在完整的天然IgG分子的两个CH2结构域之间插入了两条N端连接的支链糖链。据推测，糖类可能作为域与域间配对的替代，有助于保持CH2结构域稳定。Burton,Molec.Immunol.22:161-206(1985)。
“CH3”结构域包括在Fc区内从C末端残基延伸到CH2结构域(从341位氨基酸到抗体序列的C末端，通常为IgG的第446或447位氨基酸残基)。
“功能性Fc片段”具有天然Fc区序列所具有的“效应功能”。示例性的“效应功能”包括C1q结合；补体依赖的细胞毒作用(CDC)；Fc受体结合；抗体依赖的细胞介导的细胞毒作用(ADCC)；吞噬作用；细胞表面受体的下调(如B细胞受体；BCR) 等。这类效应功能通常需要Fc区与结合结构域(如抗体可变区)结合，并且可以使用本领域公知的多种实验方法进行评估。
具有“改变的”FcR结合亲和力或ADCC活性的IgG Fc变体的抗体，与亲本多肽或包含天然Fc序列的多肽相比，其FcR结合活性和/或ADCC活性增强或减弱。表现出与FcR“结合增强”的Fc变体与亲本多肽或包含天然IgG Fc序列的多肽相比，其与至少一种FcR具有更高的结合亲和力(例如更低的表观Kd或IC50值)。在一些实施例中，与亲本多肽相比，结合能力增强3倍，例如5、10、25、50、60、100、150、200，甚至高达500倍或结合力提高25％到1000％。表现出与FcR“结合降低”的Fc变体，与亲本多肽相比，其与至少一种FcR具有更低的亲和力(例如更高的表观Kd或IC50值)。与亲本多肽相比，其结合能力下降40％或更多。
“抗体依赖的细胞介导的细胞毒作用”或“ADCC”是一种细胞毒性形式，指分泌型的Ig与存在于某些细胞毒性细胞(例如自然杀伤细胞(NK)、中性粒细胞、和巨噬细胞)上的Fc受体(FcRs)结合，使这些细胞毒性效应细胞能够特异性结合携带抗原的靶细胞，随后使用细胞毒素杀死靶细胞。抗体“武装”细胞毒性细胞并且是这种杀伤所必需的。介导ADCC的主要细胞类型中，NK细胞只表达FcγRIII，而单核细胞表达FcγRI、FcγRII和FcγRIII。在Ravetch and Kinet,Annu.Rev.Immunol 9:457-92(1991)第464页的Table 3中总结了在造血细胞上FcR的表达。评估目标分子的ADCC活性，可以进行体外ADCC实验，在美国专利No.5,500,362或5,821,337中进行了描述。适用于此类实验的效应细胞包括外周血单核细胞(PBMC)和自然杀伤性细胞(NK)。可选地，或者此外，目标分子的ADCC活性也可以在体内进行评估，例如在如Clynes et al.PNAS(USA)95:652-656(1998)中所公开的动物模型中进行了描述。
包含Fc区变体的多肽与包含野生型IgG Fc多肽或亲本多肽相比，在人体效应细胞存在下表现出“增强的ADCC活性”或能够更有效的介导ADCC效应，所述包含Fc区变体的多肽在实验时与包含野生型IgG Fc多肽(或亲本多肽)数量上基本相同时，无论在体外或体内均能更有效的介导ADCC。通常采用本领域已知的任何体外ADCC实验方法来鉴定此类变体，例如用于鉴定ADCC活性的实验或方法，例如在动物模型中等。在一些实施例中，此类变体与野生型Fc(或亲代多肽)相比，介导ADCC的效率提高5到100倍，例如25到50倍。
“补体依赖的细胞毒作用”或“CDC”是指在补体存在的情况下裂解靶细胞。经典的补体途径的激活是由补体系统第一组分(C1q)与结合同源抗原的抗体(具有适宜结构的亚类)相结合而启动的。为了评估补体激活，可以进行CDC实验，如Gazzano-Santoro et al.,J.Immunol.Methods 202:163(1996)中所描述的。在美国专利No.6,194,551B1和WO99/51642中描述了具有改变的Fc区氨基酸序列并增加或降低的C1q结合能力的多肽变体。这些专利出版物的内容通过引用明确地并入本文中。另见Idusogie et al.J.Immunol.164:4178-4184(2000)。
除非另有说明，一种“编码氨基酸序列的核苷酸序列”包括相互之间互为简并形式且编码相同氨基酸序列的所有核苷酸序列。编码蛋白质或RNA的核苷酸序列也可包括内含子，例如编码蛋白质的核苷酸序列在某些形式中包含内含子。
术语“可操作性地连接”是指调控序列与异源核苷酸序列之间的功能性连接，从而使后者表达。例如，当第一个核苷酸序列与第二个核苷酸序列处于功能性关系时，第一个核苷酸序列与第二个核苷酸序列为可操作性地连接。例如，如果启动子影响编码序列的转录或表达，该启动子与编码序列为可操作性地连接。通常，可操作性连接的DNA序列是连续的，并且在必要时，可以在同一个阅读框中连接两个蛋白质编码区。
“同源”是指两个多肽之间或两个核酸分子之间的序列相似性或序列同一性。如果两个比较序列的同一位置为相同的碱基或氨基酸单体亚基时，例如两个DNA分子的同一位置均为腺嘌呤，则这两个DNA分子在该位置是同源的。两个序列间的同源百分比是指两个序列中共有的匹配或同源位置的数量与位置总数之比再乘以100所得函数。例如，两个序列中如果10个位置中有6个位置是相匹配或同源的，则这两个序列的同源性为60％。举例来说，DNA序列ATTGCC和TATGGC具有50％的同源性。通常来说，在比对两个序列时，以得到最大同源性为目的来进行对比。
本文所公开的抗GDF15抗体或组合物的“有效量”是指足以实现特定目的的量。“有效量”可以凭经验和通过已知的与所述目的相关的方法确定。
术语“治疗有效量”是指本文所公开的抗GDF15抗体或其组合物能够有效治疗个体的疾病或者症状的用量。例如在癌症的情况中，抗GDF15抗体或其组合物的治疗有效量是指能够减少癌细胞数量；减小肿瘤的大小或重量；抑制(即在一定程度上减缓或优选停止)肿瘤细胞对周边器官的浸润；抑制(即在一定程度上减缓或优选停止)肿瘤转移；在一定程度上抑制肿瘤的生长，和/或在一定程度上缓解与癌症相关的一种或多种症状。例如在癌症相关的恶液质的情况中，抗GDF15抗体或其组合物的治疗有效量是指能够抑制(即在一定程度上减缓或优选停止)肌肉质量的损失；抑制(即在一定程度上减缓或优选停止)脂肪质量的损失；在一定程度上恢复不自主体重的损失，在一定程度上抑制器官质量的损失，和/或在一定程度上缓解与恶液质相关的基础疾病的一种或多种症状。本文所公开的抗GDF15抗体或其组合物在某种程度上能够阻止和/或杀死现有的肿瘤细胞，它可以是细胞抑制性的或细胞毒性的。在一些实施例中，治疗有效量是指能够延长患者生存期的用量。在一些实施例中，治疗有效量是指能够改善患者无进展生存期的用量。
如本文所用的，“药学上可接受的”或“药理学上相容的”是指无生物学活性或者其它不期望性质的材料，例如该材料能够加入到给予患者的药物组合物中，而不会引起显著的不良生物反应，或者，不与组合物中包含的任何其它组分以有害的方式相互作用。药学上可接受的载体或赋形剂优选满足毒理学或制造检测的所需标准和/或包含在美国食品和药品管理局编制的非活性成分指南中。
本文中描述的本申请的实施例应理解为包含“由……组成”和/或“基本上由……组成”的实施例。
本文中提及“约”为一个数值或参数，包含(和描述)针对该值或参数本身的变体。例如，涉及“约X”的描述，包括“X”的描述。
如本文所用的，提及“不是(not)”一个数值或参数，通常表示并描述“除了(other than)”某一数值或参数之外。例如，该方法不能用于治疗X型癌症，意味着该方法通常用于治疗除X型癌症之外的其他类型的癌症。
除非上下文另有明确说明，本文和所述权利要求中所采用的单数形式“一”，“一个”和“该”包括复数对象。
抗GDF15抗体
一方面，本申请提供特异性结合GDF15的抗人、恒河猴和/或小鼠GDF15抗体。所述抗GDF15抗体包括，但不限于，人源化抗体，嵌合抗体，小鼠抗体，人抗体，以及本文所述的包含重链和/或轻链CDRs的抗体分子。一方面，本申请提供与GDF15结合的分离的抗体。预期的抗GDF15抗体包括，例如，全长抗GDF15抗体(如全长IgG1或IgG4)，抗GDF15单链抗体，抗GDF15Fc融合蛋白，多特异性(如双特异性)抗GDF15抗体，抗GDF15免疫偶联物，以及诸如此类的。在一些实施例中，抗GDF15抗体是全长抗体(如全长IgG1或IgG4)或其抗原结合片段，其特异性结合GDF15。在一些实施例中，抗GDF15抗体是Fab、Fab’、F(ab)’2、Fab’-SH、单链Fv(scFv)、Fv片段、dAb、Fd、纳米抗体(nanobody)、双链抗体(diabody)或线性抗体。在一些实施例中，特异性结合GDF15的抗体是指抗体与GDF15结合的亲和力至少是与非靶标结合亲和力的10倍以上(包括例如10、102、103、104、105、106、或107倍)。在一些实施例中，非靶标是指不是GDF15的抗原。结合亲和力可通过本领域已知的方法来测定，如ELISA，荧光激活细胞分选(FACS)分析或放射免疫沉淀分析(RIA)。Kd值可以通过本领域已知的方法来测定，如表面等离子共振(SPR)技术或生物层干涉技术(BLI)。
尽管本文广泛地讨论了包含人序列的抗GDF15抗体(例如，包含人CDR序列的人重链和轻链可变结构域)，但同时也考虑了非人抗GDF15抗体。在一些实施例中，非人抗GDF15抗体包括本文所述的抗GDF15抗体的人CDR序列和非人框架区序列，在一些实施例中，非人框架区序列包括任何的用于使用如本文所述的一种或多种人CDR序列产生重链和/或轻链可变结构域的序列，包括例如哺乳动物，例如小鼠、大鼠、兔子、猪、牛(例如，牛、公牛、水牛)、鹿、绵羊、山羊、鸡、猫、狗、雪貂、灵长类(例如，小猿，猕猴)等。在一些实施例中，非人抗GDF15抗体包括将一种或多种本文所述的人CDR序列移植到非人框架区中(例如，鼠或鸡的框架区序列)所产生的抗GDF15抗体。
示例性人GDF15的完整氨基酸序列包含SEQ ID NO：68所示的氨基酸序列或由SEQ ID NO：68所示的氨基酸序列组成。示例性人GDF15的成熟氨基酸序列包含SEQ ID NO：69所示的氨基酸序列或由SEQ ID NO：69所示的氨基酸序列组成。
在一些实施例中，本文所述抗GDF15抗体特异性识别人GDF15中的表位。在一些实施例中，所述抗GDF15抗体与除人之外其它物种的GDF15发生交叉反应。在一些实施例中，所述抗GDF15抗体对人GDF15是完全特异性的，并且不与其它非人物种发生交叉反应。
在一些实施例中，所述抗GDF15抗体与GDF15蛋白(或其片段)的至少一种等位基因变体交叉反应。在一些实施例中，等位基因变体与天然存在的GDF15蛋白(或其片段)相比，具有至多30个(如1、2、3、4、5、6、7、8、9、10、15、20、25或30个)的氨基酸取代(例如保守取代)。在一些实施例中，所述抗GDF15抗体不与GDF15蛋白(或其片段)的任何等位基因变体发生交叉反应。
在一些实施例中，所述抗GDF15抗体与GDF15蛋白的至少一种种间变体发生交叉反应。在一些实施例中，例如，GDF15蛋白(或其片段)是人GDF15，并且GDF15蛋白(或其片段)的种间变体是恒河猴中的变体。在一些实施例中，所述抗GDF15抗体不与GDF15蛋白的任何种间变体发生交叉反应。
在一些实施例中，如本文所述的任一抗GDF15抗体，所述抗GDF15抗体包含抗体重链恒定区和抗体轻链恒定区。在一些实施例中，所述抗GDF15抗体包含IgG1型重链恒定区。在一些实施例中，所述抗GDF15抗体包含IgG2型重链恒定区。在一些实施例中，所述抗GDF15抗体包含IgG3型重链恒定区。在一些实施例中，所述抗GDF15抗体包含IgG4型重链恒定区。在一些实施例中，所述重链恒定区包含(包括由…组成或基本上由…组成)氨基酸序列SEQ ID NO:64。在一些实施例中，所述重链恒定区包含(包括由…组成或基本上由…组成)氨基酸序列SEQ ID NO:65。在一些实施例中，所述抗GDF15抗体包含κ轻链恒定区。在一些实施例中，所述轻链恒定区包含(包括由…组成或基本上由…组成)氨基酸序列SEQ ID NO:66。在一些实施例中，所述抗GDF15抗体包含λ轻链恒定区。在一些实施例中，所述轻链恒定区包含(包括由…组成或基本上由…组成)氨基酸序列SEQ ID NO:67。在一些实施例中，所述抗GDF15抗体包含抗体重链可变结构域和抗体轻链可变结构域。
在一些实施例中，所述抗GDF15抗体，包含重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含X1YYMX2(SEQ ID NO:35)，其中X1为D或N，X2为S或T；HC-CDR2，其包含MISFSGTTX1ATWAKG(SEQ ID NO:36)，其中X1为H或Y；和HC-CDR3，其包含VVYAGWTYPLGI(SEQ ID NO:13)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含QASQSISSVLS(SEQ ID NO:18)；LC-CDR2，其包含EASX1X2AS(SEQ ID NO:37)，其中X1为I或T，X2为L或Q；和LC-CDR3，其包含QANYDVYNYGNP(SEQ ID NO:30)。
在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含：HC-CDR1，其包含SEQ ID NOs:1-2中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；HC-CDR2，其包含SEQ ID NOs:7-8中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和HC-CDR3，其包含SEQ ID NO:13所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代。
在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含：HC-CDR1，其包含SEQ ID NOs:1-2中任一所示的氨基酸序列，HC-CDR2，其包含SEQ ID NOs:7-8中任一所示的氨基酸序列，HC-CDR3，其包含SEQ ID NO:13所示的氨基酸序列。
在一些实施例中，所述抗GDF15抗体包含VL，所述VL包含：LC-CDR1，其包含SEQ ID NO:18所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；LC-CDR2，其包含SEQ ID NOs:23-25中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和LC-CDR3，其包含SEQ ID NO:30所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代。
在一些实施例中，所述抗GDF15抗体包含VL，所述VL包含：LC-CDR1，其包含SEQ ID NO:18所示的氨基酸序列，LC-CDR2，其包含SEQ ID NOs:23-25中任一所示的氨基酸序列，LC-CDR3，其包含SEQ ID NO:30所示的氨基酸序列。
在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含：HC-CDR1，其包含SEQ ID NOs:1-2中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；HC-CDR2，其包含SEQ ID NOs:7-8中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和HC-CDR3，其包含SEQ ID NO:13所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含SEQ ID NO:18所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；LC-CDR2，其包含SEQ ID NOs:23-25中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和LC-CDR3，其包含SEQ ID NO:30所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代。
在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含：HC-CDR1，其包含SEQ ID NOs:1-2中任一所示的氨基酸序列，HC-CDR2，其包含SEQ ID NOs:7-8中任一所示的氨基酸序列，和HC-CDR3，其包含SEQ ID NO:13所示的氨基酸序列；以及VL，所述VL包含：LC-CDR1，其包含SEQ ID NO:18所示的氨基酸序列，LC-CDR2，其包含SEQ ID NOs:23-25中任一所示的氨基酸序列，和LC-CDR3，其包含SEQ ID NO:30所示的氨基酸序列。
在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:7，HC-CDR3，其包含氨基酸序列SEQ ID NO:13，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:18，LC-CDR2，其包含氨基酸序列SEQ ID NO:23，LC-CDR3，其包含氨基酸序列SEQ ID NO:30，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:7，和HC-CDR3，其包含氨基酸序列SEQ ID NO:13；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:18，LC-CDR2，其包含氨基酸序列SEQ ID NO:23，和LC-CDR3，其包含氨基酸序列SEQ ID NO:30。
在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:7，HC-CDR3，其包含氨基酸序列SEQ ID NO:13，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:18，LC-CDR2，其包含氨基酸序列SEQ ID NO:24，LC-CDR3，其包含氨基酸序列SEQ ID NO:30，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:7，和HC-CDR3，其包含氨基酸序列SEQ ID NO:13；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:18，LC-CDR2，其包含氨基酸序列SEQ ID NO:24，和LC-CDR3，其包含氨基酸序列SEQ ID NO:30。
在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:7，HC-CDR3，其包含氨基酸序列SEQ ID NO:13，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:18，LC-CDR2，其包含氨基酸序列SEQ ID NO:25，LC-CDR3，其包含氨基酸序列SEQ ID NO:30，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:7，和HC-CDR3，其包含氨基酸序列SEQ ID NO:13；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:18，LC-CDR2，其包含氨基酸序列SEQ ID NO:25，和LC-CDR3，其包含氨基酸序列SEQ ID NO:30。
在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:2，HC-CDR2，其包含氨基酸序列SEQ ID NO:7，HC-CDR3，其包含氨基酸序列SEQ ID NO:13，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:18，LC-CDR2，其包含氨基酸序列SEQ ID NO:25，LC-CDR3，其包含氨基酸序列SEQ ID NO:30，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:2，HC-CDR2，其包含氨基酸序列SEQ ID NO:7，和HC-CDR3，其包含氨基酸序列SEQ ID NO:13；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:18，LC-CDR2，其包含氨基酸序列SEQ ID NO:25，和LC-CDR3，其包含氨基酸序列SEQ ID NO:30。
在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:8，HC-CDR3，其包含氨基酸序列SEQ ID NO:13，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:18，LC-CDR2，其包含氨基酸序列SEQ ID NO:25，LC-CDR3，其包含氨基酸序列SEQ ID NO:30，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:8，和HC-CDR3，其包含氨基酸序列SEQ ID NO:13；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:18，LC-CDR2，其包含氨基酸序列SEQ ID NO:25，和LC-CDR3，其包含氨基酸序列SEQ ID NO:30。
在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含如SEQ ID NOs:38-47中任一氨基酸序列所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，所述VL包含如SEQ ID NOs:52-59中任一氨基酸序列所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含VH，其包含如氨基酸序列SEQ ID NO:38所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:52所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含VH，其包含如氨基酸序列SEQ ID NO:39所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:53所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含VH，其包含如氨基酸序列SEQ ID NO:40所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:53所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含VH，其包含如氨基酸序列SEQ ID NO:41所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:53所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含VH，其包含如氨基酸序列SEQ ID NO:42所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:53所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含VH，其包含如氨基酸序列SEQ ID NO:43所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:53所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含VH，其包含如氨基酸序列SEQ ID NO:44所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:53所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含VH，其包含如氨基酸序列SEQ ID NO:39所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:54所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含VH，其包含如氨基酸序列SEQ ID NO:40所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:54所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含VH，其包含如氨基酸序列SEQ ID NO:41所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:54所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含VH，其包含如氨基酸序列SEQ ID NO:42所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:54所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含VH，其包含如氨基酸序列SEQ ID NO:43所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:54所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含VH，其包含如氨基酸序列SEQ ID NO:44所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:54所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含VH，其包含如氨基酸序列SEQ ID NO:39所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:55所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含VH，其包含如氨基酸序列SEQ ID NO:40所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:55所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含VH，其包含如氨基酸序列SEQ ID NO:41所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:55所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含VH，其包含如氨基酸序列SEQ ID NO:42所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:55所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含VH，其包含如氨基酸序列SEQ ID NO:43所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:55所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含VH，其包含如氨基酸序列SEQ ID NO:44所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:55所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含VH，其包含如氨基酸序列SEQ ID NO:45所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:56所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含VH，其包含如氨基酸序列SEQ ID NO:45所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:57所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含VH，其包含如氨基酸序列SEQ ID NO:46所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:58所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含VH，其包含如氨基酸序列SEQ ID NO:47所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:59所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含SEQ ID NOs:38-47中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:38-47中任一所示的氨基酸序列具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含SEQ ID NOs:52-59中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:52-59中任一所示的氨基酸序列具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含SEQ ID NOs:38-47中任一所示的氨基酸序列，以及VL，所述VL包含SEQ ID NOs:52-59中任一所示的氨基酸序列。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:38或其变体，所述变体与氨基酸序列SEQ ID NO:38具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:52或其变体，所述变体与氨基酸序列SEQ ID NO:52具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:38，以及VL，所述VL包含氨基酸序列SEQ ID NO:52。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:39或其变体，所述变体与氨基酸序列SEQ ID NO:39具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:53或其变体，所述变体与氨基酸序列SEQ ID NO:53具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:39，以及VL，所述VL包含氨基酸序列SEQ ID NO:53。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:40或其变体，所述变体与氨基酸序列SEQ ID NO:40具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:53或其变体，所述变体与氨基酸序列SEQ ID NO:53具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:40，以及VL，所述VL包含氨基酸序列SEQ ID NO:53。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:41或其变体，所述变体与氨基酸序列SEQ ID NO:41具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:53或其变体，所述变体与氨基酸序列SEQ ID NO:53具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:41，以及VL，所述VL包含氨基酸序列SEQ ID NO:53。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:42或其变体，所述变体与氨基酸序列SEQ ID NO:42具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:53或其变体，所述变体与氨基酸序列SEQ ID NO:53具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:42，以及VL，所述VL包含氨基酸序列SEQ ID NO:53。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:43或其变体，所述变体与氨基酸序列SEQ ID NO:43具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:53或其变体，所述变体与氨基酸序列SEQ ID NO:53具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:43，以及VL，所述VL包含氨基酸序列SEQ ID NO:53。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:44或其变体，所述变体与氨基酸序列SEQ ID NO:44具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:53或其变体，所述变体与氨基酸序列SEQ ID NO:53具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:44，以及VL，所述VL包含氨基酸序列SEQ ID NO:53。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:39或其变体，所述变体与氨基酸序列SEQ ID NO:39具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:54或其变体，所述变体与氨基酸序列SEQ ID NO:54具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:39，以及VL，所述VL包含氨基酸序列SEQ ID NO:54。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:40或其变体，所述变体与氨基酸序列SEQ ID NO:40具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:54或其变体，所述变体与氨基酸序列SEQ ID NO:54具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:40，以及VL，所述VL包含氨基酸序列SEQ ID NO:54。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:41或其变体，所述变体与氨基酸序列SEQ ID NO:41具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:54或其变体，所述变体与氨基酸序列SEQ ID NO:54具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:41，以及VL，所述VL包含氨基酸序列SEQ ID NO:54。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:42或其变体，所述变体与氨基酸序列SEQ ID NO:42具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:54或其变体，所述变体与氨基酸序列SEQ ID NO:54具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:42，以及VL，所述VL包含氨基酸序列SEQ ID NO:54。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:43或其变体，所述变体与氨基酸序列SEQ ID NO:43具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:54或其变体，所述变体与氨基酸序列SEQ ID NO:54具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:43，以及VL，所述VL包含氨基酸序列SEQ ID NO:54。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:44或其变体，所述变体与氨基酸序列SEQ ID NO:44具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:54或其变体，所述变体与氨基酸序列SEQ ID NO:54具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:44，以及VL，所述VL包含氨基酸序列SEQ ID NO:54。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:39或其变体，所述变体与氨基酸序列SEQ ID NO:39具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:55或其变体，所述变体与氨基酸序列SEQ ID NO:55具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:39，以及VL，所述VL包含氨基酸序列SEQ ID NO:55。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:40或其变体，所述变体与氨基酸序列SEQ ID NO:40具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:55或其变体，所述变体与氨基酸序列SEQ ID NO:55具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:40，以及VL，所述VL包含氨基酸序列SEQ ID NO:55。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:41或其变体，所述变体与氨基酸序列SEQ ID NO:41具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:55或其变体，所述变体与氨基酸序列SEQ ID NO:55具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:41，以及VL，所述VL包含氨基酸序列SEQ ID NO:55。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:42或其变体，所述变体与氨基酸序列SEQ ID NO:42具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:55或其变体，所述变体与氨基酸序列SEQ ID NO:55具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:42，以及VL，所述VL包含氨基酸序列SEQ ID NO:55。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:43或其变体，所述变体与氨基酸序列SEQ ID NO:43具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:55或其变体，所述变体与氨基酸序列SEQ ID NO:55具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:43，以及VL，所述VL包含氨基酸序列SEQ ID NO:55。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:44或其变体，所述变体与氨基酸序列SEQ ID NO:44具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:55或其变体，所述变体与氨基酸序列SEQ ID NO:55具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:44，以及VL，所述VL包含氨基酸序列SEQ ID NO:55。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:45或其变体，所述变体与氨基酸序列SEQ ID NO:45具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:56或其变体，所述变体与氨基酸序列SEQ ID NO:56具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:45，以及VL，所述VL包含氨基酸序列SEQ ID NO:56。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:45或其变体，所述变体与氨基酸序列SEQ ID NO:45具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:57或其变体，所述变体与氨基酸序列SEQ ID NO:57具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:45，以及VL，所述VL包含氨基酸序列SEQ ID NO:57。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:46或其变体，所述变体与氨基酸序列SEQ ID NO:46具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:58或其变体，所述变体与氨基酸序列SEQ ID NO:58具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:46，以及VL，所述VL包含氨基酸序列SEQ ID NO:58。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:47或其变体，所述变体与氨基酸序列SEQ ID NO:47具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:59或其变体，所述变体与氨基酸序列SEQ ID NO:59具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:47，以及VL，所述VL包含氨基酸序列SEQ ID NO:59。
在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:3，HC-CDR2，其包含氨基酸序列SEQ ID NO:9，HC-CDR3，其包含氨基酸序列SEQ ID NO:14，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:19，LC-CDR2，其包含氨基酸序列SEQ ID NO:26，LC-CDR3，其包含氨基酸序列SEQ ID NO:31，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:3，HC-CDR2，其包含氨基酸序列SEQ ID NO:9，和HC-CDR3，其包含氨基酸序列SEQ ID NO:14；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:19，LC-CDR2，其包含氨基酸序列SEQ ID NO:26，和LC-CDR3，其包含氨基酸序列SEQ ID NO:31。
在一些实施例中，所述抗GDF15抗体包含VH，其包含如氨基酸序列SEQ ID NO:48所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:60所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:48或其变体，所述变体与氨基酸序列SEQ ID NO:48具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:60或其变体，所述变体与氨基酸序列SEQ ID NO:60具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:48，以及VL，所述VL包含氨基酸序列SEQ ID NO:60。
在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:4，HC-CDR2，其包含氨基酸序列SEQ ID NO:10，HC-CDR3，其包含氨基酸序列SEQ ID NO:15，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:20，LC-CDR2，其包含氨基酸序列SEQ ID NO:27，LC-CDR3，其包含氨基酸序列SEQ ID NO:32，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:4，HC-CDR2，其包含氨基酸序列SEQ ID NO:10，和HC-CDR3，其包含氨基酸序列SEQ ID NO:15；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:20，LC-CDR2，其包含氨基酸序列SEQ ID NO:27，和LC-CDR3，其包含氨基酸序列SEQ ID NO:32。
在一些实施例中，所述抗GDF15抗体包含VH，其包含如氨基酸序列SEQ ID NO:49所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:61所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:49或其变体，所述变体与氨基酸序列SEQ ID NO:49具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:61或其变体，所述变体与氨基酸序列SEQ ID NO:61具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:49，以及VL，所述VL包含氨基酸序列SEQ ID NO:61。
在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:5，HC-CDR2，其包含氨基酸序列SEQ ID NO:11，HC-CDR3，其包含氨基酸序列SEQ ID NO:16，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:21，LC-CDR2，其包含氨基酸序列SEQ ID NO:28，LC-CDR3，其包含氨基酸序列SEQ ID NO:33，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:5，HC-CDR2，其包含氨基酸序列SEQ ID NO:11，和HC-CDR3，其包含氨基酸序列SEQ ID NO:16；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:21，LC-CDR2，其包含氨基酸序列SEQ ID NO:28，和LC-CDR3，其包含氨基酸序列SEQ ID NO:33。
在一些实施例中，所述抗GDF15抗体包含VH，其包含如氨基酸序列SEQ ID NO:50所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:62所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:50或其变体，所述变体与氨基酸序列SEQ ID NO:50具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:62或其变体，所述变体与氨基酸序列SEQ ID NO:62具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:50，以及VL，所述VL包含氨基酸序列SEQ ID NO:62。
在一些实施例中，所述抗GDF15抗体，包含重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含SYDMT(SEQ ID NO:6)；HC-CDR2，其包含IIX1X2SGX3TYYASWAKG(SEQ ID NO:79)，其中X1为N或S，X2为G、N或S，X3为N或S；和HC-CDR3，其包含GILVYADYGDHNL(SEQ ID NO:17)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含QASEDIYTNLA(SEQ ID NO:22)；LC-CDR2，其包含AASTLAS(SEQ ID NO:29)；和LC-CDR3，其包含LGVYTYISAX1GA(SEQ ID NO:81)，其中X1为D或E。
在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含：HC-CDR1，其包含SEQ ID NO:6所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；HC-CDR2，其包含SEQ ID NOs:12，75-78中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和HC-CDR3，其包含SEQ ID NO:17所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代。
在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含：HC-CDR1，其包含SEQ ID NO:6所示的氨基酸序列，HC-CDR2，其包含SEQ ID NOs:12，75-78中任一所示的氨基酸序列，HC-CDR3，其包含SEQ ID NO:17所示的氨基酸序列。
在一些实施例中，所述抗GDF15抗体包含VL，所述VL包含：LC-CDR1，其包含SEQ ID NO:22所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；LC-CDR2，其包含SEQ ID NO:29所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和LC-CDR3，其 包含SEQ ID NOs:34或80中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代。
在一些实施例中，所述抗GDF15抗体包含VL，所述VL包含：LC-CDR1，其包含SEQ ID NO:22所示的氨基酸序列，LC-CDR2，其包含SEQ ID NO:29所示的氨基酸序列，LC-CDR3，其包含SEQ ID NOs:34或80中任一所示的氨基酸序列。
在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含：HC-CDR1，其包含SEQ ID NO:6所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；HC-CDR2，其包含SEQ ID NOs:12，75-78中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和HC-CDR3，其包含SEQ ID NO:17所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含SEQ ID NO:22所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；LC-CDR2，其包含SEQ ID NO:29所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和LC-CDR3，其包含SEQ ID NOs:34或80中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代。
在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含：HC-CDR1，其包含SEQ ID NO:6所示的氨基酸序列，HC-CDR2，其包含SEQ ID NOs:12，75-78中任一所示的氨基酸序列，和HC-CDR3，其包含SEQ ID NO:17所示的氨基酸序列；以及VL，所述VL包含：LC-CDR1，其包含SEQ ID NO:22所示的氨基酸序列，LC-CDR2，其包含SEQ ID NO:29所示的氨基酸序列，和LC-CDR3，其包含SEQ ID NOs:34或80中任一所示的氨基酸序列。
在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:12，HC-CDR3，其包含氨基酸序列SEQ ID NO:17，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:22，LC-CDR2，其包含氨基酸序列SEQ ID NO:29，LC-CDR3，其包含氨基酸序列SEQ ID NO:34，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:12，和HC-CDR3，其包含氨基酸序列SEQ ID NO:17；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:22，LC-CDR2，其包含氨基酸序列SEQ ID NO:29，和LC-CDR3，其包含氨基酸序列SEQ ID NO:34。
在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:75，HC- CDR3，其包含氨基酸序列SEQ ID NO:17，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:22，LC-CDR2，其包含氨基酸序列SEQ ID NO:29，LC-CDR3，其包含氨基酸序列SEQ ID NO:80，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:75，和HC-CDR3，其包含氨基酸序列SEQ ID NO:17；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:22，LC-CDR2，其包含氨基酸序列SEQ ID NO:29，和LC-CDR3，其包含氨基酸序列SEQ ID NO:80。
在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:76，HC-CDR3，其包含氨基酸序列SEQ ID NO:17，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:22，LC-CDR2，其包含氨基酸序列SEQ ID NO:29，LC-CDR3，其包含氨基酸序列SEQ ID NO:80，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:76，和HC-CDR3，其包含氨基酸序列SEQ ID NO:17；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:22，LC-CDR2，其包含氨基酸序列SEQ ID NO:29，和LC-CDR3，其包含氨基酸序列SEQ ID NO:80。
在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:77，HC-CDR3，其包含氨基酸序列SEQ ID NO:17，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:22，LC-CDR2，其包含氨基酸序列SEQ ID NO:29，LC-CDR3，其包含氨基酸序列SEQ ID NO:80，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:77，和HC-CDR3，其包含氨基酸序列SEQ ID NO:17；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:22，LC-CDR2，其包含氨基酸序列SEQ ID NO:29，和LC-CDR3，其包含氨基酸序列SEQ ID NO:80。
在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:78，HC- CDR3，其包含氨基酸序列SEQ ID NO:17，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:22，LC-CDR2，其包含氨基酸序列SEQ ID NO:29，LC-CDR3，其包含氨基酸序列SEQ ID NO:80，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:78，和HC-CDR3，其包含氨基酸序列SEQ ID NO:17；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:22，LC-CDR2，其包含氨基酸序列SEQ ID NO:29，和LC-CDR3，其包含氨基酸序列SEQ ID NO:80。
在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含如SEQ ID NOs:51,82-89中任一氨基酸序列所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，所述VL包含如SEQ ID NOs:63,90-91中任一氨基酸序列所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含VH，其包含如氨基酸序列SEQ ID NO:51所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:63所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含VH，其包含如氨基酸序列SEQ ID NO:82所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:90所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含VH，其包含如氨基酸序列SEQ ID NO:83所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:90所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含VH，其包含如氨基酸序列SEQ ID NO:84所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:90所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含VH，其包含如氨基酸序列SEQ ID NO:85所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:90所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含VH，其包含如氨基酸序列SEQ ID NO:86所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:91所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含VH，其包含如氨基酸序列SEQ ID NO:87所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:91所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含VH，其包含如氨基酸序列SEQ ID NO:88所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:91所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含VH，其包含如氨基酸序列SEQ ID NO:89所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:91所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含SEQ ID NOs:51,82-89中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:51,82-89中任一所示的氨基酸序列具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含SEQ ID NOs:63,90-91中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:63,90-91中任一所示的氨基酸序列具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含SEQ ID NOs:51,82-89中任一所示的氨基酸序列，以及VL，所述VL包含SEQ ID NOs:63,90-91中任一所示的氨基酸序列。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:51或其变体，所述变体与氨基酸序列SEQ ID NO:51具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:63或其变体，所述变体与氨基酸序列SEQ ID NO:63具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:51，以及VL，所述VL包含氨基酸序列SEQ ID NO:63。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:82或其变体，所述变体与氨基酸序列SEQ ID NO:82具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:90或其变体，所述变体与氨基酸序列SEQ ID NO:90具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:82，以及VL，所述VL包含氨基酸序列SEQ ID NO:90。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:83或其变体，所述变体与氨基酸序列SEQ ID NO:83具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:90或其变体，所述变体与氨基酸序列SEQ ID NO:90具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:83，以及VL，所述VL包含氨基酸序列SEQ ID NO:90。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:84或其变体，所述变体与氨基酸序列SEQ ID NO:84具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:90或其变体，所述变体与氨基酸序列SEQ ID NO:90具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:84，以及VL，所述VL包含氨基酸序列SEQ ID NO:90。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:85或其变体，所述变体与氨基酸序列SEQ ID NO:85具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:90或其变体，所述变体与氨基酸序列SEQ ID NO:90具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:85，以及VL，所述VL包含氨基酸序列SEQ ID NO:90。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:86或其变体，所述变体与氨基酸序列SEQ ID NO:86具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:91或其变体，所述变体与氨基酸序列SEQ ID NO:91具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:86，以及VL，所述VL包含氨基酸序列SEQ ID NO:91。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:87或其变体，所述变体与氨基酸序列SEQ ID NO:87具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:91或其变体，所述变体与氨基酸序列SEQ ID NO:91具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:87，以及VL，所述VL包含氨基酸序列SEQ ID NO:91。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:88或其变体，所述变体与氨基酸序列SEQ ID NO:88具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:91或其变体，所述变体与氨基酸序列SEQ ID NO:91具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:88，以及VL，所述VL包含氨基酸序列SEQ ID NO:91。
在一些实施例中，所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:89或其变体，所述变体与氨基酸序列SEQ ID NO:89具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:91或其变体，所述变体与氨基酸序列SEQ ID NO:91具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述抗GDF15抗体包含VH，所述VH包含氨基酸序列SEQ ID NO:89，以及VL，所述VL包含氨基酸序列SEQ ID NO:91。
在一些实施例中，上述氨基酸取代限于本文表4中所示的“示例性取代”。在一些实施例中，氨基酸取代限于本文表4中所示的“优选取代”。
在一些实施例中，功能性表位可通过组合丙氨酸扫描法来解析。在此过程中，组合丙氨酸扫描技术可用于鉴定GDF15蛋白中与抗GDF15抗体相互作用所必需的氨基酸。在一些实施例中，该表位是构象的，同时可以采用与GDF15蛋白结合的抗GDF15抗体的晶体结构来鉴定表位。
在一些实施例中，本申请提供与本文所述的任一种抗GDF15抗体竞争性结合GDF15的抗体。在一些实施例中，提供能够与本文所述的任一种抗GDF15抗体竞争性地结合GDF15上的表位的抗体。在一些实施例中，提供抗GDF15抗体，其与包含VH和VL的抗GDF15抗体分子结合相同的表位，其中所述VH包含SEQ ID NOs:38-51，82-89中任一所示的氨基酸序列，以及所述VL包含SEQ ID NOs:52-63，90-91中任一所示的氨基酸序列。在一些实施例中，提供抗GDF15抗体，其与包含VH和VL的抗GDF15抗体竞争性地结合GDF15，其中所述VH包含SEQ ID NOs:38-51，82-89中任一所示的氨基酸序列，以及所述VL包含SEQ ID NOs:52-63，90-91中任一所示的氨基酸序列。
在一些实施例中，可以利用竞争实验来鉴定与本文所述的抗GDF15抗体竞争性结合GDF15的单克隆抗体。竞争实验可以通过识别相同的或空间上重叠的表位或者通过一个抗体竞争性抑制另一抗体与抗原结合来确定两个抗体是否结合相同的表位。在某些实施例中，这种竞争性抗体与本文所述的抗体结合相同的表位。一些示例性的竞争实验包括，但不限于如Harlow and Lane(1988)Antibodies:A Laboratory Manual ch.14(Cold Spring Harbor Laboratory，Cold Spring Harbor,N.Y.)中所提到的常规实验。用于解析抗体结合的表位的详细示例性方法如Morris(1996)"Epitope Mapping Protocols,"in Methods in Molecular Biology vol.66(Humana Press,Totowa,N.J.)中所述。在一些实施例中，如果每种抗体阻断另一种抗体结合的50％或更多，则称其结合相同的表位。在一些实施例中，与本文所述的抗GDF15抗体竞争的抗体是嵌合抗体、人源化抗体或全人抗体。
示例性抗GDF15抗体序列如表2-2A、表3-3A所示，其中根据Kabat定义方式进行CDR编号。本领域技术人员将认识到有多种已知算法来预测CDR的位置以及界定 抗体轻、重链可变区。包含如本文所述抗体的CDRs、VH和/或VL序列，但基于预测算法而非下表中所示例的抗体也在本申请的范围内。
表2示例性抗GDF15抗体CDR序列


表2A示例性抗GDF15抗体CDR序列

表3示例性序列



表3A示例性序列

GDF15
生长分化因子-15(GDF15)，又称为巨噬细胞抑制性细胞因子1(MIC-1)，是转化生长因子β(TGF-β)超家族的非典型成员。TGF-β超家族由30余个成员组成，最初被鉴定为在调控发育，分化和组织修复过程中发挥重要作用的分子。TGF-β超家族包含包括TGF-β、活化素、骨形态发生蛋白(BMP)、GDFs在内的多种配体。其中GDFs属于活化素/肌生成抑制蛋白亚类。该亚家族的几个成员已经被描述过，分别命名为GDF1-GDF15(Herpin,A.等，Dev.Comp.Immunol.2004)。人类GDF15的成熟经过一系列的翻译后修饰过程。翻译后未加工的GDF15蛋白(pre-pro-GDF15)有308个氨基酸，包括信号肽序列(29aa)、前肽(167aa)和成熟蛋白(112aa)。被合成的前体形式的pro-GDF15蛋白，通过半胱氨酸残基形成pro-GDF15同源二聚体；然后在RXXR位点被切割，C端释放成熟的二聚体GDF15蛋白和一段前肽(Wang X等人，Biochem Pharmacol，2013)。
GDF15受体GFRAL
胶质细胞来源的神经营养因子(GDNF)受体α样蛋白GFRAL作为GDF15蛋白的脑干限制性受体，主要表达于中枢神经系统(CNS)，尤其是在小鼠、大鼠、猴和人类的孤束核(NTS)和后极区(AP)(Hsu等人，Nature,2017；S.E.Mullican,et al.,2017)。在各种胚胎和成年小鼠组织中分析了GFRAL mRNA的表达情况。在成年小鼠的中枢神经系统(CNS)中检测到GRAL mRNA的两种异构体。相比之下，在检查的周围器官中，如心脏、肝脏、脾脏、肺脏、肾脏、胎盘、骨骼肌和小肠，均没有检测到GFRAL mRNA。在中枢神经系统的各个区域中，GFRAL mRNAs在大脑的某些部位，如黑质、海马区和后脑区，相对更丰富(Li等，J.Neurochem.2005.)
GFRAL蛋白是一种跨膜蛋白，通过分布在脂筏内的糖基磷脂酰肌醇(GPI)锚定在质膜上。该受体蛋白由三个富含半胱氨酸的结构域构成。GDF15能够激活专门分布在小鼠后极区和孤束核的表达GFRAL的神经元(Hsu等人，Nature,2017.)。GFRAL的共受体酪氨酸激酶RET在AP和孤束核(NTS)中表达，并在下丘脑的几个区域观察到额外的表达(Hsu，等，2017)。GDF15二聚体蛋白与两个GFRAL结合，然后招募RET分子形成复合物，从而触发自RET的磷酸化和细胞内信号传导，进一步激活其细胞内激酶域，通过脑干神经元启动多种信号通路(Shannon E.Mullican&Rangwala,2018；L.Yang,et al.,2017)。
GDF15-GFRAL信号在控制体重中发挥重要的作用。在喂养高脂肪饮食的小鼠和自发肥胖的非人类灵长类动物中，重组GDF15诱导体重下降。在这项研究中，生殖系Gfral基因敲除的小鼠(Gfral-/-)失去了由重组GDF15引起的厌食和代谢相关效应。此外，饮食引起的肥胖和胰岛素抗性在GFRAL缺陷的小鼠中加剧，表明该受体在代谢中具有平衡作用(Mullican,S.E.et al.Nat Med.2017)。
全长抗GDF15抗体
在一些实施例中，所述抗GDF15抗体是全长抗GDF15抗体。在一些实施例中，所述全长抗GDF15抗体是IgA、IgD、IgE、IgG或IgM。在一些实施例中，所述全长抗GDF15抗体包含IgG恒定区域，例如IgG1、IgG2、IgG3、IgG4或其变体的恒定区域。在一些实施例中，所述全长抗GDF15抗体包含λ轻链恒定区。在一些实施例中，所述全长抗GDF15抗体包含κ轻链恒定区。在一些实施例中，所述全长抗GDF15抗体是全长的人抗GDF15抗体。在一些实施例中，所述全长抗GDF15抗体包含小鼠免疫球蛋白Fc序列。在一些实施例中，所述全长抗GDF15抗体包含已经改变的或以其他方式改变的Fc序列，使得其具有增强的抗体依赖的细胞介导的细胞毒作用(ADCC)和补体依赖的细胞毒作用(CDC)的效应功能。
因此，例如，在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，所述抗GDF15抗体与GDF15特异性结合。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一 些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG2恒定区的全长抗GDF15抗体，所述抗GDF15抗体与GDF15特异性结合。在一些实施例中，所述IgG2是人IgG2。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG3恒定区的全长抗GDF15抗体，所述抗GDF15抗体与GDF15特异性结合。在一些实施例中，所述IgG3是人IgG3。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，所述抗GDF15抗体与GDF15特异性结合。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中所述抗GDF15抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含SEQ ID NOs:1-6中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；HC-CDR2，其包含SEQ ID NOs:7-12，75-78中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和HC-CDR3，其包含SEQ ID NOs:13-17中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含SEQ ID NOs:18-22中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代，LC-CDR2，其包含SEQ ID NOs:23-29中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和LC-CDR3，其包含SEQ ID NOs:30-34，80中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨 基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG2恒定区的全长抗GDF15抗体，其中所述抗GDF15抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含SEQ ID NOs:1-6中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；HC-CDR2，其包含SEQ ID NOs:7-12，75-78中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和HC-CDR3，其包含SEQ ID NOs:13-17中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含SEQ ID NOs:18-22中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；LC-CDR2，其包含SEQ ID NOs:23-29中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和LC-CDR3，其包含SEQ ID NOs:30-34，80中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代。在一些实施例中，所述IgG2是人IgG2。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG3恒定区的全长抗GDF15抗体，其中所述抗GDF15抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含SEQ ID NOs:1-6中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代，HC-CDR2，其包含SEQ ID NOs:7-12，75-78中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和HC-CDR3，其包含SEQ ID NOs:13-17中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含SEQ ID NOs:18-22中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；LC-CDR2，其包含SEQ ID NOs:23-29中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和LC-CDR3，其包含SEQ ID NOs:30-34，80中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代。在一些实施例中，所述IgG3是人IgG3。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中所述抗GDF15抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含 SEQ ID NOs:1-6中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；HC-CDR2，其包含SEQ ID NOs:7-12，75-78中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；和HC-CDR3，其包含SEQ ID NOs:13-17中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含SEQ ID NOs:18-22中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代，LC-CDR2，其包含SEQ ID NOs:23-29中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代，和LC-CDR3，其包含SEQ ID NOs:30-34，80中任一所示的氨基酸序列或其变体，所述变体包含至多约3个(例如1、2或3个)氨基酸的取代。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中所述抗GDF15抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含SEQ ID NOs:1-6中任一所示的氨基酸序列，HC-CDR2，其包含SEQ ID NOs:7-12，75-78中任一所示的氨基酸序列，和HC-CDR3，其包含SEQ ID NOs:13-17中任一所示的氨基酸序列，或者所述重链可变结构域的变体，其HC-CDR序列中包含至多约5个(例如1、2、3、4或5个)氨基酸的取代；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含SEQ ID NOs:18-22中任一所示的氨基酸序列，LC-CDR2，其包含SEQ ID NOs:23-29中任一所示的氨基酸序列，和LC-CDR3，其包含SEQ ID NOs:30-34，80中任一所示的氨基酸序列，或者所述轻链可变结构域的变体，其LC-CDR序列中包含至多约5个(例如1、2、3、4或5个)氨基酸的取代。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中所述抗GDF15抗体包含a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含 SEQ ID NOs:1-6中任一所示的氨基酸序列，HC-CDR2，其包含SEQ ID NOs:7-12，75-78中任一所示的氨基酸序列，和HC-CDR3，其包含SEQ ID NOs:13-17中任一所示的氨基酸序列，或者所述重链可变结构域的变体，其HC-CDR序列中包含至多约5个(例如1、2、3、4或5个)氨基酸的取代；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含SEQ ID NOs:18-22中任一所示的氨基酸序列，LC-CDR2，包含SEQ ID NOs:23-29中任一所示的氨基酸序列，和LC-CDR3，其包含SEQ ID NOs:30-34，80中任一所示的氨基酸序列，或者所述轻链可变结构域的变体，其LC-CDR序列中包含至多约5个(例如1、2、3、4或5个)氨基酸的取代。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中所述抗GDF15抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含SEQ ID NOs:1-6中任一所示的氨基酸序列，HC-CDR2，其包含SEQ ID NOs:7-12，75-78中任一所示的氨基酸序列，和HC-CDR3，其包含SEQ ID NOs:13-17中任一所示的氨基酸序列；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含SEQ ID NOs:18-22中任一所示的氨基酸序列，LC-CDR2，其包含SEQ ID NOs:23-29中任一所示的氨基酸序列，和LC-CDR3，其包含SEQ ID NOs:30-34，80中任一所示的氨基酸序列。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中所述抗GDF15抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含SEQ ID NOs:1-6中任一所示的氨基酸序列，HC-CDR2，其包含SEQ ID NOs:7-12，75-78中任一所示的氨基酸序列，和HC-CDR3，其包含SEQ ID NOs:13-17中任一所示的氨基酸序列；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含SEQ ID NOs:18-22中任一所示的氨基酸序列，LC-CDR2，其包含SEQ ID NOs:23-29中任一所示的氨基酸序列，和LC-CDR3，其包含SEQ ID NOs:30-34，80中任一 所示的氨基酸序列。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中所述抗GDF15抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:7，和HC-CDR3，其包含氨基酸序列SEQ ID NO:13；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:18，LC-CDR2，其包含氨基酸序列SEQ ID NO:23，和LC-CDR3，其包含氨基酸序列SEQ ID NO:30。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中所述抗GDF15抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:7，和HC-CDR3，其包含氨基酸序列SEQ ID NO:13；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:18，LC-CDR2，其包含氨基酸序列SEQ ID NO:24，和LC-CDR3，其包含氨基酸序列SEQ ID NO:30。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中所述抗GDF15抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:7，和HC-CDR3，其包含氨基酸序列SEQ ID NO:13；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:18，LC-CDR2，其包含氨基酸 序列SEQ ID NO:25，和LC-CDR3，其包含氨基酸序列SEQ ID NO:30。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中所述抗GDF15抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:2，HC-CDR2，其包含氨基酸序列SEQ ID NO:7，和HC-CDR3，其包含氨基酸序列SEQ ID NO:13；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:18，LC-CDR2，其包含氨基酸序列SEQ ID NO:25，和LC-CDR3，其包含氨基酸序列SEQ ID NO:30。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中所述抗GDF15抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:8，和HC-CDR3，其包含氨基酸序列SEQ ID NO:13；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:18，LC-CDR2，其包含氨基酸序列SEQ ID NO:25，和LC-CDR3，其包含氨基酸序列SEQ ID NO:30。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中所述抗GDF15抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:3，HC-CDR2，其包含氨基酸序列SEQ ID NO:9，和HC-CDR3，其包含氨基酸序列SEQ ID NO:14；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:19，LC-CDR2，其包含氨基酸 序列SEQ ID NO:26，和LC-CDR3，其包含氨基酸序列SEQ ID NO:31。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中所述抗GDF15抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:4，HC-CDR2，其包含氨基酸序列SEQ ID NO:10，和HC-CDR3，其包含氨基酸序列SEQ ID NO:15；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:20，LC-CDR2，其包含氨基酸序列SEQ ID NO:27，和LC-CDR3，其包含氨基酸序列SEQ ID NO:32。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中所述抗GDF15抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:5，HC-CDR2，其包含氨基酸序列SEQ ID NO:11，和HC-CDR3，其包含氨基酸序列SEQ ID NO:16；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:21，LC-CDR2，其包含氨基酸序列SEQ ID NO:28，和LC-CDR3，其包含氨基酸序列SEQ ID NO:33。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中所述抗GDF15抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:12，和HC-CDR3，其包含氨基酸序列SEQ ID NO:17；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:22，LC-CDR2，其包含氨基酸 序列SEQ ID NO:29，和LC-CDR3，其包含氨基酸序列SEQ ID NO:34。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中所述抗GDF15抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:75，和HC-CDR3，其包含氨基酸序列SEQ ID NO:17；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:22，LC-CDR2，其包含氨基酸序列SEQ ID NO:29，和LC-CDR3，其包含氨基酸序列SEQ ID NO:80。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中所述抗GDF15抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:76，和HC-CDR3，其包含氨基酸序列SEQ ID NO:17；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:22，LC-CDR2，其包含氨基酸序列SEQ ID NO:29，和LC-CDR3，其包含氨基酸序列SEQ ID NO:80。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中所述抗GDF15抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:77，和HC-CDR3，其包含氨基酸序列SEQ ID NO:17；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:22，LC-CDR2，其包含氨基酸 序列SEQ ID NO:29，和LC-CDR3，其包含氨基酸序列SEQ ID NO:80。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中所述抗GDF15抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:78，和HC-CDR3，其包含氨基酸序列SEQ ID NO:17；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:22，LC-CDR2，其包含氨基酸序列SEQ ID NO:29，和LC-CDR3，其包含氨基酸序列SEQ ID NO:80。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中所述抗GDF15抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:7，和HC-CDR3，其包含氨基酸序列SEQ ID NO:13；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:18，LC-CDR2，其包含氨基酸序列SEQ ID NO:23，和LC-CDR3，其包含氨基酸序列SEQ ID NO:30。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中所述抗GDF15抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:7，和HC-CDR3，其包含氨基酸序列SEQ ID NO:13；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:18，LC-CDR2，其包含氨基酸 序列SEQ ID NO:24，和LC-CDR3，其包含氨基酸序列SEQ ID NO:30。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中所述抗GDF15抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:7，和HC-CDR3，其包含氨基酸序列SEQ ID NO:13；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:18，LC-CDR2，其包含氨基酸序列SEQ ID NO:25，和LC-CDR3，其包含氨基酸序列SEQ ID NO:30。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中所述抗GDF15抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:2，HC-CDR2，其包含氨基酸序列SEQ ID NO:7，和HC-CDR3，其包含氨基酸序列SEQ ID NO:13；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:18，LC-CDR2，其包含氨基酸序列SEQ ID NO:25，和LC-CDR3，其包含氨基酸序列SEQ ID NO:30。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中所述抗GDF15抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:8，和HC-CDR3，其包含氨基酸序列SEQ ID NO:13；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:18，LC-CDR2，其包含氨基酸 序列SEQ ID NO:25，和LC-CDR3，其包含氨基酸序列SEQ ID NO:30。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中所述抗GDF15抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:3，HC-CDR2，其包含氨基酸序列SEQ ID NO:9，和HC-CDR3，其包含氨基酸序列SEQ ID NO:14；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:19，LC-CDR2，其包含氨基酸序列SEQ ID NO:26，和LC-CDR3，其包含氨基酸序列SEQ ID NO:31。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中所述抗GDF15抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:4，HC-CDR2，其包含氨基酸序列SEQ ID NO:10，和HC-CDR3，其包含氨基酸序列SEQ ID NO:15；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:20，LC-CDR2，其包含氨基酸序列SEQ ID NO:27，和LC-CDR3，其包含氨基酸序列SEQ ID NO:32。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中所述抗GDF15抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:5，HC-CDR2，其包含氨基酸序列SEQ ID NO:11，和HC-CDR3，其包含氨基酸序列SEQ ID NO:16；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:21，LC-CDR2，其包含氨基酸 序列SEQ ID NO:28，和LC-CDR3，其包含氨基酸序列SEQ ID NO:33。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中所述抗GDF15抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:12，和HC-CDR3，其包含氨基酸序列SEQ ID NO:17；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:22，LC-CDR2，其包含氨基酸序列SEQ ID NO:29，和LC-CDR3，其包含氨基酸序列SEQ ID NO:34。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中所述抗GDF15抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:75，和HC-CDR3，其包含氨基酸序列SEQ ID NO:17；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:22，LC-CDR2，其包含氨基酸序列SEQ ID NO:29，和LC-CDR3，其包含氨基酸序列SEQ ID NO:80。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中所述抗GDF15抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:76，和HC-CDR3，其包含氨基酸序列SEQ ID NO:17；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:22，LC-CDR2，其包含氨基酸 序列SEQ ID NO:29，和LC-CDR3，其包含氨基酸序列SEQ ID NO:80。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中所述抗GDF15抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:77，和HC-CDR3，其包含氨基酸序列SEQ ID NO:17；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:22，LC-CDR2，其包含氨基酸序列SEQ ID NO:29，和LC-CDR3，其包含氨基酸序列SEQ ID NO:80。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中所述抗GDF15抗体包含：a)重链可变结构域，所述重链可变结构域包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:78，和HC-CDR3，其包含氨基酸序列SEQ ID NO:17；以及b)轻链可变结构域，所述轻链可变结构域包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:22，LC-CDR2，其包含氨基酸序列SEQ ID NO:29，和LC-CDR3，其包含氨基酸序列SEQ ID NO:80。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：重链可变结构域(VH)，所述VH包含SEQ ID NOs:38-51，82-89中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:38-51，82-89中任一所示的氨基酸序列具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及轻链可变结构域(VL)，所述VL包含SEQ ID NOs: 52-63，90-91中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:52-63，90-91中任一所示的氨基酸序列具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG2恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：重链可变结构域(VH)，所述VH包含SEQ ID NOs:38-51，82-89中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:38-51，82-89中任一所示的氨基酸序列具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及轻链可变结构域(VL)，所述VL包含SEQ ID NOs:52-63，90-91中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:52-63，90-91中任一所示的氨基酸序列具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述IgG2是人IgG2。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG3恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：重链可变结构域(VH)，所述VH包含SEQ ID NOs:38-51，82-89中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:38-51，82-89中任一所示的氨基酸序列具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及轻链可变结构域(VL)，所述VL包含SEQ ID NOs:52-63，90-91中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:52-63，90-91中任一所示的氨基酸序列具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性。在一些实施例中，所述IgG3是人IgG3。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：重链可变结构域(VH)，所述VH包含SEQ ID NOs:38-51，82-89中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:38-51，82-89中任一所示的氨基酸序列具有至少约80％(例如至少80％、85％、90％、95％、96％、97％、98％或99％)序列同一性；以及轻链可变结构域(VL)，所述VL包含SEQ ID NOs:52-63，90-91中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:52-63，90-91中任一所示的氨基酸序列具有至少约80％(例如至少80％、85％、90％、95％、 96％、97％、98％或99％)序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：重链可变结构域(VH)，所述(VH)包含SEQ ID NOs:38-51，82-89中任一所示的氨基酸序列，以及轻链可变结构域(VL)，所述(VL)包含SEQ ID NOs:52-63，90-91中任一所示的氨基酸序列。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：重链可变结构域(VH)，所述VH包含SEQ ID NOs:38-51，82-89中任一所示的氨基酸序列，以及轻链可变结构域(VL)，所述VL包含SEQ ID NOs:52-63，90-91中任一所示的氨基酸序列。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:38或其变体，所述变体与氨基酸序列SEQ ID NO:38具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:52或其变体，所述变体与氨基酸序列SEQ ID NO:52具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区 包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:39或其变体，所述变体与氨基酸序列SEQ ID NO:39具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:53或其变体，所述变体与氨基酸序列SEQ ID NO:53具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:40或其变体，所述变体与氨基酸序列SEQ ID NO:40具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:53或其变体，所述变体与氨基酸序列SEQ ID NO:53具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:41或其变体，所述变体与氨基酸序列SEQ ID NO:41具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:53或其变体，所述变体与氨基酸序列SEQ ID NO:53具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:42或其变体，所述变体与氨基酸序列SEQ ID NO:42具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:53或其变体，所述变体与氨基酸序列SEQ ID NO:53具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:43或其变体，所述变体与氨基酸序列SEQ ID NO:43具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:53或其变体，所述变体与氨基酸序列SEQ ID NO:53具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:44或其变体，所述变体与氨基酸序列SEQ ID NO:44具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:53或其变体，所述变体与氨基酸序列SEQ ID NO:53具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:39或其变体，所述变体与氨基酸序列SEQ ID NO:39具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ  ID NO:54或其变体，所述变体与氨基酸序列SEQ ID NO:54具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:40或其变体，所述变体与氨基酸序列SEQ ID NO:40具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:54或其变体，所述变体与氨基酸序列SEQ ID NO:54具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:41或其变体，所述变体与氨基酸序列SEQ ID NO:41具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:54或其变体，所述变体与氨基酸序列SEQ ID NO:54具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:42或其变体，所述变体与氨基酸序列SEQ ID NO:42具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:54或其变体，所述变体与氨基酸序列SEQ ID NO:54具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列 SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:43或其变体，所述变体与氨基酸序列SEQ ID NO:43具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:54或其变体，所述变体与氨基酸序列SEQ ID NO:54具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:44或其变体，所述变体与氨基酸序列SEQ ID NO:44具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:54或其变体，所述变体与氨基酸序列SEQ ID NO:54具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:39或其变体，所述变体与氨基酸序列SEQ ID NO:39具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:55或其变体，所述变体与氨基酸序列SEQ ID NO:55具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区 包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:40或其变体，所述变体与氨基酸序列SEQ ID NO:40具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:55或其变体，所述变体与氨基酸序列SEQ ID NO:55具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:41或其变体，所述变体与氨基酸序列SEQ ID NO:41具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:55或其变体，所述变体与氨基酸序列SEQ ID NO:55具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:42或其变体，所述变体与氨基酸序列SEQ ID NO:42具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:55或其变体，所述变体与氨基酸序列SEQ ID NO:55具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:43或其变体，所述变体与氨基酸序列SEQ ID NO:43具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:55或其变体，所述变体与氨基酸序列SEQ ID NO:55具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:44或其变体，所述变体与氨基酸序列SEQ ID NO:44具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:55或其变体，所述变体与氨基酸序列SEQ ID NO:55具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:45或其变体，所述变体与氨基酸序列SEQ ID NO:45具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:56或其变体，所述变体与氨基酸序列SEQ ID NO:56具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:45或其变体，所述变体与氨基酸序列SEQ ID NO:45具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ  ID NO:57或其变体，所述变体与氨基酸序列SEQ ID NO:57具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:46或其变体，所述变体与氨基酸序列SEQ ID NO:46具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:58或其变体，所述变体与氨基酸序列SEQ ID NO:58具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:47或其变体，所述变体与氨基酸序列SEQ ID NO:47具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:59或其变体，所述变体与氨基酸序列SEQ ID NO:59具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:48或其变体，所述变体与氨基酸序列SEQ ID NO:48具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:60或其变体，所述变体与氨基酸序列SEQ ID NO:60具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列 SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:49或其变体，所述变体与氨基酸序列SEQ ID NO:49具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:61或其变体，所述变体与氨基酸序列SEQ ID NO:61具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:50或其变体，所述变体与氨基酸序列SEQ ID NO:50具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:62或其变体，所述变体与氨基酸序列SEQ ID NO:62具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:51或其变体，所述变体与氨基酸序列SEQ ID NO:51具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:63或其变体，所述变体与氨基酸序列SEQ ID NO:63具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区 包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:82或其变体，所述变体与氨基酸序列SEQ ID NO:82具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:90或其变体，所述变体与氨基酸序列SEQ ID NO:90具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:83或其变体，所述变体与氨基酸序列SEQ ID NO:83具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:90或其变体，所述变体与氨基酸序列SEQ ID NO:90具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:84或其变体，所述变体与氨基酸序列SEQ ID NO:84具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:90或其变体，所述变体与氨基酸序列SEQ ID NO:90具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:85或其变体，所述变体与氨基酸序列SEQ ID NO:85具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:90或其变体，所述变体与氨基酸序列SEQ ID NO:90具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:86或其变体，所述变体与氨基酸序列SEQ ID NO:86具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:91或其变体，所述变体与氨基酸序列SEQ ID NO:91具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:87或其变体，所述变体与氨基酸序列SEQ ID NO:87具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:91或其变体，所述变体与氨基酸序列SEQ ID NO:91具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:88或其变体，所述变体与氨基酸序列SEQ ID NO:88具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ  ID NO:91或其变体，所述变体与氨基酸序列SEQ ID NO:91具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG1恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:89或其变体，所述变体与氨基酸序列SEQ ID NO:89具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:91或其变体，所述变体与氨基酸序列SEQ ID NO:91具有至少约80％序列同一性。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:38或其变体，所述变体与氨基酸序列SEQ ID NO:38具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:52或其变体，所述变体与氨基酸序列SEQ ID NO:52具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:39或其变体，所述变体与氨基酸序列SEQ ID NO:39具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:53或其变体，所述变体与氨基酸序列SEQ ID NO:53具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列 SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:40或其变体，所述变体与氨基酸序列SEQ ID NO:40具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:53或其变体，所述变体与氨基酸序列SEQ ID NO:53具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:41或其变体，所述变体与氨基酸序列SEQ ID NO:41具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:53或其变体，所述变体与氨基酸序列SEQ ID NO:53具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:42或其变体，所述变体与氨基酸序列SEQ ID NO:42具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:53或其变体，所述变体与氨基酸序列SEQ ID NO:53具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区 包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:43或其变体，所述变体与氨基酸序列SEQ ID NO:43具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:53或其变体，所述变体与氨基酸序列SEQ ID NO:53具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:44或其变体，所述变体与氨基酸序列SEQ ID NO:44具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:53或其变体，所述变体与氨基酸序列SEQ ID NO:53具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:39或其变体，所述变体与氨基酸序列SEQ ID NO:39具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:54或其变体，所述变体与氨基酸序列SEQ ID NO:54具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:40或其变体，所述变体与氨基酸序列SEQ ID NO:40具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:54或其变体，所述变体与氨基酸序列SEQ ID NO:54具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:41或其变体，所述变体与氨基酸序列SEQ ID NO:41具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:54或其变体，所述变体与氨基酸序列SEQ ID NO:54具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:42或其变体，所述变体与氨基酸序列SEQ ID NO:42具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:54或其变体，所述变体与氨基酸序列SEQ ID NO:54具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:43或其变体，所述变体与氨基酸序列SEQ ID NO:43具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ  ID NO:54或其变体，所述变体与氨基酸序列SEQ ID NO:54具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:44或其变体，所述变体与氨基酸序列SEQ ID NO:44具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:54或其变体，所述变体与氨基酸序列SEQ ID NO:54具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:39或其变体，所述变体与氨基酸序列SEQ ID NO:39具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:55或其变体，所述变体与氨基酸序列SEQ ID NO:55具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:40或其变体，所述变体与氨基酸序列SEQ ID NO:40具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:55或其变体，所述变体与氨基酸序列SEQ ID NO:55具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列 SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:41或其变体，所述变体与氨基酸序列SEQ ID NO:41具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:55或其变体，所述变体与氨基酸序列SEQ ID NO:55具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:42或其变体，所述变体与氨基酸序列SEQ ID NO:42具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:55或其变体，所述变体与氨基酸序列SEQ ID NO:55具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:43或其变体，所述变体与氨基酸序列SEQ ID NO:43具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:55或其变体，所述变体与氨基酸序列SEQ ID NO:55具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区 包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:44或其变体，所述变体与氨基酸序列SEQ ID NO:44具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:55或其变体，所述变体与氨基酸序列SEQ ID NO:55具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:45或其变体，所述变体与氨基酸序列SEQ ID NO:45具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:56或其变体，所述变体与氨基酸序列SEQ ID NO:56具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:45或其变体，所述变体与氨基酸序列SEQ ID NO:45具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:57或其变体，所述变体与氨基酸序列SEQ ID NO:57具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:46或其变体，所述变体与氨基酸序列SEQ ID NO:46具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:58或其变体，所述变体与氨基酸序列SEQ ID NO:58具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:47或其变体，所述变体与氨基酸序列SEQ ID NO:47具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:59或其变体，所述变体与氨基酸序列SEQ ID NO:59具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:48或其变体，所述变体与氨基酸序列SEQ ID NO:48具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:60或其变体，所述变体与氨基酸序列SEQ ID NO:60具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:49或其变体，所述变体与氨基酸序列SEQ ID NO:49具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ  ID NO:61或其变体，所述变体与氨基酸序列SEQ ID NO:61具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:50或其变体，所述变体与氨基酸序列SEQ ID NO:50具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:62或其变体，所述变体与氨基酸序列SEQ ID NO:62具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:51或其变体，所述变体与氨基酸序列SEQ ID NO:51具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:63或其变体，所述变体与氨基酸序列SEQ ID NO:63具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:82或其变体，所述变体与氨基酸序列SEQ ID NO:82具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:90或其变体，所述变体与氨基酸序列SEQ ID NO:90具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列 SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:83或其变体，所述变体与氨基酸序列SEQ ID NO:83具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:90或其变体，所述变体与氨基酸序列SEQ ID NO:90具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:84或其变体，所述变体与氨基酸序列SEQ ID NO:84具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:90或其变体，所述变体与氨基酸序列SEQ ID NO:90具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:85或其变体，所述变体与氨基酸序列SEQ ID NO:85具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:90或其变体，所述变体与氨基酸序列SEQ ID NO:90具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区 包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:86或其变体，所述变体与氨基酸序列SEQ ID NO:86具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:91或其变体，所述变体与氨基酸序列SEQ ID NO:91具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:87或其变体，所述变体与氨基酸序列SEQ ID NO:87具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:91或其变体，所述变体与氨基酸序列SEQ ID NO:91具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:88或其变体，所述变体与氨基酸序列SEQ ID NO:88具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:91或其变体，所述变体与氨基酸序列SEQ ID NO:91具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种包含IgG4恒定区的全长抗GDF15抗体，其中抗GDF15抗体包含：VH，其包含氨基酸序列SEQ ID NO:89或其变体，所述变体与氨基酸序列SEQ ID NO:89具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:91或其变体，所述变体与氨基酸序列SEQ ID NO:91具有至少约80％序列同一性。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成以及轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
结合亲和力
结合亲和力采用Kd、Koff、Kon或Ka表示。如本文所用，术语Koff是指抗体从抗原/抗体复合物中解离的速率常数，通过动力学选择装置测定。术语Kon是指抗体与抗原结合形成抗原/抗体复合物的结合速率常数。本文所用的平衡解离常数Kd是指特定抗体抗原相互作用时的解离常数，是指在抗体分子溶液中，抗原占据所有抗体结合位点的一半并且达到平衡时所需的抗原浓度，等于Koff/Kon。Kd的测定假设所有的结合分子均在溶液中。抗体与细胞壁连接的情况，例如在酵母表达系统中，相应的平衡解离速率常数采用EC50来表示，其是Kd的一个良好的近似值。亲和结合常数Ka是解离常数Kd的倒数。
解离常数(Kd)可以作为反应抗体部分与抗原亲和力的指标。例如，可以通过Scatchard方法使用标记有各种标记物的抗体，和Biacore仪器(由Amersham Biosciences制造)进行简单分析，根据用户手册或附带试剂盒，通过表面等离子体共振来分析生物分子间的相互作用。使用这些方法得到的Kd值，用单位M来表示。与靶标特异性结合的抗体可能具有，例如≤10-7M、≤10-8M、≤10-9M、≤10-10M、≤10- 11M、≤10-12M或≤10-13M的Kd值。
抗体的结合特异性可以通过本领域已知的方法进行实验测定。这些方法包括，但不限于Western blots、ELISA-、RIA-、ECL-、IRMA-、EIA-、BIAcore测试和肽扫描等。
在一些实施例中，所述抗GDF15抗体特异性结合GDF15靶标，其Kd值为10-7M至10-13M(例如10-7M至10-13M、10-8M至10-13M、10-9M至10-13M或10-10M至10-12M)。因此，在一些实施例中，抗GDF15抗体与GDF15之间结合的Kd值为10- 7M至10-13M、1×10-7M至5×10-13M、10-7M至10-12M、10-7M至10-11M、10-7M至10-10M、10-7M至10-9M、10-8M至10-13M、1×10-8M至5×10-13M、10-8M至10- 12M、10-8M至10-11M、10-8M至10-10M、10-8M至10-9M、5×10-9M至1×10-13M、 5×10-9M至1×10-12M、5×10-9M至1×10-11M、5×10-9M至1×10-10M、10-9M至10- 13M、10-9M至10-12M、10-9M至10-11M、10-9M至10-10M、5×10-10M至1×10- 13M、5×10-10M至1×10-12M、5×10-10M至1×10-11M、10-10M至10-13M、1×10-10M至5×10-13M、1×10-10M至1×10-12M、1×10-10M至5×10-12M、1×10-10M至1×10- 11M、10-11M至10-13M、1×10-11M至5×10-13M、10-11M至10-12M、10-12M至10- 13M。在一些实施例中，抗GDF15抗体与GDF15之间结合的Kd值为10-7M至10-13M。
在一些实施例中，抗GDF15抗体与非靶标之间结合的Kd值高于抗GDF15抗体与靶标的Kd值，并且本文中引用的一些实施例中，抗GDF15抗体与靶标(例如，GDF15)的结合亲和力高于抗GDF15抗体与非靶标的结合亲和力。一些实施例中，非靶标是指非GDF15的抗原。在一些实施例中，抗GDF15抗体(针对GDF15)与非GDF15靶标结合的Kd值间至少相差10倍，例如10-100倍、100-1000倍、103-104倍、104-105倍、105-106倍、106-107倍、107-108倍、108-109倍、109-1010倍、1010-1011倍、1011-1012倍。
在一些实施例中，所述抗GDF15抗体与非靶标结合的Kd值为10-1M至10-6M(例如10-1M至10-6M、10-1M至10-5M、10-2M至10-4M)。在一些实施例中，所述非靶标是指非GDF15的抗原。因此，在一些实施例中，抗GDF15抗体与非GDF15靶标之间结合的Kd值为10-1M至10-6M、1×10-1M至5×10-6M、10-1M至10-5M、1×10-1M至5×10-5M、10-1M至10-4M、1×10-1M至5×10-4M、10-1M至10-3M、1×10-1M至5×10-3M、10-1M至10-2M、10-2M至10-6M、1×10-2M至5×10-6M、10-2M至10-5M、1×10-2M至5×10-5M、10-2M至10-4M、1×10-2M至5×10-4M、10-2M至10-3M、10-3M至10-6M、1×10-3M至5×10-6M、10-3M至10-5M、1×10-3M至5×10-5M、10-3M至10-4M、10-4M至10-6M、1×10-4M至5×10-6M、10-4M至10-5M、10-5M至10-6M。
在一些实施例中，当提及抗GDF15抗体以高结合亲和力特异性地识别GDF15靶标，并以低结合亲和力结合非靶标时，所述抗GDF15抗体与GDF15靶标结合的Kd值为10-7M至10-13M(例如10-7M至10-13M、10-8M至10-13M、10-9M至10-13M、10- 10M至10-12M)，并且与非靶标结合的Kd值为10-1M至10-6M(例如10-1M至10-6M、10-1M至10-5M、10-2M至10-4M)。
在一些实施例中，当提及抗GDF15抗体特异性地识别GDF15时，将所述抗GDF15抗体的结合亲和力与对照抗GDF15抗体(例如Hu01G06-127)的结合亲和力进行比较。在一些实施例中，对照抗GDF15抗体与GDF15之间结合的Kd值可以是本申请所述的抗GDF15抗体与GDF15之间结合的Kd值的至少2倍，例如2倍、3倍、4倍、5倍、6倍、7倍、8倍、9倍、10倍、10-100倍、100-1000倍、103-104倍。
核酸
编码抗GDF15抗体的核酸分子也被考虑在内。在一些实施例中，提供一种(或一组)编码全长抗GDF15抗体的核酸，包括本文所述的任一种全长抗GDF15抗体。在一些实施例中，本文所述的抗GDF15抗体的核酸(或一组核酸)还可以包括编码多肽标签的核酸序列(例如蛋白纯化标签，His标签、HA标签)。
同时本文还考虑了包含抗GDF15抗体的分离的宿主细胞，编码抗GDF15抗体多肽组分的分离的核酸，或者包含编码本文所述的抗GDF15抗体多肽组分的核酸的载体。
本申请还包括这些核酸序列的变体。例如，变体包括至少在中等严格杂交条件下与编码本申请的抗GDF15抗体的核酸序列杂交的核苷酸序列。
本申请同时还提供可将本申请中核酸序列插入到其中的载体。
简言之，将编码抗GDF15抗体的天然或合成的核酸插入到合适的表达载体中，使得核酸可操作性的连接到5’和3’端调控元件，例如包括启动子(例如淋巴细胞特异性启动子)和3’非翻译区(UTR)，可表达抗GDF15抗体(例如全长的抗GDF15抗体)。所述载体可适用于在真核宿主细胞中复制和整合。典型的克隆与表达载体包含调控目标核酸序列的表达的转录和翻译终止子、起始序列和启动子。
本申请所述的核酸也可以通过使用标准的基因递送方案，用于核酸免疫和基因治疗。核酸递送方法是本领域已知的。例如参见U.S.Pat.Nos.5,399,346、5,580,859、5,589,466，通过引用其全部内容并入本文。在一些实施例中，本申请还提供基因治疗载体。
可以将核酸克隆到许多类型的载体中。例如，可以将核酸克隆到载体中，所述载体包括，但不限于，质粒、噬菌粒、噬菌体衍生物、动物病毒和柯斯质粒。特别感兴趣的载体包括表达载体、复制载体、探针生成载体和测序载体。
此外，表达载体可以以病毒载体的形式提供给细胞。病毒载体技术是本领域熟知的，并且描述于例如Green and Sambrook(2013,Molecular Cloning:A Laboratory Manual,Cold Spring Harbor Laboratory,New York)，以及其它病毒学或分子生物学手册中。可用作载体的病毒包括，但不限于，逆转录病毒、腺病毒、腺相关病毒、疱疹病毒和慢病毒。通常，合适的载体包括一个在至少一种生物体中起作用的复制起点、启动子序列、方便的限制性内切酶位点以及一个或多个选择标记物(参见例如，WO 01/96584；WO 01/29058；和U.S.Pat.No.6,326,193)。
已经开发了许多基于病毒的系统，用于将基因转移到哺乳动物细胞中。例如，逆转录病毒为基因递送系统提供了便利的平台。可以应用本领域已知的技术，将选择的基因插入载体中并包装在逆转录病毒颗粒中。然后分离重组病毒，在体内或体外递送至受试者的细胞中。许多逆转录病毒系统在本领域中是已知的。在一些实施例中，使用腺病毒载体。许多腺病毒载体在本领域中是已知的。在一些实施例中，使用慢病毒 载体。衍生自逆转录病毒的载体，例如慢病毒，是实现长期基因转移的合适工具，因为它们使得转基因长期稳定的整合以及在子代细胞中繁殖。慢病毒载体相对于衍生自肿瘤的逆转录病毒例如小鼠白血病病毒具有额外的优势，因为它们可以转导非分裂细胞，例如肝细胞。同时，其还具有低免疫原性的额外优势。
其它的启动子元件，例如，增强子，调控转录起始频率。通常它们位于起始位点上游30-110bp处，虽然最近发现很多启动子也包含起始位点下游的功能元件。启动子元件之间的间隔通常是灵活的，所以当元件彼此之间位置互换或移动时仍保持启动子的功能。在胸苷激酶(tk)启动子中，启动子元件之间的间隔增加到50bp活性才会开始下降。
合适启动子的一个示例是即时早期巨细胞病毒(CMV)启动子序列。该启动子序列是一个很强的组成型启动子序列，可以驱动任何与其可操作性连接的多核苷酸序列高水平表达。合适启动子的另一个示例是延伸因子1α(EF-1α)启动子。然而，也可以使用其它组成型启动子，包括但不限于猿猴病毒40(SV40)早期启动子、小鼠乳腺肿瘤病毒(MMTV)、人免病缺陷病毒长末端重复序列(HIV-LTR)启动子、MoMuLV启动子、禽类白血病病毒启动子、Epstein-Barr病毒即刻早期启动子、劳斯氏肉瘤病毒启动子以及人类基因启动子，例如包括但不限于肌动蛋白启动子、肌球蛋白启动子、血红蛋白启动子和肌酸激酶启动子。此外，不应将本申请局限在仅使用组成型启动子，诱导型启动子也是本申请考虑的部分。诱导型启动子的使用提供了一种分子开关，当需要这种表达时，能启动其与之可操作性连接的多核苷酸序列表达，当不需要时，则关闭表达。诱导型启动子包含，但不局限于，金属硫蛋白启动子、糖皮质激素启动子、孕酮启动子和四环素启动子。
在一些实施例中，抗GDF15抗体的表达是可诱导的。在一些实施例中，编码抗GDF15抗体的核酸序列可操作的连接到诱导型启动子上，包括本文所述的任一诱导型启动子。
诱导型启动子
诱导型启动子的使用提供了一种分子开关，当需要表达时，可启动与之可操作性连接的多核苷酸序列表达，而在不需要表达时，则关闭表达。真核细胞中适用的示例性诱导型启动子包括，但不限于，激素调节元件(例如，参见Mader,S.and White,J.H.(1993)Proc.Natl.Acad.Sci.USA 90:5603-5607)、合成配体调节元件(参见Spencer,D.M.et al(1993)Science 262:1019-1024)以及电离辐射调控元件(参见Manome,Y.et al.(1993)Biochemistry 32:10607-10613；Datta,R.et al.(1992)Proc.Natl.Acad.Sci.USA 89:1014-10153)。其它适用于体内或体外哺乳动物系统的示例性诱导型启动子参见Gingrich et al.(1998)Annual Rev.Neurosci 21:377-405。在一些实施例中，用于表达抗GDF15抗体的诱导型启动子系统为Tet系统。在一些实施例中，用于表达抗GDF15抗体的诱导型启动子系统为大肠杆菌lac抑制系统。
本申请所采用的一个示例性诱导型启动子系统为Tet系统。该系统是基于Gossen等(1993)描述的Tet系统。在一个示例性实施例中，目标多核苷酸由包含一个或多个Tet操纵子(TetO)位点的启动子控制。在非激活状态，Tet阻遏物(TetR)与TetO位点结合并抑制启动子的转录。在激活状态，例如，在存在诱导剂如四环素(Tc)、无水四环素、多西环素(Dox)或其活性类似物的情况下，诱导剂会使TetR从TetO上释放，从而导致转录发生。多西环素是四环素抗生素家族中的一员，其化学名为1-二甲氨基-2,4a,5,7-五羟基-11-甲基-4,6-二氧基-1,4a,11,11a,12,12a-六氢四烯-3-甲酰胺。
在一个实施例中，TetR经密码子优化适用于在哺乳动物细胞中表达，例如小鼠或人类细胞。由于遗传密码的简并性，大多数氨基酸由不止一个密码子编码，从而使得给定核酸的序列具有大量的变体，而其编码的氨基酸序列没有任何改变。然而，许多生物体在密码子使用方面存在差异，也称为“密码子偏好”(即，给定氨基酸使用特定密码子的偏好)。密码子偏好通常与特定密码子的优势tRNA种类的存在有关，反过来又提高了mRNA翻译的效率。因此可以通过密码子优化来定制源自特定物种的编码序列(例如，原核生物)，以提高其在不同物种(例如，真核生物)中的表达。
Tet系统的其它具体变体，包括以下的“Tet-Off”和“Tet-On”系统。在Tet-off系统中，转录在Tc或Dox存在下是失活的。在该系统中，由TetR与单纯疱疹病毒VP16强转录激活结构域融合组成的四环素调控的转录激活蛋白(tTA)，在四环素反应启动子元件(TRE)转录控制下调控靶核酸的表达。TRE元件由TetO序列串联与启动子(通常是来源于人巨细胞病毒即刻早期启动子的最小启动子序列)融合组成。在不存在Tc或Dox的情况下，tTA结合TRE并激活靶基因的转录。在存在Tc或Dox的情况下，tTA不能结合TRE，靶基因不能表达。
相反，在Tet-On系统中，转录在Tc或Dox存在下是激活的。Tet-On系统是基于反向四环素调控的转录激活因子rtTA。与tTA一样，rtTA是由TetR阻遏物与VP16转录激活结构域组成的融合蛋白。然而，TetR的DNA结合区中4个氨基酸的变化改变了rtTA的结合特性，使其在存在Dox的情况下只能识别靶转基因TRE上的tetO序列。所以在Tet-On系统中，只有在存在Dox的情况下，rtTA才能激活TRE调控的靶基因的转录。
另一种诱导型启动子系统是大肠杆菌的lac阻遏物系统(参见Brown et al.,Cell 49:603-612(1987))。Lac阻遏物系统通过调控与包含lac操纵子(lacO)的启动子可操作性连接的目标多核苷酸的转录发挥功能。Lac阻遏物(lacR)与LacO结合，进而阻止目标多核苷酸的转录。通过合适的诱导剂来诱导目标多核苷酸的表达，例如，异丙基-β-D硫代半乳糖吡喃苷(IPTG)。
为了评估多肽或其部分的表达，待导入细胞的表达载体还可包含选择标记基因或报告基因或二者都有，以便于从病毒载体转染或感染的细胞群体中识别和选择表达细胞。在其他方面，选择标记可以携带在单独的DNA片段上并在共转染实验中使用。 选择标记基因或报告基因都可侧接于合适的调控序列，使其在宿主细胞中能够表达。有用的选择标记包括，例如，抗生素耐药基因，如neo以及类似基因。
报告基因可用于鉴定潜在的转染细胞和评价调控序列的功能。通常，报告基因是不存在于受体生物体或组织中或不由受体生物体或组织表达的基因，其编码一种多肽，其表达表现为一些易于检测的特性，例如酶活性。当DNA导入受体细胞后，在合适的时间检测报告基因的表达。合适的报告基因可包括编码荧光素酶、β-半乳糖苷酶、氯霉素乙酰转移酶、分泌碱性磷酸酶或绿色荧光蛋白的基因(参见,Ui-Tel et al.,2000 FEBS Letters 479:79-82)。合适的表达系统是公知的，可以通过已知的技术制备或通过商业途径获得。通常，把可显示报告基因最高表达水平的最小5’侧翼区的构建体认定为启动子。此类启动子区可以与报告基因连接，并用于评估某些物质在调节启动子驱动的转录中能力。
在一些实施例中，提供编码本文所述的任一种全长抗GDF15抗体的核酸。在一些实施例中，所述核酸包括编码全长抗GDF15抗体重链和轻链的一个或多个核酸序列。在一些实施例中，所述一个或多个核酸序列中的每一个包含在单独的载体中。在一些实施例中，至少有一些核酸序列包含在同一载体中。在一些实施例中，所有核酸序列包含在同一载体中。载体可以选自，例如，哺乳动物表达载体和病毒载体(如源自逆转录病毒、腺病毒、腺相关病毒、疱疹病毒和慢病毒的载体)。
将基因导入细胞并表达的方法在本领域是已知的。在涉及表达载体的上下文中，通过本领域的任何方法载体可以很容易地导入宿主细胞中，如哺乳动物细胞、细菌、酵母或昆虫细胞。例如表达载体可以通过物理、化学或生物方法导入宿主细胞。
将多核苷酸导入宿主细胞的物理方法包括磷酸钙沉淀、脂质体转染、基因枪法、显微注射、电穿孔法以及诸如此类。制备包含载体和/或外源核酸的细胞的方法在本领域是熟知的。参见例如Green and Sambrook(2013,Molecular Cloning:A Laboratory Manual,Cold Spring Harbor Laboratory,New York)。在一些实施例中，通过磷酸钙转染法将多核苷酸导入宿主细胞。
将目标多核苷酸导入宿主细胞的生物学方法包括使用DNA和RNA载体。病毒载体，特别是逆转录病毒载体，已成为将基因插入哺乳动物细胞，例如人类细胞中的最广泛使用的方法。其它病毒载体可以源自慢病毒、痘病毒、单纯疱疹病毒1型、腺病毒和腺相关病毒等。参见如U.S.Pat.Nos.5,350,674和5,585,362。
将多核苷酸导入宿主细胞的化学方法包括胶体分散系统，例如高分子复合物、纳米胶囊、微球、磁珠和以脂质为基础的系统，其包括水包油乳剂、胶团、混合胶团和脂质体。一种在体内和体外被用作递送载体的示例性胶体系统是脂质体(例如，人工膜囊)。
在使用非病毒递送系统的情况下，示例性的递送载体是脂质体。考虑使用脂质制剂将核酸导入宿主细胞(体外、离体或体内)。在另一方面，所述核酸可以与脂质结合。与脂质结合的核酸可被包裹进脂质体的水性内部，散布在脂质体的脂质双层内， 通过与脂质体和寡核苷酸结合的连接分子连接在脂质体，包埋在脂质体中，与脂质体形成复合物，分散在含有脂质的溶液中，与脂质混合，与脂质结合，悬浮在脂质中，包含在胶束中或与胶束混合，或以其它方式与脂质结合。脂质、脂质/DNA或脂质/表达载体相关的组合物在溶液中不限于任何特定结构。例如，它们可能以双分子层结构、以胶束或以“塌陷”结构存在。它们也可以简单的分散在溶液中，可能形成大小或形状不均匀的聚集体。脂质是脂肪物质，可以是天然存在的或是合成的脂质。例如，脂质包括天然存在于细胞质中的脂肪滴，以及含有长链脂肪烃及其衍生物的一类化合物，例如脂肪酸、醇、胺、氨基醇和醛。
无论采用何种方法将外源核酸导入宿主细胞中或以其他方式将细胞暴露于本申请的抑制剂中，为了确认重组DNA序列存在于宿主细胞中，可以进行多种实验。这类实验包括例如本领域技术人员熟知的“分子生物学”实验。例如Southern和Northern blotting，RT-PCR和PCR；“生物化学”实验，例如检测某一特定多肽存在或不存在，例如通过免疫学方法(ELISAs和Western blots)或者通过本文所述的实验来进行鉴定均落入本申请范围内。
抗GDF15抗体的制备
在一些实施例中，所述抗GDF15抗体是单克隆抗体或源于单克隆抗体。在一些实施例中，所述抗GDF15抗体包含来自单克隆抗体的VH和VL，或者其变体。在一些实施例中，所述抗GDF15抗体进一步包括来自单克隆抗体的CH1和CL区域，或者其变体。单克隆抗体可以应用例如本领域已知的方法制备，包括杂交瘤细胞法、噬菌体展示方法或应用重组DNA法。此外，示例性的噬菌体展示法在本文及以下的实施例中进行了描述。
在杂交瘤细胞法中，通常采用免疫剂免疫仓鼠、小鼠或其他适合的宿主动物，以引发产生或能够产生与免疫剂特异性结合的抗体的淋巴细胞。或者，可以在体外免疫淋巴细胞。免疫剂可包括目标蛋白的多肽或融合蛋白。通常，如果需要人源细胞，采用外周血淋巴细胞(PBLs)，而如果需要非人哺乳动物来源细胞，则会使用脾细胞或淋巴结细胞。使用适当的融合剂将淋巴细胞与永生细胞系进行融合，例如聚乙二醇，以形成杂交瘤细胞。永生细胞系通常是转化的哺乳动物细胞，尤其是啮齿类、牛科和人源的骨髓瘤细胞。通常采用大鼠或小鼠骨髓瘤细胞系。杂交瘤细胞可以在合适的培养基中进行培养，所述培养基优选含有一种或多种抑制未融合永生细胞生长或存活的物质。例如，如果亲本细胞缺乏次黄嘌呤-鸟嘌呤磷酸核糖转移酶(HGPRT或HPRT)，则杂交瘤细胞培养基通常包括次黄嘌呤、氨蝶呤和胸苷(HAT培养基)，该培养基能阻止HGPRT缺陷细胞生长。
在一些实施例中，永生化细胞系有效融合，通过所选择的抗体生产细胞保证抗体高水平稳定表达，并且对某些培养基敏感，例如HAT培养基。在一些实施例中，永生细胞系是小鼠骨髓瘤细胞系，可以从例如，加利福尼亚圣地亚哥的索尔克细胞保藏中 心和弗吉尼亚马纳萨斯的美国典型培养物保藏中心获得。同时还描述了人骨髓瘤和鼠-人杂交骨髓瘤细胞系用于制备人源单克隆抗体。
然后可以测定培养杂交瘤细胞的培养基中是否存在针对多肽的单克隆抗体。由杂交瘤细胞产生的单克隆抗体的结合特异性可以通过免疫沉淀法或体外结合实验确定，如放射性免疫测定法(RIA)或酶联免疫吸附法(ELISA)。此类技术或分析方法在本领域是已知的。单克隆抗体的结合亲和力可以通过例如Munson and Pollard,Anal.Biochem.,107:220(1980)中所述的斯卡查德(Scatchard)分析确定。
在鉴定出所需的杂交瘤细胞后，可以通过有限稀释法对目标克隆进行亚克隆，并通过标准方法进行培养。基于此目的适合的培养基包括，例如改良Eagle培养基(DMEM)和RPMI-1640培养基。或者，杂交瘤细胞可以在哺乳动物体内以腹水的形式生长。
亚克隆分泌的单克隆抗体可以通过常规免疫球蛋白纯化方法从培养基或腹水中分离或纯化，例如蛋白A-琼脂糖凝胶、羟基磷灰石色谱层析、凝胶电泳、透析或亲和层析。
在一些实施例中，根据本文所述的任一抗GDF15抗体，所述抗GDF15抗体包含选自抗体文库(例如展示scFv或Fab片段的噬菌体文库)的克隆的序列。所述克隆可以通过筛选具有所需活性的抗体片段组合文库的方法进行鉴定。例如，本领域已知多种方法用于产生噬菌体展示文库以及筛选这些文库来获得所需结合特性的抗体。这些方法在例如Hoogenboom et al.,Methods in Molecular Biology 178:1-37(O'Brien et al.,ed.,Human Press,Totowa,N.J.,2001)中进行了综述，并且在例如McCafferty et al.,Nature 348:552-554；Clackson et al.,Nature 352:624-628(1991)；Marks et al.,J.Mol.Biol.222:581-597(1992)；Marks and Bradbury,Methods in Molecular Biology 248:161-175(Lo,ed.,Human Press,Totowa,N.J.,2003)；Sidhu et al.,J.Mol.Biol.338(2):299-310(2004)；Lee et al.,J.Mol.Biol.340(5):1073-1093(2004)；Fellouse,Proc.Natl.Acad.Sci.USA 101(34):12467-12472(2004)；and Lee et al.,J.Immunol.Methods 284(1-2):119-132(2004)中进行了进一步描述。
在某些噬菌体展示方法中，通过聚合酶链式反应(PCR)分别克隆VH和VL基因的所有组成成分，并在噬菌体文库中随机重组，然后筛选能够结合抗原的噬菌体，如Winter et al.,Ann.Rev.Immunol.,12:433-455(1994)中所述。噬菌体通常以scFv片段或以Fab片段形式展示抗体片段。免疫来源的文库噬菌体提供针对免疫原的高亲和力抗体而不需要构建杂交瘤细胞。或者，可以克隆天然库(例如来自人)，来提供针对多种非自身抗原和自身抗原的单一抗体来源，而不需任何免疫，如Griffiths et al.,EMBO J,12:725-734(1993)中所述。最后，天然文库也可以通过克隆来自干细胞的非重排V-gene片段，并使用包含随机序列的PCR引物编码CDR3高变区并且在体外完成重排的方法进行制备，如Hoogenboom and Winter,J.Mol.Biol.,227:381-388(1992)中所述。描述人抗体噬菌体文库的专利出版物包括，例如U.S.Pat.No. 5,750,373和US Patent Publication Nos.2005/0079574、2005/0119455、2005/0266000、2007/0117126、2007/0160598、2007/0237764、2007/0292936和2009/0002360。
通过噬菌体展示筛选文库中能够特异性结合靶标GDF15的抗GDF15抗体部分的方法来制备所述的抗GDF15抗体。该文库可以是人scFv噬菌体展示文库，具有至少1×109(例如至少1×109、2.5×109、5×109、7.5×109、1×1010、2.5×1010、5×1010、7.5×1010或1×1011)种多样性的独特的人抗体片段。在一些实施例中，所述文库是人天然文库，通过从健康受试者的PMBCs和脾脏中提取的DNA构建，包含所有人重链和轻链亚家族。在一些实施例中，所述文库是人天然文库，通过从各种疾病患者体内分离的PMBCs中提取的DNA构建，例如自身免疫病的患者、癌症患者和感染性疾病的患者。在一些实施例中，所述文库是半合成的人文库，其中重链CDR3完全是随机的，所有氨基酸(除了半胱氨酸)以相同的概率存在于任何给定的位置。(参见例如,Hoet,R.M.et al.,Nat.Biotechnol.23(3):344-348,2005)。在一些实施例中，半合成的人文库的重链CDR3长度在5到24个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23或24个)氨基酸之间。在一些实施例中，所述文库是全合成的噬菌体展示文库。在一些实施例中，所述文库是非人噬菌体展示文库。
与靶标GDF15具有高亲和力的噬菌体克隆可以通过噬菌体与靶标GDF15的迭代结合进行筛选，所述靶标GDF15与固相支持物结合(例如用于溶液淘选的珠子或用于细胞淘选的哺乳动物细胞)，接下来去除未结合的噬菌体，并洗脱特异性结合噬菌体。随后，洗脱结合的噬菌体克隆并用于感染合适的宿主细胞，例如E.coli XL1-Blue，进行表达和纯化。可以通过多轮淘选(例如，2、3、4、5、6或更多轮)，例如溶液淘选、细胞淘选或两者结合以富集特异性结合GDF15的噬菌体克隆。富集的噬菌体克隆与靶标GDF15的特异性结合可以通过本领域已知的任何方法进行检测，包括例如ELISA和FACS。
筛选抗体文库的另一种方法是在酵母细胞表面展示蛋白质。Wittrup等(美国专利6,699,658和6,696,251)开发了一种酵母细胞展示文库的方法。在此酵母展示系统中，一个组分包括锚定在酵母细胞壁上的酵母凝集素蛋白(Aga1)，另一个组分包括凝集素蛋白Aga2的第二个亚基，该亚基可以通过二硫键与Aga1蛋白结合进而展示在酵母细胞表面上。通过将Aga1基因整合到酵母染色体中来表达Aga1蛋白。将单链可变片段(scFv)文库与酵母展示质粒中的Aga2基因融合，将其转化后，该文库由于附加的营养标记的存在可保留在酵母中。Aga1和Aga2蛋白均在半乳糖诱导型启动子的控制下表达。
人抗体V基因库(VH和VK片段)是使用一组简并引物通过PCR方法获得(Sblattero，D.and Bradbury,A.Immunotechnology 3,271-278 1998)。PCR模板来自可商购的RNA或cDNA，包括PBMC，脾脏，淋巴结，骨髓和扁桃体。将独立的VH和VK PCR文库合并后，通过重叠延伸PCR将其组装成scFv形式(Sheets，M.D.et al, Proc.Natl.Acad.Sci.USA 95,6157–6162 1998)。为了构建酵母scFv展示文库，通过同源重组将所得的scFv PCR产物克隆到酵母中的酵母展示质粒中。(Chao,G,et al,Nat Protoc.2006；1(2):755-68.Miller KD,et al.Current Protocols in Cytometry 4.7.1-4.7.30,2008)。
可以利用哺乳动物细胞展示系统来筛选抗GDF15抗体，其中抗体部分展示在细胞表面上并通过抗原导向的筛选方法分离出特异性靶向GDF15的抗体(如U.S.patent No.7,732,195B2中所述)。可以建立展示大量人类IgG抗体基因的中国仓鼠卵巢(CHO)细胞文库，并将其用于发现表达高亲和力抗体基因的克隆。已开发出另一种展示系统，该系统通过可变剪接使同一蛋白同时在细胞表面展示和分泌，其中展示的蛋白表型保持与基因型相关，使得可同时在生物物理和基于细胞功能的分析中表征该分泌的可溶性抗体。该方法克服了先前哺乳动物细胞展示的许多局限性，能够直接筛选和成熟化全长的、糖基化的IgGs形式的抗体(Peter M.Bowers,et al,Methods 2014,65：44-56)。瞬时表达系统适用于在抗体基因恢复之前进行的单轮抗原选择，因此对于从较小文库中选择抗体最有用。稳定的外显体载体提供了一种有吸引力的选择。外显体载体可以高效转染并稳定地维持在低拷贝数，从而允许多轮淘选以及更复杂抗体库的解析。
IgG文库是基于分离自一群人类供体的种系序列V基因片段与重排的(D)J区域的连接构建而成。将从2000个人体血液样本中收集的RNA反转录为cDNA，使用VH和VK特异性引物扩增VH和VK片段，并通过凝胶提取纯化。将VH和VK片段分别亚克隆到包含IgG1或K恒定区的展示载体中，然后电穿孔或转导293T到细胞，从而制备IgG文库。为了制备scFv抗体展示文库，连接VH和VK以产生scFv，然后亚克隆到展示载体中，再将其电穿孔或转导293T细胞。众所周知，IgG文库是基于分离自一群供体的种系序列V基因片段与重排的(D)J区域构建而成，供体可以是小鼠，大鼠，兔或猴。
单克隆抗体也可以通过重组DNA方法进行制备，例如U.S.Patent No.4,816,567中所述。编码本申请中所述单克隆抗体的DNA可以通过常规方法(例如通过能特异性结合编码鼠源抗体轻链和重链基因的寡聚核苷酸探针)轻易的分离和测序。如上所述的杂交瘤细胞或本申请的GDF15特异性噬菌体克隆可以作为这种DNA的来源。分离后，可将DNA置于表达载体中，然后该载体转染入宿主细胞，例如猿猴COS细胞、中华仓鼠卵巢癌(CHO)细胞或不产生免疫球蛋白的骨髓瘤细胞中，获得在重组宿主细胞中合成的单克隆抗体。所述DNA也可以被修饰，例如用编码序列取代人重链和轻链恒定区和/或用框架区替换同源非人序列(U.S.Patent No.4,816,567；Morrison et al.,supra)，或通过共价键连接免疫球蛋白的编码序列的全部或部分非免疫球蛋白多肽的编码序列。这种非免疫球蛋白多肽可以取代本申请中抗体的恒定区，或可以取代本申请中抗体可变结构域中的一个抗原结合位点，形成嵌合的二价抗体。
所述抗体可以是单价抗体。制备单价抗体的方法是本领域已知的。例如，一种涉及免疫球蛋白轻链和修饰重链的重组表达方法。通常在Fc区的任意位置截短重链，以阻止重链相互交联。或者，相关的半胱氨酸残基被其它氨基酸残基取代或被缺失以防止交联。
体外方法也适用于制备单价抗体。消化抗体产生抗体片段，特别是Fab片段，可以使用任何本领域已知的方法完成。
具有所需结合特异性(抗体-抗原结合位点)的抗体可变结构域可以与免疫球蛋白恒定区融合。优选与免疫球蛋白重链恒定区进行融合，其包括至少部分铰链，CH2和CH3区。在一些实施例中，包含轻链结合必要位点的第一重链恒定区(CH1)至少出现在一种融合体中。编码免疫球蛋白重链融合体的DNA，如果需要，还可以包括编码免疫球蛋白轻链的DNA，被插入进独立的表达载体中，并共转染至合适的宿主生物中。
全人和人源化抗体
所述抗GDF15抗体(如全长的抗GDF15抗体)可以是全人抗体或人源化抗体。非人(如小鼠)抗体部分的人源化形式是嵌合的免疫球蛋白、免疫球蛋白链或其片段(例如Fv、Fab、Fab’、F(ab’)2、scFv或抗体的其他抗原结合子序列)，其通常包括最少的源于非人免疫球蛋白的序列。人源化抗体包括人免疫球蛋白、免疫球蛋白链或其片段(受体抗体)，其中受体CDR的残基被具有所需特异性、亲和力和性能的非人源(供体抗体)CDR残基取代，例如小鼠、大鼠或兔子的CDR。在一些实施例中，人免疫球蛋白Fv框架区残基被相应的非人源残基取代。人源化抗体还可以包含既不属于受体抗体也不在引入的CDR或框架区序列中的氨基酸残基。通常，人源化抗体包含至少一个，通常两个可变结构域，其中全部或基本上全部CDR区对应于非人免疫球蛋白的CDR区，全部或基本上全部框架区是人免疫球蛋白共有序列。
通常，人源化抗体含有一个或多个从非人源引入的氨基酸残基。那些非人源氨基酸残基通常被称为“移入”残基，通常来自“移入”可变结构域。根据一些实施例，人源化基本上可以按照Winter和其同事的如下方法进行(Jones et al.,Nature,321:522-525(1986)；Riechmann et al.,Nature,332:323-327(1988)；Verhoeyen et al.,Science,239:1534-1536(1988))，通过用啮齿动物CDRs或CDR序列取代人源抗体的相应序列。因此，这种“人源化”抗体部分(U.S.Patent No.4,816,567)，其基本上少于完整的人源抗体，其可变结构域已被来自非人源的相应序列所取代。在实际中，人源化抗体部分是典型的人源抗体部分，其中一些CDR残基和可能的一些框架区残基被来自啮齿类抗体中类似位点的残基所取代。
全人抗体是人源化的一种替代方式。例如，目前可以制备在免疫后能够产生完整的全人抗体文库而不产生内源性免疫球蛋白的转基因动物(例如，小鼠)。例如，已有报道，嵌合和种系突变小鼠中抗体重链连接区(JH)基因的纯合子缺失，完全抑制 了内源性抗体的产生。将人种系免疫球蛋白基因阵列转移到这种种系突变小鼠体内，可在抗原刺激下产生人源抗体，参见，例如akobovits et al.,PNAS USA,90:2551(1993)；Jakobovits et al.,Nature,362:255-258(1993)；Bruggemann et al.,Year in Immunol.,7:33(1993)；U.S.Patent Nos.5,545,806,5,569,825,5,591,669,5,545,807；和WO 97/17852。或者，可以通过将人类免疫球蛋白基因座引入转基因动物中(例如内源性免疫球蛋白基因已经被部分或全部沉默的小鼠)来制备全人抗体。抗原刺激后，可以发现全人抗体的产生在各个方面都与其在人类中的产生非常相似，包括基因重排、组装和抗体文库。这种方法在例如U.S.Patent Nos.5,545,807；5,545,806；5,569,825；5,625,126；5,633,425；and 5,661,016,and Marks et al.,Bio/Technology,10:779-783(1992)；Lonberg et al.,Nature,368:856-859(1994)；Morrison,Nature,368:812-813(1994)；Fishwild et al.,Nature Biotechnology,14:845-851(1996)；Neuberger,Nature Biotechnology,14:826(1996)；Lonberg and Huszar,Intern.Rev.Immunol.,13:65-93(1995)中进行了描述。
全人抗体也以通过体外活化B细胞(见U.S.Patents 5,567,610and 5,229,275)或通过使用本领域已知的各种技术来产生，包括噬菌体展示文库。Hoogenboom and Winter,J.Mol.Biol.,227:381(1991)；Marks et al.,J.Mol.Biol.,222:581(1991).Cole et al.和Boerner et al.等人的技术也可以用于制备全人单克隆抗体。见Cole et al.,Monoclonal Antibodies and Cancer Therapy,Alan R.Liss,p.77(1985)and Boerner et al.,J.Immunol.,147(1):86-95(1991)。
抗GDF15抗体变体
在一些实施例中，本文提供的抗GDF15抗体变体(例如，全长的抗GDF15抗体)的氨基酸序列也在考虑中。例如，可能需要改善抗体的结合亲和力和/或其它生物学活性。抗体变体的氨基酸序列可以通过在编码抗体的核苷酸序列中引入适当的修饰或通过肽合成来制备。此类修饰包括例如，抗体氨基酸序列中残基的缺失和/或插入和/或取代。可以通过氨基酸残基缺失、插入和取代的任一组合来完成最终的构建，使其具有所需的特征。例如，抗原结合性。
在一些实施例中，提供具有一个或多个氨基酸取代的抗GDF15抗体变体。取代突变的目标位点包括高变区(HVRs)和框架区(FRs)。可以在目标抗体中引入氨基酸取代，筛选所需活性的产物，例如，改善的生物活性，保持/改善抗原结合能力，降低的免疫原性，或改善的ADCC或CDC。
保守取代如下表4所示。
表4保守取代

根据侧链性质将氨基酸分为不同类别：
a、疏水氨基酸：去甲亮氨酸Norleucine、蛋氨酸Met、丙氨酸Ala、缬氨酸Val、亮氨酸Leu、异亮氨酸Ile；
b、中性亲水性氨基酸：半胱氨酸Cys、丝氨酸Ser、苏氨酸Thr、天冬酰胺Asn、谷氨酰胺Gln；
c、酸性氨基酸：天冬氨酸Asp、谷氨酸Glu；
d、碱性氨基酸：组氨酸His、赖氨酸Lys、精氨酸Arg；
e、含有影响链方向的氨基酸：甘氨酸Gly、脯氨酸Pro；
f、芳香族氨基酸：色氨酸Trp、酪氨酸Tyr、苯丙氨酸Phe。
非保守氨基酸的取代包含将以上一种类别取代为另一种类别。
一种示例性的取代变体是亲和力成熟的抗体，可采用例如以噬菌体展示为基础的亲和力成熟技术而方便地产生。简言之，将一个或多个CDR残基进行突变，变体抗体部分展示在噬菌体上，并筛选具有特定生物活性(例如，基于GFRAL/RET下游信号抑制实验或结合亲和力的生物学活性)的变体。可以在HVRs区进行改变(例如，取代)来获得改善的基于GFRAL/RET下游信号抑制实验或结合亲和力的生物学活性。可以在HVR的“热点区”产生改变，即在体细胞成熟过程中发生高频突变的密码子编码的残基(参见，例如Chowdhury,Methods Mol.Biol.207:179-196(2008))，和/或在特异的决定性残基(SDRs)，检测所得变体VH和VL的结合亲和力。从二级文库中构 建和重新选择亲和力成熟的方法已经在一些文献中进行描述，例如，Hoogenboom et al.in Methods in Molecular Biology 178:1-37(O'Brien et al.,ed.,Human Press,Totowa,NJ,(2001))。
在一些亲和力成熟的实施例中，通过多种方法中的任一种(例如易错PCR，链改组或寡核苷酸定向突变)，将多样性引入选择的用于亲和力成熟的可变基因中。然后创建二级文库。对该文库进行筛选，鉴定出具有所需亲和力的抗体变体。另一种引入多样性的方法包括HVR介导的方式，其中几个HVR残基(例如，一次4-6个残基)被随机化。涉及抗原结合的HVR残基被特异性地识别，例如，采用丙氨酸扫描诱变或建模。通常CDR-H3和CDR-L3区域尤其是重点靶标。
在一些实施例中，取代、插入或缺失可能发生在一个或多个HVRs内，只要这种改变基本上不降低抗体结合抗原的能力。例如，可以在HVRs中产生基本上不降低结合亲和力的保守性改变(例如，本文中提供的保守性取代)。这些改变可能发生在HVR“热点区”或SDRs区域之外。在一些实施例中上文提供的变体VH和VL序列，每一个HVR或者是未发生改变，或者包含不超过1个、2个或3个氨基酸取代。
一种有用的可以鉴定出抗体中能被靶向性突变的氨基酸残基或区域的方法称为“丙氨酸扫描突变”，如Cunningham and Wells(1989)Science,244:1081-1085中所述。在该方法中，一个或一组目标残基(例如，带电残基如精氨酸、天冬氨酸、组氨酸、赖氨酸和谷氨酸)被中性或带负电荷氨基酸(例如，丙氨酸或谷氨酸)取代，以此来确定抗体与抗原相互作用是否受到影响。可以在氨基酸的位置进一步引入取代，来证明该位置对初始取代具有功能敏感性。或者/另外，通过抗原-抗体复合物的晶体结构来鉴定抗体和抗原之间的接触位点。这些接触位点残基和邻近残基可作为取代候选物而被靶向或消除。筛选变体，确定它们是否具有所需要的性质。
氨基酸序列的插入，包括在氨基端和/或羧基末端的融合，长度范围从1个残基到包含100个或更多个残基的多肽，还包括在序列内插入1个或多个氨基酸残基。末端插入的例子包括N末端具有甲硫氨酰残基的抗体。抗体分子的其它插入变体，包括在抗体分子N-末端或C-末端融合一个酶(例如，ADEPT)或增加抗体血清半衰期的多肽。
Fc区变体
在一些实施例中，将一个或多个氨基酸修饰引入本文所述的抗体(例如，全长抗GDF15抗体或抗GDF15抗体融合蛋白)的Fc区，从而产生Fc区变体。在一些实施例中，Fc区变体具有增强的ADCC效能，通常与结合Fc的受体(FcRs)有关。在一些实施例中，Fc区变体具有降低的ADCC效能。有很多关于Fc序列的改变或突变影响其效能的例子，例如，WO 00/42072和Shields et al.J Biol.Chem.9(2):6591-6604(2001)描述了与FcRs的结合增强或减弱的抗体变体。这些出版物的内容通过引用并入本文。
抗体依赖的细胞介导的细胞毒作用(ADCC)是治疗性抗体针对肿瘤细胞的作用机制。ADCC是细胞介导的免疫防御，当靶细胞膜表面的抗原被特异性抗体(例如，抗GDF15抗体)结合，免疫系统的效应细胞主动裂解靶细胞(例如，癌细胞)。通常ADCC效应涉及由抗体激活的NK细胞。NK细胞表达Fc受体CD16。该受体识别并结合与靶细胞表面相结合的抗体分子的Fc部分。NK细胞表面最常见的Fc受体为CD16或FcγRIII。Fc受体与抗体Fc区的结合导致NK细胞的活化，释放细胞裂解颗粒，随后靶细胞凋亡。ADCC对肿瘤细胞的杀伤作用可以通过转染高亲和力FcR的NK-92细胞的特异性实验来测定。其结果与不表达FcR的野生型NK-92进行比较。
在一些实施例中，本申请还提供抗GDF15抗体变体(例如全长抗GDF15抗体变体)，其包含具有部分但不是全部的效应功能Fc区，使得其在体内具有延长的半衰期，然而特定的效应功能(例如CDC或ADCC)是非必需的或有害的，这种抗GDF15抗体成为本申请理想的候选。通过在体外和/或体内进行细胞毒性检测来确认CDC和/或ADCC活性的减少/消除。例如，通过Fc受体(FcR)结合试验来确认抗体缺乏FcγR结合能力(因此可能缺乏ADCC活性)但依然保留FcRn的结合能力。介导ADCC的主要细胞中，NK细胞仅表达FcγRIII，而单核细胞表达FcγRI、FcγRII和FcγRIII。Ravetch and Kinet Annu.Rev.Immunol.9:457-492(1991)第464页的表3中总结了FcR在造血细胞上的表达。在体外评估目标分子的ADCC活性的非限制性实例在U.S.Pat.No.5,500,362中进行了描述(参见例如Hellstrom,I.et al.Proc.Nat'l Acad.Sci.USA 83:7059-7063(1986)and Hellstrom,I et al.,Proc.Nat'l Acad.Sci.USA 82:1499-1502(1985)；U.S.Pat.No.5,821,337(see Bruggemann,M.et al.,J.Exp.Med.166:1351-1361(1987))。或者，可以采用非放射性检测方法(参见，例如ACTITM流式细胞术非放射性细胞毒性检测(CellTechnology,Inc.Mountain View,Calif.)和CYTOTOX 96TM非放射性细胞毒性检测(Promega,Madison,Wis.))。此类检测实验采用的效应细胞包括外周血单核细胞(PBMC)和自然杀伤细胞(NK)。或者，另外地，目标分子的ADCC活性在体内进行检测，例如，在动物模型中，如Clynes et al.Proc.Nat'l Acad.Sci.USA 95:652-656(1998)中所述。同时还可以进行C1q结合试验来确认抗体不能与C1q结合，从而缺乏CDC活性。参见，例如WO 2006/029879和WO 2005/100402中C1q和C3c结合ELISA。为了评估补体激活情况，可进行CDC检测(参见，例如Gazzano-Santoro et al.,J.Immunol.Methods 202:163(1996)；Cragg,M.S.et al.,Blood 101:1045-1052(2003)；和Cragg,M.S.and M.J.Glennie,Blood 103:2738-2743(2004))。使用本领域已知的方法来测定FcRn结合和体内清除/半衰期(参见，例如，Petkova,S.B.et al.,Int'l.Immunol.18(12):1759-1769(2006))。
具有降低的效应功能的抗体，包括在Fc区残基238、265、269、270、297、327和329位进行一个或多个残基的取代(U.S.Pat.No.6,737,056)。这些Fc变体包括在265、269、270、297和327位进行两个或多个残基的取代的Fc变体，包括被称为 “DANA”的Fc变体，其在265和297位残基取代为丙氨酸(U.S.Pat.No.7,332,581)。
这类与FcRs结合能力提高或降低的抗体变体已有描述(参见例如U.S.Pat.No.6,737,056；WO 2004/056312，和Shields et al.,J.Biol.Chem.9(2):6591-6604(2001))。
在一些实施例中，提供一种抗GDF15抗体(例如全长的抗GDF15抗体)变体，其包含具有一个或多个能够增强ADCC效应的氨基酸取代的Fc区变体。在一些实施例中，Fc区变体包含一个或多个能够增强ADCC效应的氨基取代，这些取代的位置在Fc区的298、333和/或334位(EU残基编号)。在一些实施例中，所述抗GDF15抗体(例如，全长的抗GDF15抗体)变体包括在Fc区的S298A，E333A和K334A位氨基酸取代。
在一些实施例中，Fc区的改变导致C1q结合和/或补体依赖性细胞毒作用(CDC)的改变(即增强或减弱)，参见U.S.Pat.No.6,194,551,WO 99/51642，和Idusogie et al.,J.Immunol.164:4178-4184(2000)中所述。
在一些实施例中，提供一种抗GDF15抗体(例如全长的抗GDF15抗体)变体，其包含具有一个或多个氨基酸取代的Fc区变体，能够延长半衰期或增强与Fc受体(FcRn)的结合。具有延长半衰期和改善FcRn结合的抗体在US 2005/0014934A1(Hinton等)中有所描述。这些抗体Fc区包含一个或多个氨基酸取代，增强了Fc区与FcRn的结合。这些Fc变体在Fc区包含238、256、265、272、286、303、305、307、311、312、317、340、356、360、362、376、378、380、382、413、424或434位的残基中的一个或多个取代，例如Fc区434位残基的取代(U.S.Pat.No.7,371,826)。
同时参见Duncan&Winter,Nature 322:738-40(1988)；U.S.Pat.No.5,648,260；U.S.Pat.No.5,624,821和WO 94/29351中提供其它Fc区变体的例子。
本申请考虑了包括本文所述的任一种Fc变体或其组合的抗GDF15抗体(例如全长抗GDF15抗体)。
糖基化变体
在一些实施例中，对本文所提供的抗GDF15抗体(例如全长抗GDF15抗体)进行改变，以增加或降低抗NGF抗体糖基化的程度。通过改变抗NGF抗体或其多肽部分的氨基酸序列以此来增加或去除一个或多个糖基化位点，可以方便地实现添加或删除抗GDF15抗体上的糖基化位点。
其中抗GDF15抗体包含Fc区，可以改变与其连接的糖。由哺乳动物细胞产生的天然抗体通常包含分支的双触角寡糖，该寡糖通常通过N-连接与Fc区CH2结构域Asn297连接，参见例如Wright et al.，TIBTECH 15:26-32(1997)。所述寡糖可包含多种糖类，例如甘露糖、N-乙酰氨基葡萄糖苷(GlcNAc)、半乳糖和唾液酸，以及与 双触角寡糖结构“茎”部的GlcNAc相连接的海藻糖。在一些实施例中，可对本申请的抗GDF15抗体进行寡糖修饰，从而产生具有某些改进特性的抗GDF15抗体变体。
与Fc区的CH2结构域连接的N-聚糖是异质的。CHO细胞中产生的抗体或Fc融合蛋白通过岩藻糖基转移酶活性被岩藻糖基化，参见Shoji-Hosaka et al.,J.Biochem.2006,140:777-83。通常，可以在人血清中检测出一小部分天然存在的非岩藻糖基化IgGs。Fc区的N-糖基化对于其与FcγR结合很重要；而非岩藻糖基化的N-聚糖增强了Fc与FcγRIIIa的结合能力。与FcRIIIa结合能力增强使得ADCC效应增强，这在需要细胞毒性的某些抗体治疗应用中是有利的。
在一些实施例中，当不需要Fc介导的细胞毒作用时，增强的效应功能可能是有害的。在一些实施例中，Fc片段或CH2结构域是非糖基化的。在一些实施例中，通过对CH2结构域中的N-糖基化位点进行突变以阻止其糖基化。
在一些实施例中，提供抗GDF15抗体(例如全长的抗GDF15抗体)变体，其包含Fc区，其中连接于Fc区的糖类结构具有减少的岩藻糖或缺乏岩藻糖，这可能会增强ADCC功能。具体地，本文提供抗GDF15抗体，其相对于野生型CHO细胞产生的相同抗GDF15抗体具有减少的岩藻糖。也就是说，它们的特征在于，与天然CHO细胞(例如，产生天然糖基化形式的CHO细胞，含有天然FUT8基因的CHO细胞)产生的抗体相比，具有更少量的岩藻糖。在一些实施例中，所述抗GDF15抗体的N-连接聚糖具有少于50％、40％、30％、20％、10％或5％的岩藻糖。例如，该抗GDF15抗体的岩藻糖含量可能是1％-80％、1％-65％、5％-65％或20％-40％。在一些实施例中，所述抗GDF15抗体的N-连接聚糖不包含岩藻糖，即，其中抗GDF15抗体完全不含岩藻糖，或没有岩藻糖或是去岩藻糖基化。岩藻糖的含量是通过计算连接到Asn297上的糖链内岩藻糖平均含量相对于通过MALDI-TOF质谱测量的所有连接在Asn297上的糖结构(如复合、杂交或甘露糖结构)的总量来确定的，如WO 2008/077546所述。Asn297是指位于Fc区297位的天冬酰胺残基(EU Fc区残基编号体系)。然而，由于抗体的微小序列变化，Asn297也可位于297位的上游或下游±3个氨基酸，即在294和300位之间。这些岩藻糖基化变体可能具有增强的ADCC功能。参见例如US Patent Publication Nos.US 2003/0157108(Presta,L.)，US 2004/0093621(Kyowa Hakko Kogyo Co.,Ltd)。与“去岩藻糖基化”或“岩藻糖缺乏”的抗体变体相关的出版物的实例包括，US 2003/0157108；WO 2000/61739；WO 2001/29246；US 2003/0115614；US 2002/0164328；US 2004/0093621；US 2004/0132140；US 2004/0110704；US 2004/0110282；US 2004/0109865；WO 2003/085119；WO 2003/084570；WO 2005/035586；WO 2005/035778；WO 2005/053742；WO 2002/031140；Okazaki et al.J.Mol.Biol.336:1239-1249(2004)；Yamane-Ohnuki et al.Biotech.Bioeng.87:614(2004)。能够产生去岩藻糖基化抗体的细胞系包括缺乏蛋白岩藻糖基化功能的Lec13CHO细胞(Ripka et al.Arch.Biochem.Biophys.249:533-545(1986)；US Pat Appl No US 2003/0157108A1,Presta,L；和WO 2004/056312A1,Adams et al.,尤其是实 施例11)，和基因敲除细胞系，例如α-1,6-岩藻糖基转移酶基因，FUT8基因敲除的CHO细胞(参见Yamane-Ohnuki et al.Biotech.Bioeng.87:614(2004)；Kanda,Y.et al.,Biotechnol.Bioeng.,94(4):680-688(2006)；和WO2003/085107)。
抗GDF15抗体(例如全长抗GDF15抗体)变体进一步提供二等分寡糖，例如，其中连接于抗GDF15抗体Fc区的双触角寡糖被GlcNAc等分。这种抗GDF15抗体(例如全长的抗GDF15抗体)变体可能具有减少的岩藻糖基化和/或增强的ADCC功能。这类抗体变体的实例在WO 2003/011878(Jean-Mairet et al.)；U.S.Pat.No.6,602,684(Umana et al.)；US 2005/0123546(Umana et al.)，和Ferrara et al.,Biotechnology and Bioengineering,93(5):851-861(2006)中有所描述。还提供抗GDF15抗体(例如全长的抗GDF15抗体)变体，其在与Fc区连接的寡糖中具有至少一个半乳糖残基。这类抗GDF15抗体变体可能具有增强的CDC功能。这类变体在例如WO1997/30087(Patel et al.)；WO 1998/58964(Raju,S.)；和WO 1999/22764(Raju,S.)中有所描述。
在一些实施例中，所述抗GDF15抗体(例如全长抗GDF15抗体)变体包含能与FcγRIII结合的Fc区。在一些实施例中，包含Fc区的所述抗GDF15抗体(例如全长抗GDF15抗体)变体在人效应细胞(例如T细胞)存在下具有ADCC活性，或者与具有人野生型IgG1Fc区的其他相同抗GDF15抗体(例如全长抗GDF15抗体)相比，在人效应细胞存在下，具有增强的ADCC活性。
半胱氨酸工程变体
在一些实施例中，需要制备半胱氨酸工程化的抗GDF15抗体(例如全长抗GDF15抗体)，在该抗体中一个或多个氨基酸残基被半胱氨酸残基取代。在一些实施例中，取代残基出现在抗GDF15抗体的可及位点。通过用半胱氨酸取代那些残基，具有活性的巯基基团位于抗GDF15抗体的可及位点，可以用于将该抗GDF15抗体与其它部分偶联，例如药物部分或接头-药物部分，来制备如本文中进一步描述的抗GDF15免疫偶联物。半胱氨酸工程化的抗GDF15抗体(例如，全长抗GDF15抗体)可以按照例如U.S.Pat.No.7,521,541所述进行制备。
衍生物
在一些实施例中，本文所提供的抗GDF15抗体(例如全长抗GDF15抗体)可进一步修饰以包含本领域已知并且容易获得的其它非蛋白部分。适用于衍生化抗GDF15抗体的部分包括，但不限于，水溶性聚合物。水溶性聚合物的非限制性实例包括，但不限于，聚乙二醇(PEG)、乙二醇/丙二醇共聚物、羧甲基纤维素、右旋糖酐、聚乙烯醇、聚乙烯吡咯烷酮、聚-1,3-二氧戊烷、聚-1,3,6-三氧杂环已烷、乙烯/马来酸酐共聚物、聚氨基酸(均聚物或无规共聚物)、右旋糖酐或聚(n-乙烯基吡咯烷酮)聚乙二醇、丙二醇均聚物、环氧丙烷/环氧乙烷共聚物、聚氧乙基化多元醇(例如甘油)、聚乙烯醇及其混合物。聚乙二醇丙醛由于其在水中的稳定性，在制造中具有优势。聚合物可以具有任意分子量，可以是支链或非支链的。连接在抗GDF15抗体上的聚合物 数量可以变化，并且如果连接多于一个多聚物，它们可以是相同的或不同的分子。通常，用于衍生化的聚合物的数量和/或类型可基于以下考虑因素来确定，包括但不限于，需要改进抗GDF15抗体的特性或功能，抗GDF15抗体衍生物是否用于特定条件下的治疗等。
药物组合物
本文还提供包含任一种抗GDF15抗体(例如全长抗GDF15抗体)、编码抗体的核酸、包含编码抗体的核酸的载体或者包含本文所述的核酸或载体的宿主细胞的组合物(例如药物组合物，在这里也称为制剂)。在一些实施例中，提供一种药物组合物，包含本文所述的任一种抗GDF15抗体和药学上可接受的载体。
可通过混合具有所需纯度的抗GDF15抗体与任选的药学上可接受的载体、赋形剂或稳定剂(Remington's Pharmaceutical Sciences 16th edition,Osol,A.Ed.(1980))获得合适的抗GDF15抗体制剂，制备成冻干制剂或液体制剂形式。可接受的载体、赋形剂或稳定剂在所用剂量和浓度下对接受者无毒，包括缓冲剂如：磷酸盐、柠檬酸和其它有机酸；抗氧化剂，包括抗坏血酸和蛋氨酸；防腐剂(例如十八烷基二甲基苄基氯化铵；六甲基氯化铵；苯扎氯铵；苄索氯铵；苯酚；丁醇或苄醇；对羟基苯甲酸烷基酯，如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯；邻苯二酚；间苯二酚；环己醇；3-戊醇和间甲酚)；低分子量(少于10个残基)多肽；蛋白质，例如血清白蛋白、明胶或免疫球蛋白；亲水性聚合物，如聚乙烯吡咯烷酮；氨基酸，例如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸；单糖、二糖和其它碳水化合物，包括葡萄糖、甘露糖或糊精；螯合剂如EDTA；糖类，如蔗糖、甘露醇、海藻糖或山梨糖醇；成盐反离子如钠；金属复合物(如锌-蛋白复合物)；和/或非离子表面活性剂如TWEENTM，PLURONICSTM或聚乙二醇(PEG)；示例性制剂如WO98/56418中所述，并通过引用明确并入本文。适合皮下给药的冻干制剂在WO97/04801中有所描述。这类冻干制剂可通过合适的稀释剂重构成高蛋白浓度的制剂，并且重构的制剂可以通过皮下给药的方式给予本文中待治疗个体。阳离子脂质体或脂质体可以用于将本申请中的抗GDF15抗体递送至细胞。
本文所述的制剂除包含抗GDF15抗体(例如全长抗GDF15抗体)之外，还可以包含一种或多种治疗特定病症所必要的其它活性物质，优选具有活性互补且彼此无不良反应的物质。例如，除了抗GDF15抗体之外，可能需要进一步包含抗癌剂，免疫刺激剂，化学治疗试剂，活化素A或活化素A受体ActRIIB的抑制剂(如抗活化素A抗体或其抗原结合片段、抗ActRIIB抗体或抗原结合片段、活化素A的小分子抑制剂、ActRIIB的小分子抑制剂，以及ActRIIB的诱饵受体如可溶性ActRIIB受体、可溶性ActRIIB受体与Fc分子的融合物)，IL-6或IL-6受体IL-6R的抑制剂(如抗IL-6抗体或其抗原结合片段、抗IL-6R抗体或其抗原结合片段、IL-6的小分子抑制剂、IL-6R的小分子抑制剂、以及IL-6R的诱饵受体如可溶性IL-6R受体、可溶性IL-6R受体与Fc 分子的融合物)，TNFα或IL-1的抑制剂(如抗TNFα抗体或其抗原结合片段、抗IL-1抗体或其抗原结合片段、TNFα或IL-1的小分子抑制剂、以及TNFα或IL-1的诱饵受体如可溶性TNFα或IL-1受体、可溶性TNFα或IL-1与Fc分子的融合物)，生长素释放肽，黑皮质素肽抑制剂等。这些分子以对预期目的有效的量组合存在。其它物质的有效量取决于制剂中的抗GDF15抗体的含量，疾病或病症或治疗的类型，以及如上所述的其它因素。这些药物通常以与本文描述的相同剂量和给药途径使用，或者以目前应用剂量的1％至99％使用。
所述抗GDF15抗体(例如，全长抗GDF15抗体)也可以包埋在例如通过凝聚技术和界面聚合制备的微胶囊中，例如分别在胶体药物递送系统(例如，脂质体、白蛋白微球、微乳液、纳米颗粒和纳米胶囊)中或粗乳液中的羟甲基纤维素或明胶-微胶囊和聚(甲基丙烯酸甲酯)微胶囊。可以制备缓释制剂。
可以制备抗GDF15抗体(例如，全长抗GDF15抗体)的缓释制剂。缓释制剂的适合的实例包括含有抗体(或其片段)的固体疏水聚合物半透性基质，这些基质是成型制品的形式，例如，薄膜或微胶囊。缓释基质的实例包括聚酯、水凝胶(例如，聚(2-羟乙基甲基丙烯酸酯)或聚(乙烯醇))、聚乳酸(U.S.Pat.No.3,773,919)，L-谷氨酸和L-谷氨酸乙酯共聚物，不可降解的乙烯-醋酸乙烯酯，可降解的乳酸-乙醇酸共聚物如LUPRON DEPOTTM(由乳酸-乙醇酸共聚物和醋酸亮丙瑞林组成的可注射微球)以及聚-D(-)-3-羟基丁酸。虽然诸如乙烯-醋酸乙烯酯和乳酸-乙醇酸之类的聚合物可以使分子的释放超过100天，某些水凝胶可以在更短的时间内释放蛋白质。当包封的抗体在体内长时间停留时，它们会因暴露于37℃的潮湿环境中发生变性或聚集，可能导致生物活性的丧失或免疫原性的改变。可以根据相应的机制，设计合理的策略来稳定抗GDF15抗体。例如，如果发现聚集机制是通过硫代二硫化物交换形成分子间S-S键，则可以通过修饰巯基残基、在酸性溶液中冻干、控制含水量、使用适当的添加剂、以及开发特定的聚合物基质组合物来实现稳定化。
在一些实施例中，所述抗GDF15抗体(例如全长抗GDF15抗体)配制在含有柠檬酸盐、氯化钠、乙酸盐、琥珀酸盐、甘氨酸、聚山梨酯80(吐温80)或上述任何组合的缓冲液中。
用于体内给药的制剂必须是无菌的。这可以通过例如应用无菌过滤膜过滤而容易地实现。
使用抗GDF15抗体的治疗方法
抗GDF15抗体(例如，全长的抗GDF15抗体)和/或本申请所述的组合物可以施用于个体(例如，哺乳动物，如人类)来治疗与GDF15信号通路失调导致的疾病和/或病症(例如，癌症，恶液质，代谢性疾病)，这些疾病包括但不限于癌症(如脑癌、黑素瘤、肺癌、胃肠道肿瘤、结肠癌、胰腺癌、前列腺癌、乳腺癌、口腔癌、肝癌、白血病、霍奇金淋巴瘤，非霍奇金淋巴瘤、膀胱癌、子宫颈癌、子宫体癌、睾丸 癌，甲状腺癌、肾癌、胆囊癌、多发性骨髓瘤、鼻咽癌、喉癌、咽癌，食道癌等)，恶液质，肾衰竭、脓毒症、AIDS、慢性阻塞性肺病引起的恶液质，恶液质相关的体重减少，放疗、化疗引起的恶心呕吐，晚期慢性小管间质性肾炎，孕吐，肝硬化，肌少症，代谢性疾病(如脂肪和能量代谢失衡、调节食欲、调节体重)。因此，本申请在一些实施例中，提供一种治疗GDF15信号通路失调导致的疾病和/或病症(例如，癌症，恶液质，代谢性疾病)的方法，包括向个体施用有效量的包含抗GDF15抗体(例如，全长的抗GDF15抗体)的组合物(例如，药物组合物)，例如本文所述的任一种抗GDF15抗体(例如，全长的抗GDF15抗体)，在一些实施例中，所述个体是人类。
例如，在一些实施例中，提供一种用于治疗与GDF15信号通路相关的疾病(例如，癌症，恶液质，代谢性疾病)的个体的方法，包括向所述个体施用有效量的包含特异性结合人GDF15上表位的GDF15抗体(例如，全长抗GDF15抗体)的药物组合物，其中所述表位包含人GDF15的位氨基酸残基。在一些实施例中，所述抗GDF15抗体是全长抗体。在一些实施例中，所述全长抗GDF15抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，癌症(如脑癌、黑素瘤、肺癌、胃肠道肿瘤、结肠癌、胰腺癌、前列腺癌、乳腺癌、口腔癌、肝癌、白血病、霍奇金淋巴瘤，非霍奇金淋巴瘤、膀胱癌、子宫颈癌、子宫体癌、睾丸癌，甲状腺癌、肾癌、胆囊癌、多发性骨髓瘤、鼻咽癌、喉癌、咽癌，食道癌等)，恶液质，肾衰竭、脓毒症、AIDS、慢性阻塞性肺病引起的恶液质，恶液质相关的体重减少，放疗、化疗引起的恶心呕吐，晚期慢性小管间质性肾炎，孕吐，肝硬化，肌少症，代谢性疾病(如脂肪和能量代谢失衡、调节食欲、调节体重)。在一些实施例中，所述个体是人类。
例如，在一些实施例中，提供一种用于治疗与GDF15信号通路相关的疾病(例如，癌症，恶液质，代谢性疾病)的个体的方法，包括向所述个体施用有效量的包含抗GDF15抗体(例如，全长抗GDF15抗体)的药物组合物，重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含X1YYMX2(SEQ ID NO:35)，其中X1为D或N，X2为S或T；HC-CDR2，其包含MISFSGTTX1ATWAKG(SEQ ID NO:36)，其中X1为H或Y；和HC-CDR3，其包含VVYAGWTYPLGI(SEQ ID NO:13)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含QASQSISSVLS(SEQ ID NO:18)；LC-CDR2，其包含EASX1X2AS(SEQ ID NO:37)，其中X1为I或T，X2为L或Q；和LC-CDR3，其包含QANYDVYNYGNP(SEQ ID NO:30)。在一些实施例中，所述抗GDF15抗体是全长抗体。在一些实施例中，所述全长抗GDF15抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，癌症(如脑癌、黑素瘤、肺癌、胃肠道肿瘤、结肠癌、胰腺癌、前列腺癌、乳腺癌、口腔癌、肝癌、白血病、霍奇金淋巴瘤，非霍奇金淋巴瘤、膀胱癌、子宫颈癌、子宫体癌、睾丸癌，甲状腺癌、肾癌、胆囊癌、多发性骨髓瘤、鼻咽癌、喉癌、咽癌，食道癌等)，恶液质，肾衰竭、 脓毒症、AIDS、慢性阻塞性肺病引起的恶液质，恶液质相关的体重减少，放疗、化疗引起的恶心呕吐，晚期慢性小管间质性肾炎，孕吐，肝硬化，肌少症，代谢性疾病(如脂肪和能量代谢失衡、调节食欲、调节体重)。在一些实施例中，所述个体是人类。
在一些实施例中，提供一种用于治疗与GDF15信号通路相关的疾病(例如，癌症，恶液质，代谢性疾病)的个体的方法，包括向所述个体施用有效量的包含抗GDF15抗体的组合物，其中所述抗体包含VH，所述VH包含：HC-CDR1，其包含SEQ ID NOs:1-2中任一所示的氨基酸序列，HC-CDR2，其包含SEQ ID NOs:7-8中任一所示的氨基酸序列，和HC-CDR3，其包含SEQ ID NO:13所示的氨基酸序列，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含SEQ ID NO:18所示的氨基酸序列，LC-CDR2，其包含SEQ ID NOs:23-25中任一所示的氨基酸序列，和LC-CDR3，其包含SEQ ID NO:30所示的氨基酸序列，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，提供一种用于治疗与GDF15信号通路相关的疾病(例如，癌症，恶液质，代谢性疾病)的个体的方法，包括向所述个体施用有效量的包含抗GDF15抗体的组合物，其中所述抗体包含：VH，所述VH包含SEQ ID NOs:38-47中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:38-47中任一所示的氨基酸序列具有至少约80％序列同一性；以及VL，所述VL包含SEQ ID NOs:52-59中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:52-59中任一所示的氨基酸序列具有至少约80％序列同一性。
在一些实施例中，本文所述抗GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种用于治疗与GDF15信号通路相关的疾病(例如，癌症，恶液质，代谢性疾病)的个体的方法，包括向所述个体施用有效量的包含抗GDF15抗体的组合物，其中所述抗体包含：VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:7，和HC-CDR3，其包含氨基酸序列SEQ ID NO:13，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:18，LC-CDR2，其包含氨基酸序列SEQ ID NO:23，和LC-CDR3，其包含氨基酸序列SEQ ID NO:30，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，本文所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:38或其变体，所述变体与氨基酸序列SEQ ID NO:38具有至少约80％序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:52或其变体，所述变体与氨基酸序列SEQ ID NO:52具有至少约80％序列同一性。在一些实施例中，本文所述抗GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，本文所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:39或其变体，所述变体与氨基酸序列SEQ ID NO:39具有至少约80％序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:53或其变体，所述变体与氨基酸序列SEQ ID NO:53具有至少约80％序列同一性。在一些实施例中，本文所述抗GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，本文所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:40或其变体，所述变体与氨基酸序列SEQ ID NO:40具有至少约80％序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:53或其变体，所述变体与氨基酸序列SEQ ID NO:53具有至少约80％序列同一性。在一些实施例中，本文所述抗GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，本文所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:41或其变体，所述变体与氨基酸序列SEQ ID NO:41具有至少约80％序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:53或其变体，所述变体与氨基酸序列SEQ ID NO:53具有至少约80％序列同一性。在一些实施例中，本文所述抗GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链 恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，本文所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:42或其变体，所述变体与氨基酸序列SEQ ID NO:42具有至少约80％序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:53或其变体，所述变体与氨基酸序列SEQ ID NO:53具有至少约80％序列同一性。在一些实施例中，本文所述抗GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，本文所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:43或其变体，所述变体与氨基酸序列SEQ ID NO:43具有至少约80％序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:53或其变体，所述变体与氨基酸序列SEQ ID NO:53具有至少约80％序列同一性。在一些实施例中，本文所述抗GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，本文所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:44或其变体，所述变体与氨基酸序列SEQ ID NO:44具有至少约80％序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:53或其变体，所述变体与氨基酸序列SEQ ID NO:53具有至少约80％序列同一性。在一些实施例中，本文所述抗GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，本文所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:39或其变体，所述变体与氨基酸序列SEQ ID NO:39具有至少约80％序列 同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:54或其变体，所述变体与氨基酸序列SEQ ID NO:54具有至少约80％序列同一性。在一些实施例中，本文所述抗GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，本文所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:40或其变体，所述变体与氨基酸序列SEQ ID NO:40具有至少约80％序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:54或其变体，所述变体与氨基酸序列SEQ ID NO:54具有至少约80％序列同一性。在一些实施例中，本文所述抗GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，本文所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:41或其变体，所述变体与氨基酸序列SEQ ID NO:41具有至少约80％序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:54或其变体，所述变体与氨基酸序列SEQ ID NO:54具有至少约80％序列同一性。在一些实施例中，本文所述抗GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，本文所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:42或其变体，所述变体与氨基酸序列SEQ ID NO:42具有至少约80％序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:54或其变体，所述变体与氨基酸序列SEQ ID NO:54具有至少约80％序列同一性。在一些实施例中，本文所述抗GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸 序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，本文所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:43或其变体，所述变体与氨基酸序列SEQ ID NO:43具有至少约80％序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:54或其变体，所述变体与氨基酸序列SEQ ID NO:54具有至少约80％序列同一性。在一些实施例中，本文所述抗GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，本文所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:44或其变体，所述变体与氨基酸序列SEQ ID NO:44具有至少约80％序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:54或其变体，所述变体与氨基酸序列SEQ ID NO:54具有至少约80％序列同一性。在一些实施例中，本文所述抗GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，本文所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:39或其变体，所述变体与氨基酸序列SEQ ID NO:39具有至少约80％序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:55或其变体，所述变体与氨基酸序列SEQ ID NO:55具有至少约80％序列同一性。在一些实施例中，本文所述抗GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，本文所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:40或其变体，所述变体与氨基酸序列SEQ ID NO:40具有至少约80％序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:55或其变体，所述变体与氨基酸序列SEQ ID NO:55具有至少约80％序列同一性。在一些实施例中，本文所述抗 GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，本文所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:41或其变体，所述变体与氨基酸序列SEQ ID NO:41具有至少约80％序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:55或其变体，所述变体与氨基酸序列SEQ ID NO:55具有至少约80％序列同一性。在一些实施例中，本文所述抗GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，本文所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:42或其变体，所述变体与氨基酸序列SEQ ID NO:42具有至少约80％序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:55或其变体，所述变体与氨基酸序列SEQ ID NO:55具有至少约80％序列同一性。在一些实施例中，本文所述抗GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，本文所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:43或其变体，所述变体与氨基酸序列SEQ ID NO:43具有至少约80％序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:55或其变体，所述变体与氨基酸序列SEQ ID NO:55具有至少约80％序列同一性。在一些实施例中，本文所述抗GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，本文所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:44或其变体，所述变体与氨基酸序列SEQ ID NO:44具有至少约80％序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:55或其变体，所述变体与氨基酸序列SEQ ID NO:55具有至少约80％序列同一性。在一些实施例中，本文所述抗GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种用于治疗与GDF15信号通路相关的疾病(例如，癌症，恶液质，代谢性疾病)的个体的方法，包括向所述个体施用有效量的包含抗GDF15抗体的组合物，其中所述抗体包含：VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:7，和HC-CDR3，其包含氨基酸序列SEQ ID NO:13，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:18，LC-CDR2，其包含氨基酸序列SEQ ID NO:24，和LC-CDR3，其包含氨基酸序列SEQ ID NO:30，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，本文所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:45或其变体，所述变体与氨基酸序列SEQ ID NO:45具有至少约80％序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:56或其变体，所述变体与氨基酸序列SEQ ID NO:56具有至少约80％序列同一性。在一些实施例中，本文所述抗GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种用于治疗与GDF15信号通路相关的疾病(例如，癌症，恶液质，代谢性疾病)的个体的方法，包括向所述个体施用有效量的包含抗GDF15抗体的组合物，其中所述抗体包含：VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:7，和HC-CDR3，其包含氨基酸序列SEQ ID NO:13，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:18，LC-CDR2，其包含氨基酸序列SEQ ID NO:25，和LC-CDR3，其包 含氨基酸序列SEQ ID NO:30，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，本文所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:45或其变体，所述变体与氨基酸序列SEQ ID NO:45具有至少约80％序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:57或其变体，所述变体与氨基酸序列SEQ ID NO:57具有至少约80％序列同一性。在一些实施例中，本文所述抗GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种用于治疗与GDF15信号通路相关的疾病(例如，癌症，恶液质，代谢性疾病)的个体的方法，包括向所述个体施用有效量的包含抗GDF15抗体的组合物，其中所述抗体包含：VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:2，HC-CDR2，其包含氨基酸序列SEQ ID NO:7，和HC-CDR3，其包含氨基酸序列SEQ ID NO:13，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:18，LC-CDR2，其包含氨基酸序列SEQ ID NO:25，和LC-CDR3，其包含氨基酸序列SEQ ID NO:30，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，本文所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:46或其变体，所述变体与氨基酸序列SEQ ID NO:46具有至少约80％序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:58或其变体，所述变体与氨基酸序列SEQ ID NO:58具有至少约80％序列同一性。在一些实施例中，本文所述抗GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种用于治疗与GDF15信号通路相关的疾病(例如，癌症，恶液质，代谢性疾病)的个体的方法，包括向所述个体施用有效量的包含抗GDF15抗体的组合物，其中所述抗体包含：VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:8，和HC-CDR3，其包含氨基酸序列SEQ ID NO:13，或者所述VH的变体，其HC-CDRs中包含 至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:18，LC-CDR2，其包含氨基酸序列SEQ ID NO:25，和LC-CDR3，其包含氨基酸序列SEQ ID NO:30，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，本文所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:47或其变体，所述变体与氨基酸序列SEQ ID NO:47具有至少约80％序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:59或其变体，所述变体与氨基酸序列SEQ ID NO:59具有至少约80％序列同一性。在一些实施例中，本文所述抗GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
例如，在一些实施例中，提供一种用于治疗与GDF15信号通路相关的疾病(例如，癌症，恶液质，代谢性疾病)的个体的方法，包括向所述个体施用有效量的包含抗GDF15抗体(例如，全长抗GDF15抗体)的药物组合物，重链可变结构域(VH)，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:3，HC-CDR2，其包含氨基酸序列SEQ ID NO:9，和HC-CDR3，其包含氨基酸序列SEQ ID NO:14，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(VL)，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:19，LC-CDR2，其包含氨基酸序列SEQ ID NO:26，和LC-CDR3，其包含氨基酸序列SEQ ID NO:31，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗GDF15抗体是全长抗体。在一些实施例中，所述全长抗GDF15抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，癌症(如脑癌、黑素瘤、肺癌、胃肠道肿瘤、结肠癌、胰腺癌、前列腺癌、乳腺癌、口腔癌、肝癌、白血病、霍奇金淋巴瘤，非霍奇金淋巴瘤、膀胱癌、子宫颈癌、子宫体癌、睾丸癌，甲状腺癌、肾癌、胆囊癌、多发性骨髓瘤、鼻咽癌、喉癌、咽癌，食道癌等)，恶液质，肾衰竭、脓毒症、AIDS、慢性阻塞性肺病引起的恶液质，恶液质相关的体重减少，放疗、化疗引起的恶心呕吐，晚期慢性小管间质性肾炎，孕吐，肝硬化，肌少症，代谢性疾病(如脂肪和能量代谢失衡、调节食欲、调节体重)。在一些实施例中，所述个体是人类。
在一些实施例中，提供一种用于治疗与GDF15信号通路相关的疾病(例如，癌症，恶液质，代谢性疾病)的个体的方法，包括向所述个体施用有效量的包含抗GDF15抗体的组合物，其中所述抗体包含：VH，所述VH包含SEQ ID NO:48所示的氨基酸序列或其变体，所述变体与SEQ ID NO:48所示的氨基酸序列具有至少约80％ 序列同一性；以及VL，所述VL包含SEQ ID NO:60所示的氨基酸序列或其变体，所述变体与SEQ ID NO:60所示的氨基酸序列具有至少约80％序列同一性。
在一些实施例中，本文所述抗GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
例如，在一些实施例中，提供一种用于治疗与GDF15信号通路相关的疾病(例如，癌症，恶液质，代谢性疾病)的个体的方法，包括向所述个体施用有效量的包含抗GDF15抗体(例如，全长抗GDF15抗体)的药物组合物，重链可变结构域(VH)，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:4，HC-CDR2，其包含氨基酸序列SEQ ID NO:10，和HC-CDR3，其包含氨基酸序列SEQ ID NO:15，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(VL)，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:20，LC-CDR2，其包含氨基酸序列SEQ ID NO:27，和LC-CDR3，其包含氨基酸序列SEQ ID NO:32，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗GDF15抗体是全长抗体。在一些实施例中，所述全长抗GDF15抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，癌症(如脑癌、黑素瘤、肺癌、胃肠道肿瘤、结肠癌、胰腺癌、前列腺癌、乳腺癌、口腔癌、肝癌、白血病、霍奇金淋巴瘤，非霍奇金淋巴瘤、膀胱癌、子宫颈癌、子宫体癌、睾丸癌，甲状腺癌、肾癌、胆囊癌、多发性骨髓瘤、鼻咽癌、喉癌、咽癌，食道癌等)，恶液质，肾衰竭、脓毒症、AIDS、慢性阻塞性肺病引起的恶液质，恶液质相关的体重减少，放疗、化疗引起的恶心呕吐，晚期慢性小管间质性肾炎，孕吐，肝硬化，肌少症，代谢性疾病(如脂肪和能量代谢失衡、调节食欲、调节体重)。在一些实施例中，所述个体是人类。
在一些实施例中，提供一种用于治疗与GDF15信号通路相关的疾病(例如，癌症，恶液质，代谢性疾病)的个体的方法，包括向所述个体施用有效量的包含抗GDF15抗体的组合物，其中所述抗体包含：VH，所述VH包含SEQ ID NO:49所示的氨基酸序列或其变体，所述变体与SEQ ID NO:49所示的氨基酸序列具有至少约80％序列同一性；以及VL，所述VL包含SEQ ID NO:61所示的氨基酸序列或其变体，所述变体与SEQ ID NO:61所示的氨基酸序列具有至少约80％序列同一性。
在一些实施例中，本文所述抗GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例 中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
例如，在一些实施例中，提供一种用于治疗与GDF15信号通路相关的疾病(例如，癌症，恶液质，代谢性疾病)的个体的方法，包括向所述个体施用有效量的包含抗GDF15抗体(例如，全长抗GDF15抗体)的药物组合物，重链可变结构域(VH)，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:5，HC-CDR2，其包含氨基酸序列SEQ ID NO:11，和HC-CDR3，其包含氨基酸序列SEQ ID NO:16，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(VL)，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:21，LC-CDR2，其包含氨基酸序列SEQ ID NO:28，和LC-CDR3，其包含氨基酸序列SEQ ID NO:33，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。在一些实施例中，所述抗GDF15抗体是全长抗体。在一些实施例中，所述全长抗GDF15抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，癌症(如脑癌、黑素瘤、肺癌、胃肠道肿瘤、结肠癌、胰腺癌、前列腺癌、乳腺癌、口腔癌、肝癌、白血病、霍奇金淋巴瘤，非霍奇金淋巴瘤、膀胱癌、子宫颈癌、子宫体癌、睾丸癌，甲状腺癌、肾癌、胆囊癌、多发性骨髓瘤、鼻咽癌、喉癌、咽癌，食道癌等)，恶液质，肾衰竭、脓毒症、AIDS、慢性阻塞性肺病引起的恶液质，恶液质相关的体重减少，放疗、化疗引起的恶心呕吐，晚期慢性小管间质性肾炎，孕吐，肝硬化，肌少症，代谢性疾病(如脂肪和能量代谢失衡、调节食欲、调节体重)。在一些实施例中，所述个体是人类。
在一些实施例中，提供一种用于治疗与GDF15信号通路相关的疾病(例如，癌症，恶液质，代谢性疾病)的个体的方法，包括向所述个体施用有效量的包含抗GDF15抗体的组合物，其中所述抗体包含：VH，所述VH包含SEQ ID NO:50所示的氨基酸序列或其变体，所述变体与SEQ ID NO:50所示的氨基酸序列具有至少约80％序列同一性；以及VL，所述VL包含SEQ ID NO:62所示的氨基酸序列或其变体，所述变体与SEQ ID NO:62所示的氨基酸序列具有至少约80％序列同一性。
在一些实施例中，本文所述抗GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
例如，在一些实施例中，提供一种用于治疗与GDF15信号通路相关的疾病(例如，癌症，恶液质，代谢性疾病)的个体的方法，包括向所述个体施用有效量的包含抗GDF15抗体(例如，全长抗GDF15抗体)的药物组合物，重链可变结构域(VH)，所述VH包含：重链互补决定区(HC-CDR)1，其包含SYDMT(SEQ ID  NO:6)；HC-CDR2，其包含IIX1X2SGX3TYYASWAKG(SEQ ID NO:79)，其中X1为N或S，X2为G、N或S，X3为N或S；和HC-CDR3，其包含GILVYADYGDHNL(SEQ ID NO:17)；以及轻链可变结构域(VL)，所述VL包含：轻链互补决定区(LC-CDR)1，其包含QASEDIYTNLA(SEQ ID NO:22)；LC-CDR2，其包含AASTLAS(SEQ ID NO:29)；和LC-CDR3，其包含LGVYTYISAX1GA(SEQ ID NO:81)，其中X1为D或E。在一些实施例中，所述抗GDF15抗体是全长抗体。在一些实施例中，所述全长抗GDF15抗体是IgG1或IgG4抗体。在一些实施例中，所述疾病或病症选自例如，癌症(如脑癌、黑素瘤、肺癌、胃肠道肿瘤、结肠癌、胰腺癌、前列腺癌、乳腺癌、口腔癌、肝癌、白血病、霍奇金淋巴瘤，非霍奇金淋巴瘤、膀胱癌、子宫颈癌、子宫体癌、睾丸癌，甲状腺癌、肾癌、胆囊癌、多发性骨髓瘤、鼻咽癌、喉癌、咽癌，食道癌等)，恶液质，肾衰竭、脓毒症、AIDS、慢性阻塞性肺病引起的恶液质，恶液质相关的体重减少，放疗、化疗引起的恶心呕吐，晚期慢性小管间质性肾炎，孕吐，肝硬化，肌少症，代谢性疾病(如脂肪和能量代谢失衡、调节食欲、调节体重)。在一些实施例中，所述个体是人类。
在一些实施例中，提供一种用于治疗与GDF15信号通路相关的疾病(例如，癌症，恶液质，代谢性疾病)的个体的方法，包括向所述个体施用有效量的包含抗GDF15抗体的组合物，其中所述抗体包含VH，所述VH包含：HC-CDR1，其包含SEQ ID NO:6所示的氨基酸序列，HC-CDR2，其包含SEQ ID NOs:12，75-78中任一所示的氨基酸序列，和HC-CDR3，其包含SEQ ID NO:17所示的氨基酸序列，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含SEQ ID NO:22所示的氨基酸序列，LC-CDR2，其包含SEQ ID NO:29所示的氨基酸序列，和LC-CDR3，其包含SEQ ID NOs:34，80中任一所示的氨基酸序列，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，提供一种用于治疗与GDF15信号通路相关的疾病(例如，癌症，恶液质，代谢性疾病)的个体的方法，包括向所述个体施用有效量的包含抗GDF15抗体的组合物，其中所述抗体包含：VH，所述VH包含SEQ ID NOs:51，82-89中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:51，82-89中任一所示的氨基酸序列具有至少约80％序列同一性；以及VL，所述VL包含SEQ ID NOs:63，90-91中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:63，90-91中任一所示的氨基酸序列具有至少约80％序列同一性。
在一些实施例中，本文所述抗GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种用于治疗与GDF15信号通路相关的疾病(例如，癌症，恶液质，代谢性疾病)的个体的方法，包括向所述个体施用有效量的包含抗GDF15抗体(例如，全长抗GDF15抗体)的药物组合物，重链可变结构域(VH)，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:12，和HC-CDR3，其包含氨基酸序列SEQ ID NO:17，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及轻链可变结构域(VL)，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:22，LC-CDR2，其包含氨基酸序列SEQ ID NO:29，和LC-CDR3，其包含氨基酸序列SEQ ID NO:34，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，本文所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:51或其变体，所述变体与氨基酸序列SEQ ID NO:51具有至少约80％序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:63或其变体，所述变体与氨基酸序列SEQ ID NO:63具有至少约80％序列同一性。在一些实施例中，本文所述抗GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种用于治疗与GDF15信号通路相关的疾病(例如，癌症，恶液质，代谢性疾病)的个体的方法，包括向所述个体施用有效量的包含抗GDF15抗体的组合物，其中所述抗体包含：VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:75，和HC-CDR3，其包含氨基酸序列SEQ ID NO:17，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:22，LC-CDR2，其包含氨基酸序列SEQ ID NO:29，和LC-CDR3，其包含氨基酸序列SEQ ID NO:80，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，本文所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:82或其变体，所述变体与氨基酸序列SEQ ID NO:82具有至少约80％序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:90或其变体，所述变体与氨基酸序列SEQ ID NO:90具有至少约80％序列同一性。在一些实施例中，本文所述抗GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含 或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种用于治疗与GDF15信号通路相关的疾病(例如，癌症，恶液质，代谢性疾病)的个体的方法，包括向所述个体施用有效量的包含抗GDF15抗体的组合物，其中所述抗体包含：VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:76，和HC-CDR3，其包含氨基酸序列SEQ ID NO:17，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:22，LC-CDR2，其包含氨基酸序列SEQ ID NO:29，和LC-CDR3，其包含氨基酸序列SEQ ID NO:80，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，本文所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:83或其变体，所述变体与氨基酸序列SEQ ID NO:83具有至少约80％序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:90或其变体，所述变体与氨基酸序列SEQ ID NO:90具有至少约80％序列同一性。在一些实施例中，本文所述抗GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种用于治疗与GDF15信号通路相关的疾病(例如，癌症，恶液质，代谢性疾病)的个体的方法，包括向所述个体施用有效量的包含抗GDF15抗体的组合物，其中所述抗体包含：VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:77，和HC-CDR3，其包含氨基酸序列SEQ ID NO:17，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:22，LC-CDR2，其包含氨基酸序列SEQ ID NO:29，和LC-CDR3，其包含氨基酸序列SEQ ID NO:80，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，本文所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:84或其变体，所述变体与氨基酸序列SEQ ID NO:84具有至少约80％序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:90或其变体，所述变体与氨基酸序列SEQ ID NO:90具有至少约80％序列同一性。在一些实施例中，本文所述抗GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所 述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，提供一种用于治疗与GDF15信号通路相关的疾病(例如，癌症，恶液质，代谢性疾病)的个体的方法，包括向所述个体施用有效量的包含抗GDF15抗体的组合物，其中所述抗体包含：VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:78，和HC-CDR3，其包含氨基酸序列SEQ ID NO:17，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:22，LC-CDR2，其包含氨基酸序列SEQ ID NO:29，和LC-CDR3，其包含氨基酸序列SEQ ID NO:80，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
在一些实施例中，本文所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:85或其变体，所述变体与氨基酸序列SEQ ID NO:85具有至少约80％序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:90或其变体，所述变体与氨基酸序列SEQ ID NO:90具有至少约80％序列同一性。在一些实施例中，本文所述抗GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，本文所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:86或其变体，所述变体与氨基酸序列SEQ ID NO:86具有至少约80％序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:91或其变体，所述变体与氨基酸序列SEQ ID NO:91具有至少约80％序列同一性。在一些实施例中，本文所述抗GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，本文所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:87或其变体，所述变体与氨基酸序列SEQ ID NO:87具有至少约80％序列 同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:91或其变体，所述变体与氨基酸序列SEQ ID NO:91具有至少约80％序列同一性。在一些实施例中，本文所述抗GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，本文所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:88或其变体，所述变体与氨基酸序列SEQ ID NO:88具有至少约80％序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:91或其变体，所述变体与氨基酸序列SEQ ID NO:91具有至少约80％序列同一性。在一些实施例中，本文所述抗GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，本文所述抗GDF15抗体包含：VH，所述VH包含氨基酸序列SEQ ID NO:89或其变体，所述变体与氨基酸序列SEQ ID NO:89具有至少约80％序列同一性；以及VL，所述VL包含氨基酸序列SEQ ID NO:91或其变体，所述变体与氨基酸序列SEQ ID NO:91具有至少约80％序列同一性。在一些实施例中，本文所述抗GDF15抗体是包含IgG1或IgG4恒定区的全长抗GDF15抗体。在一些实施例中，所述IgG1是人IgG1。在一些实施例中，所述IgG4是人IgG4。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:64组成。在一些实施例中，重链恒定区包含或由氨基酸序列SEQ ID NO:65组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:66组成。在一些实施例中，轻链恒定区包含或由氨基酸序列SEQ ID NO:67组成。
在一些实施例中，所述个体是哺乳动物(例如人、非人灵长类、大鼠、小鼠、牛、马、猪、绵羊、山羊、狗、猫等)。在一些实施例中，所述个体是人类。在一些实施例中，所述个体是临床患者、临床试验志愿者、实验动物等。在一些实施例中，所述个体年龄小于60岁(包括例如小于50、40、30、25、20、15或10岁)。在一些实施例中，所述个体年龄大于60岁(包括例如大于70、80、90或100岁)。在一些实施例中，所述个体是被诊断为或在遗传角度上易患本文所描述的一种或多种疾病或病症(例如癌症，恶液质，代谢性疾病)。在一些实施例中，所述个体具有一种或多种与本文所述的一种或多种疾病或病症相关的风险因子。
在一些实施例中，本申请提供一种向个体中在其表面表达GDF15的细胞递送抗GDF15抗体(例如本文所述的任一种抗GDF15抗体，例如分离的抗GDF15抗体)的方法，所述方法包括向该个体施用包含抗GDF15抗体的组合物。
癌症，恶液质，代谢性疾病或其它任何表现出GDF15异常表达的疾病的许多诊断方法和这些疾病的临床描述在本领域是已知的。这类方法包括，但不限于，例如免疫组化、PCR以及荧光原位杂交(FISH)。
在一些实施例中，本申请所述抗GDF15抗体(例如全长抗GDF15抗体)和/或组合物与第二、第三或第四药剂(包括例如抗癌剂，免疫刺激剂，化学治疗试剂，活化素A或活化素A受体ActRIIB的抑制剂(如抗活化素A抗体或其抗原结合片段、抗ActRIIB抗体或抗原结合片段、活化素A的小分子抑制剂、ActRIIB的小分子抑制剂，以及ActRIIB的诱饵受体如可溶性ActRIIB受体、可溶性ActRIIB受体与Fc分子的融合物)，IL-6或IL-6受体IL-6R的抑制剂(如抗IL-6抗体或其抗原结合片段、抗IL-6R抗体或其抗原结合片段、IL-6的小分子抑制剂、IL-6R的小分子抑制剂、以及IL-6R的诱饵受体如可溶性IL-6R受体、可溶性IL-6R受体与Fc分子的融合物)，TNFα或IL-1的抑制剂(如抗TNFα抗体或其抗原结合片段、抗IL-1抗体或其抗原结合片段、TNFα或IL-1的小分子抑制剂、以及TNFα或IL-1的诱饵受体如可溶性TNFα或IL-1受体、可溶性TNFα或IL-1与Fc分子的融合物)，生长素释放肽，黑皮质素肽抑制剂等)联合使用来治疗与GDF15信号通路相关的疾病。
采用例如肿瘤消退、肿瘤重量或尺寸的减少、进展时间、生存期、无进展生存期、总体响应率、响应持续时间、生存质量、蛋白表达水平和/或活性来评估癌症治疗。可以采用确定治疗效果的方法，包括例如，通过放射成像来检测是否响应。
在一些实施例中，治疗的效果以肿瘤生长抑制百分率(％TGI)来评估，使用等式100-(T/C×100)来计算，其中T是已治疗肿瘤的相对平均肿瘤体积，C是未治疗肿瘤的相对平均肿瘤体积。在一些实施例中，％TGI约为10％、20％、30％、40％、50％、60％、70％、80％、90％、91％、92％、93％、94％、95％或超过95％。
采用例如肌肉质量损失的抑制、脂肪质量损失的抑制、不自主体重损失的恢复、器官质量损失的抑制来评估癌症相关的恶液质的治疗。可以采用确定治疗效果的方法，包括例如，通过放射成像来检测是否响应。
在一些实施例中，治疗效果通过恶液质患者中体重逆转水平来评估，通过与施用抗体前相比初始体重变化率来计算。在一些实施例中，不自主的体重损失恢复至少约1％、2％、5％、10％、15％、20％、25％、30％或35％。
在一些实施例中，治疗效果通过恶液质患者中脂肪质量损失抑制水平来评估。在一些实施例中，脂肪质量损失抑制至少约10％、20％、30％、40％、50％、60％、70％、80％、90％、91％、92％、93％、94％、95％或超过95％。
在一些实施例中，治疗效果通过恶液质患者中肌肉质量损失抑制水平来评估。在一些实施例中，脂肪质量损失抑制至少约10％、20％、30％、40％、50％、60％、70％、80％、90％、91％、92％、93％、94％、95％或超过95％。
抗GDF15抗体的给药剂量和方法
施用于个体(例如人)的抗GDF15抗体(例如分离的抗GDF15抗体)组合物的剂量可能因特定组合物、给药方式和治疗疾病类型的不同而不同。在一些实施例中，组合物(例如，包含抗GDF15抗体的组合物)的量可在癌症，恶液质，代谢性疾病治疗中有效产生客观响应(例如，部分响应或完全响应)。在一些实施例中，抗GDF15抗体组合物的量足以在个体中产生完全响应。在一些实施例中，抗GDF15抗体组合物的量足以在个体中产生部分响应。在一些实施例中，抗GDF15抗体组合物的给药剂量(例如当单独施用时)足以在使用抗GDF15抗体组合物治疗的个体群体中产生高于20％、25％、30％、35％、40％、45％、50％、55％、60％、64％、65％、70％、75％、80％、85％或90％的总响应率。个体对本文所述治疗方法的响应可通过，例如，恶液质患者中体重逆转的水平来确定。
在一些实施例中，组合物(例如包含分离的抗GDF15抗体的组合物)的量足以延长个体的无进展生存期。在一些实施例中，组合物的量足以延长个体的总体生存期。在一些实施例中，在使用抗GDF15抗体组合物治疗的个体群体中，组合物的量(例如当单独施用时)足以产生高于50％、60％、70％或77％的临床益处。
在一些实施例中，组合物(例如包含分离的抗GDF15抗体的组合物)的量，单独使用或与第二，第三、和/或第四药剂联合使用时，是指在治疗前或与未接受治疗的其他受试者的相应活性相比，足以控制症状和减少病情加重的风险的量。可以采用标准方法来测量该疗效的大小，例如纯化酶的体外检测、基于细胞的检测、动物模型或人体试验。
在一些实施例中，当将组合物施用于个体时，组合物中抗GDF15抗体(例如全长的抗GDF15抗体)的量低于引起毒性效应(即，一种高于临床可接受毒性水平的效应)的水平，或者处于潜在副作用可以控制或耐受的水平。
在一些实施例中，遵循相同的给药方案，组合物的量接近的组合物的最大耐受剂量(MTD)。在一些实施例中，组合物的量高于MTD的80％、90％、95％或98％。
在一些实施例中，组合物中抗GDF15抗体(例如全长的抗GDF15抗体)的含量在0.001μg到1000μg的范围之内。
在如上所述任一个实施例中，组合物中的抗GDF15抗体(例如全长的抗GDF15抗体)的有效量，按照体重时计算，为0.1μg/kg到100mg/kg的范围之内。
抗GDF15抗体组合物可通过多种途径施用于个体(如人类)，包括，例如静脉注射、动脉内给药、腹腔注射、肺内给药、口服给药、吸入给药、血管内给药、肌肉注射、气管内给药、皮下注射、眼内给药、鞘内给药、粘膜给药或经皮给药。在一些实 施例中，使用组合物的缓释制剂。在一些实施例中，组合物通过静脉给药。在一些实施例中，组合物通过动脉给药。在一些实施例中，组合物通过腹膜内给药。在一些实施例中，组合物通过肝内给药。在一些实施例中，组合物通过肝动脉输注给药。在一些实施例中，组合物施用于远离第一病灶的部位。
制品及试剂盒
在本申请的一些实施例中，提供一种制品，所述制品包含一种物质，所述物质能够用于治疗与GDF15信号通路相关的疾病(例如，癌症，恶液质，代谢性疾病)，或者用于递送抗GDF15抗体(例如一种全长抗GDF15抗体)到表面表达GDF15的细胞。所述制品可以包括一种容器以及在容器上或随该容器附带的标签或包装说明书。合适的容器包括，例如瓶子、小瓶、注射器等。容器可以由多种材料制成，例如玻璃或塑料。通常，该容器内装有能够有效治疗本文所述疾病或病症的组合物，并且具有一个无菌端口(例如该容器可以是一个静脉输液袋或是一个具有皮下注射针头可刺穿盖子的小瓶)。组合物中的至少一种活性物质即为本申请所述的抗GDF15抗体。标签或包装说明书标示了该组合物可以用于治疗的特定病症。标签或包装说明书进一步包含给患者施用抗GDF15抗体组合物的说明书。包括联合治疗的制品和试剂盒均在本文的考虑范围之内。
包装说明书是指通常包含在治疗产品的商业包装内的说明书，其包含关于与这些治疗产品使用有关的适应症、用法、剂量、施用、禁忌症和/或警告信息。在一些实施例中，包装说明书标明该组合物可以用于治疗与GDF15信号通路相关的疾病(例如癌症，恶液质，代谢性疾病)。在一些实施例中，包装说明书标明该组合物可以用于治疗以下的疾病，包括癌症(如脑癌、黑素瘤、肺癌、胃肠道肿瘤、结肠癌、胰腺癌、前列腺癌、乳腺癌、口腔癌、肝癌、白血病、霍奇金淋巴瘤，非霍奇金淋巴瘤、膀胱癌、子宫颈癌、子宫体癌、睾丸癌，甲状腺癌、肾癌、胆囊癌、多发性骨髓瘤、鼻咽癌、喉癌、咽癌，食道癌等)，恶液质，肾衰竭、脓毒症、AIDS、慢性阻塞性肺病引起的恶液质，恶液质相关的体重减少，放疗、化疗引起的恶心呕吐，晚期慢性小管间质性肾炎，孕吐，肝硬化，肌少症，代谢性疾病(如脂肪和能量代谢失衡、调节食欲、调节体重)。
此外，所述制品还可以包括第二容器，其包含药学上可接受的缓冲液，例如抑菌性注射用水(BWFI)、磷酸盐缓冲液、格林氏溶液或葡萄糖溶液。还可以包括从商业和用户角度而言所需的其他材料，包括其他缓冲液、稀释液、过滤器、针头和注射器。
同时还涉及可用于各种目的的试剂盒，例如用于治疗与GDF15信号通路相关的疾病(例如癌症，恶液质，代谢性疾病)，或者用于递送抗GDF15抗体(例如全长抗GDF15抗体)到表面表达GDF15的细胞中，任选与制品组合。本申请的试剂盒包括一个或多个容器，其包含抗GDF15抗体组合物(或单剂量形式和/或制品)，并且在 一些实施例中，进一步包含另一种药剂(例如本文所述的药剂)和/或与本文所述任一方法相一致的使用说明书。该试剂盒可进一步包括选择适合治疗个体的描述。本申请中试剂盒中所附带的使用说明书通常是标签或包装说明书上的书面说明(例如包含在试剂盒内的纸页)，机器可读的说明(例如，磁性或光学储存光盘上的说明)也是可以接受的。
例如，在一些实施例中，试剂盒包括一种包含抗GDF15抗体(例如全长的抗GDF15抗体)的组合物。在一些实施例中，试剂盒包括：a)包含本文所述的任一种抗GDF15抗体的组合物，和b)至少一种有效量的其它药剂，其能够增强抗GDF15抗体的效果(如治疗效果、检测效果)。在一些实施例中，试剂盒包括：a)包含本文所述的任一种抗GDF15抗体的组合物，和b)向个体施用抗GDF15抗体组合物用于治疗与GDF15信号通路相关的疾病(例如癌症，恶液质，代谢性疾病)的使用说明书。在一些实施例中，试剂盒包括：a)包含本文所述的任一种抗GDF15抗体的组合物，和b)至少一种有效量的其它药剂，其能够增强抗GDF15抗体的效果(如治疗效果、检测效果)和c)向个体施用抗GDF15抗体组合物和其它物质用于治疗与GDF15信号通路相关的疾病(例如癌症，恶液质，代谢性疾病)的使用说明书。所述抗GDF15抗体和其他物质可以存在于独立的容器或同一个容器中。例如，该试剂盒可以包括一种特定组合物或两种或更多种组合物，其中一种组合物包括抗GDF15抗体，另一种组合物包括另一种药剂。
在一些实施例中，试剂盒包含一种(或一组)编码抗GDF15抗体(例如全长的抗GDF15抗体)的核酸。在一些实施例中，试剂盒包含：a)一种(或一组)编码抗GDF15抗体(例如全长的抗GDF15抗体)的核酸，和b)一种表达核酸(或一组核酸)的宿主细胞。在一些实施例中，试剂盒包含：a)一种(或一组)编码抗GDF15抗体(例如全长的抗GDF15抗体)的核酸，和b)使用说明书，适用于：i)在宿主细胞中表达抗GDF15抗体，ii)制备包含抗GDF15抗体的组合物，和iii)向个体施用包含抗GDF15抗体的组合物来治疗与GDF15信号通路相关的疾病(例如癌症，恶液质，代谢性疾病)。在一些实施例中，试剂盒包括：a)一种(或一组)编码抗GDF15抗体(例如全长的抗GDF15抗体)的核酸，b)一种表达核酸(或一组核酸)的宿主细胞，和c)使用说明书，适用于：i)在宿主细胞中表达抗GDF15抗体，ii)制备包含抗GDF15抗体的组合物，和iii)向个体施用包含抗GDF15抗体的组合物来治疗与GDF15信号通路相关的疾病(例如癌症，恶液质，代谢性疾病)。
本申请所述的试剂盒以合适的形式进行包装。合适的包装包括，但不限于，小瓶、瓶子、广口瓶、软包装(例如密封的聚酯薄膜或塑料袋)等。试剂盒可以任选地提供其它的组分，例如缓冲液和说明信息。因此，本申请还提供制品，其包括小瓶、瓶子、广口瓶、软包装(例如密封的聚酯薄膜或塑料袋)等。
关于抗GDF15抗体组合物的使用说明书，通常包括一些信息，诸如，剂量，给药周期和给药途径等。容器可以是单位剂量的，大包装的(如，多剂量包装)或亚单位 剂量的。例如，提供一种包含足够剂量的如本文所述的抗GDF15抗体(例如全长的抗GDF15抗体)的试剂盒以对个体进行长期有效的治疗，例如一周、8天、9天、10天、11天、12天、13天、2周、3周、4周、6周、8周、3个月、4个月、5个月、7个月、8个月、9个月或更长时间。试剂盒还可包含多单位剂量的抗GDF15抗体、药物组合物和使用说明书，并且以足够在药房中储存和使用的量进行包装，例如，医院药房和复方药房。
本领域的技术人员将认识到在本申请的范围和宗旨内可能的若干实施例。现在将通过参考以下非限制性实施例来更详细地描述本申请。以下实施例进一步阐明本申请，但不应解释为以任何方式进行限制其范围。
具体实施方式
在下述公开的实施例中，适用如下缩写：GDF15(Growth Differentiation Factor-15，生长和分化因子15)；GFRAL(GDNF family receptorα-like，GDNF家族受体α样蛋白)；RET(Tyrosine kinase receptor，酪氨酸激酶受体)；
实施例1：制备重组GDF15抗原并筛选抗GDF15抗体
制备重组的全长人、猴、鼠GDF15蛋白
通过亚克隆将编码人、恒河猴或小鼠GDF15的cDNA构建到哺乳动物细胞表达载体中。在上述cDNA上添加His标签和/或hFc标签和/或其它的本领域技术人员常用标签，构建并表达出含有人、恒河猴或小鼠GDF15的融合蛋白，例如人GDF15-his(SEQ ID NO：73)、人GDF15-hFc(SEQ ID NO：70)、恒河猴GDF15-hFc(SEQ ID NO：71)、小鼠GDF15-hFc(SEQ ID NO：72)。
对重组的GDF15蛋白，包括人GDF15-his、人GDF15-hFc、恒河猴GDF15-hFc或小鼠GDF15-hFc等，进行表达纯化。简言之，将含有上述融合蛋白基因的表达载体分别转染293F细胞，并将上述细胞在37℃、5％CO2、120rpm条件下培养5天，分别收集细胞培养液。
根据制造商的操作说明，使用镍柱(Ni)纯化具有His标签的重组蛋白。具体操作如下：采用常州天地人和生物科技有限公司的Ni-NTA(5ml)进行固定化金属亲和层析(IMAC)。上样后，首先用10个柱体积的平衡液(PBS，pH7.2)冲洗柱子，再使用10个柱体积的溶液洗杂(PBS+20mM咪唑，pH7.2)，随后使用5个柱体积的洗脱液(PBS+250mM咪唑，pH7.2-7.4)洗脱并收集目的蛋白，用合适截留分子量的超滤管浓缩换液至PBS。
根据制造商的操作说明，采用MabCap At 4FF预装柱纯化具有hFc标签的重组蛋白。具体操作如下：采用常州天地人和生物科技有限公司的5ml MabCap At 4FF预装柱进行蛋白纯化。上样后，首先用10～15个柱体积的平衡液(PBS，pH7.2)冲洗柱子，然后使用5～6个柱体积洗脱液(0.1M Gly、0.15M NaCl，pH3.2)洗脱并收集目的 蛋白，加入适量1M Tris调节pH至中性，用合适截留分子量的超滤管浓缩换液至PBS。
筛选抗GDF15抗体
使用人GDF15-his作为抗原，与等份(v/v)佐剂一起免疫新西兰兔。收集免疫后的兔血清，ELISA检测上述血清中的总IgG滴度。几轮免疫后，使用兔脾脏构建293T细胞展示库。简言之，取免疫后的兔脾脏，分选B细胞，提取RNA，经逆转录获得cDNA，采用VH和VK特异性引物扩增VH和VK片段，经过胶回收纯化后，将VH和VK连入慢病毒穿梭载体中，构建成完整的抗体并将其包装入慢病毒后感染293T细胞，获得293T细胞展示库。
筛选抗GDF15抗体：从上述293T细胞展示库中分离特异性识别GDF15的抗体。简言之，使用流式细胞仪，分选出结合人GDF15-hFc的阳性单细胞，培养于96孔板中。将人GDF15-his蛋白包被于酶标板中，加入293T细胞表达上清，筛选出与人GDF15-his结合的阳性克隆，提取阳性克隆的基因组DNA(gDNA)，采用VH和VK特异性引物PCR扩增VH和VK片段，然后测序得到候选先导抗体序列。候选先导抗体的重链和轻链可变结构域序列如表2和表3所示。
实施例2：制备和表征全长的抗GDF15抗体
制备抗GDF15全长抗体
将测序得到的兔抗GDF15抗体序列的VL和VH，分别构建入兔源真核表达载体pTTa1-rab-CLB4(包含轻链恒定区)和pTTa1-rab Ig1-H(包含IgG1重链恒定区)中。将分别提取的表达轻链或重链的质粒，共转染293F细胞，37℃、8％CO2、120rpm培养5天，用蛋白A亲和层析柱纯化培养液。简言之，首先采用6倍柱体积50mM PBS缓冲液(包含0.15M NaCl，pH7.2)以150cm/h的流速平衡蛋白A柱。培养液上清(调节pH至7.2)以150cm/h流速流穿柱子。进一步平衡该柱后，采用50mM柠檬酸钠缓冲液(pH3.5)洗脱，收集洗脱液，调节pH值至中性。利用脱盐柱将IgG溶液置换于PBS缓冲液中，超滤浓缩后测定IgG浓度，获得全长的抗GDF15抗体。
抗GDF15抗体的亲和力检测
ELISA结合试验：将纯化后的单克隆抗体与人GDF15-his蛋白进行结合试验，该试验用于鉴定抗GDF15抗体的结合活性。简言之，将待检测的抗GDF15抗体包被到96孔板中(200ng/孔)，37℃孵育1小时，PBST洗涤后使用1％BSA室温封闭1h。随后加入梯度稀释的人GDF15-his溶液100μl/孔(剂量范围0～50μg/ml)，孵育后向各孔中加入100μl抗his标签二抗(抗his-HRP(1:2000)，博尔西，货号BHR790)，最后使用TMB溶液显色(100μl/孔)，并用2M H2SO4终止反应。测定OD450，并通过PRISM软件生成结合曲线，分析各候选抗体与抗原人GDF15的亲和力，计算EC50值。
结果如表5所示，抗GDF15抗体能够有效地结合人GDF15，其结合活性优于阳性对照抗体Hu01G06-127-IgG1或与之相当。
表5：抗GDF15抗体与人GDF15的结合活性
抗GDF15抗体中和活性的检测：
通过ELISA实验检测浓度梯度的抗GDF15抗体对GDF15和GFRAL受体结合的抑制活性，以IC50值作为衡量候选分子中和活性的标准。简言之，用100ng/孔的GFRAL-his蛋白(SEQ ID NO：74)包被96孔板，37℃孵育1小时，PBST溶液洗涤后用1％BSA于37℃封闭1小时。随后每孔加入梯度稀释的待检测抗体(剂量范围0～10μg/ml)，并立即加入等体积的人GDF15-hFc蛋白(0.5μg/ml)，完成孵育并洗涤后，向各孔中加入100μl抗人IgG二抗(山羊抗人IgG-HRP，Sigma，A8667)。最后使用TMB溶液显色(100μl/孔)，并用2M H2SO4终止反应。测定OD450，并通过PRISM生成结合曲线，计算IC50值。
结果如表6所示，9个抗GDF15抗体的IC50值达到nM级别，表明抗GDF15抗体能够有效地阻断GDF15与其受体GFRAL的结合，其中和活性优于阳性对照抗体Hu01G06-127-IgG1或与之相当。
表6：抗GDF15抗体中和活性
抗GDF15抗体生物学活性检测：
在GDF15-GFRAL/RET信号通路中，成熟的GDF15蛋白结合细胞表面的2个GFRAL蛋白后，招募另外两个共受体RET蛋白，形成一个复合物，诱发RET胞内信号肽的激活，进一步引起RET-Ras-Erk-SRF等关键信号传导。在293T细胞中过表达 GFRAL和RET蛋白，同时转入RET蛋白下游关键因子SRE的报告基因质粒，完成细胞转染及单克隆细胞株筛选，通过报告基因表达水平来评估抗GDF15抗体在细胞水平的生物学活性。
简言之，将携带人GFRAL/RET蛋白编码基因的质粒及携带RET下游蛋白报告基因的质粒pGL4.33[luc2p/SRE/Hygro](E1340，Promega)共转染293T细胞，筛选获得目的单克隆细胞株293T-GFRAL/RET-Luc。将293T-GFRAL/RET-Luc细胞接种在黑色避光96孔板中，过夜培养后，加入人GDF15-his蛋白稀释液(15ng/ml，含0.1％BSA的细胞培养液)，同时加入等体积梯度稀释的抗GDF15抗体(浓度范围0～0.5μg/ml)，37℃、5％CO2继续培养6小时。最后使用荧光素酶底物显色，读取信号发光值。通过PRISM生成抑制曲线，计算IC50值，用于分析各候选抗体的生物学活性。
结果如表7所示，抗GDF15抗体的IC50值均达到nM级别，表明抗GDF15抗体能够有效地阻断GFRAL和RET下游信号的激活，其生物学活性优于阳性对照抗体Hu01G06-127-IgG1或与之相当。
表7：抗GDF15抗体细胞生物学活性
抗GDF15抗体体内疾病模型活性检测：
选用肿瘤恶病质动物模型(HT1080模型)验证抗GDF15抗体的体内生物学活性。简言之，通过向NCG小鼠皮下注射HT1080细胞(1×106个细胞/每只动物)(ATCC，货号CCL-121)进行造模，在小鼠成瘤，且相对于正常小鼠出现体重明显下降后进行分组。模型组分为给药组和空白对照组，给药组进行单次静脉注射候选抗体GDF-R37-rabIg1(10mpk)，空白对照组注射PBS或生理盐水；正常小鼠组注射PBS或生理盐水。通过绘制小鼠体重变化率曲线来检测候选抗体的生物学活性。
结果如图1所示，示例性抗GDF15抗体GDF-R37-rabIg1能够有效地恢复模型组小鼠的体重。
实施例3:抗GDF15抗体的人源化
分别以获得的兔先导抗体GDF-R37-rabIg1的VH/VL的CDR典型结构为基础，将重、轻链可变区序列与抗体种系数据库中的序列进行比较，获得同源性高的人种系模 板。将兔抗体的CDR区移植到选定的人种系模板上以产生人源化的可变区，再与相应的人IgG恒定区(优选为IgG1重链(LALA)和κ轻链)重组。随后，以兔抗体的三维结构为基础对包埋残基、与CDR区有直接相互作用的残基以及对VH和VL的构象有重要影响的残基进行回复突变，并优化CDR区化学不稳定的氨基酸残基，从而获得18个人源化分子。人源化抗体的重链和轻链可变结构域序列如表2和表3所示。
另外，按照如上所述的人源化方法，同样对先导抗体GDF-R54-rabIg1进行人源化以及CDR区域的风险点改造，从而获得8个人源化分子hum_R54-1～hum_R54-8。人源化抗体的重链和轻链的可变结构域序列如表2A和表3A所示。
实施例4:人源化抗体的表征
采用实施例2中的相应的实验方案，分别检测人源化抗GDF15抗体的亲和力和生物活性，包括亲和力检测、中和活性检测以及生物学活性检测。
ELISA法检测抗GDF15抗体的亲和力
采用实施例2所述的亲和力检测方案，检测人源化后的抗体(人IgG1形式)与GDF15蛋白结合的能力。
来源于先导抗体GDF-R37-rabIg1的人源化分子结合活性的结果如图2A-2C所示，与先导抗体GDF-R37-rabIg1相比，人源化后的抗体(人IgG1形式)均表现出与之相当的GDF15结合活性，表明人源化并没有影响抗体的结合能力。
来源于先导抗体GDF-R54-rabIg1的人源化分子结合活性的结果如表11所示，人源化后的抗体(人IgG1形式)hum_R54-1、hum_R54-2、hum_R54-3、hum_R54-4、hum_R54-5、hum_R54-6、hum_R54-7、hum_R54-8均能够有效结合GDF15，其结合活性与阳性对照抗体Hu01G06-127-IgG1相当。
表11：人源化后抗GDF15抗体亲和力活性
ELISA检测抗GDF15抗体中和活性
采用实施例2所述的中和活性检测方案，检测人源化后的抗体(人IgG1形式)对GDF15和GFRAL结合的抑制能力。
来源于先导抗体GDF-R37-rabIg1的人源化分子中和活性的结果如表8A、图3A-3C所示，与先导抗体GDF-R37-rabIg1相比，人源化的抗GDF15抗体(人IgG1形式)均 表现出与之相当的中和活性，表明人源化的抗体能有效地抑制GDF15和GFRAL的结合。
来源于先导抗体GDF-R54-rabIg1的人源化分子中和活性的结果如表8B所示，人源化后的抗体(人IgG1形式)hum_R54-1、hum_R54-2、hum_R54-3、hum_R54-4、hum_R54-5、hum_R54-6、hum_R54-7、hum_R54-8均能够有效地阻断GDF15与其受体GFRAL的结合，其中和活性与阳性对照抗体Hu01G06-127-IgG1相当，甚至比阳性对照抗体更优。
表8A：人源化后抗GDF15抗体中和活性
表8B：人源化后抗GDF15抗体中和活性
检测抗GDF15抗体生物学活性
采用实施例2所述的生物学活性检测方案，检测人源化后的抗体(人IgG1形式)对GFRAL和RET下游信号激活的抑制活性。
来源于先导抗体GDF-R37-rabIg1的人源化分子的生物学活性结果如图4A-4D所示，与先导抗体GDF-R37-rabIg1相比，人源化后的抗体(人IgG1形式)均表现出与之相当的抑制作用。
来源于先导抗体GDF-R54-rabIg1的人源化分子的生物学活性结果如表12所示，人源化后的抗体(人IgG1形式)hum_R54-1、hum_R54-2、hum_R54-3、hum_R54-4、 hum_R54-5、hum_R54-6、hum_R54-7、hum_R54-8均能够有效地抑制GFRAL和RET下游信号的激活，其抑制活性与阳性对照抗体Hu01G06-127-IgG1相当或比阳性对照抗体更优。
表12：人源化后抗GDF15抗体生物学活性
Biacore法检测抗GDF15抗体亲和力
采用Biacore 8K(GE)表征抗GDF15抗体分别与人GDF15、恒河猴GDF15、小鼠GDF15的亲和力。将抗GDF15抗体固定于传感器芯片CM5上，检测不同浓度下的抗体分别与不同种属GDF15蛋白的亲和力，用SPR技术测量抗体的结合速率和解离速率，并确定结合亲和力，抗GDF15抗体的Kon、Koff以及Kd值如表9所示。
结果如表9所示，示例性人源化抗体hum-R37-2，hum-R37-5，hum-R37-8(人IgG1形式)不仅结合人的GDF15，还和恒河猴的GDF15有结合，与小鼠GDF15有较弱的结合。
表9：Biacore法检测人源化后分子的亲和力活性
实施例5：抗GDF15抗体的药代动力学
将16只SD大鼠随机分为四组，每组4只，雌雄各半。各组大鼠分别静脉注射10mpk人源化后的示例性抗GDF15抗体Hum-R37-2、Hum-R37-5、Hum-R37-8， Hu01G06-127-IgG1抗体作为阳性对照。首先在抗体注射前采集血液，随后依次在注射后的5min、1h、5h、1d、3d、7d、10d、14d和17d采集血液。血液离心后，收集血浆，用ELISA法检测各样本中的血药浓度。使用软件6.0版，通过非房室模型(NCA)确定药代动力学参数。使用各抗体各自的平均浓度值，用线性梯形法则以及线性内插法和均匀加权测定所有PK参数，包括最大血清浓度(Cmax)、最大血清浓度的时间(Tmax)、半衰期(T1/2)、表观分布容积(Vd)、清除率(Cl)、从给药时间开始至最后采样时间点测量浓度的曲线下面积(AUC(0-t))和从给药时间开始到无穷大时间的血药浓度时间曲线下面积(AUC(0-∞))等。
结果如表10所示，试验期间，未见给药相关的异常临床表现，给药抗体的各组动物间血浆药物浓度变化趋势基本一致。
表10：抗GDF15抗体药代动力学指标
实施例6：抗GDF15抗体体内疾病模型活性检测
选用小鼠快速减重模型(GDF15-hFc造模)验证抗GDF15抗体的体内生物学活性。简言之，通过向C57/BL6小鼠皮下注射人GDF15-hFc蛋白(造模剂量为2mpk)进行造模，在相较于正常小鼠出现体重明显下降后，分别进行单次静脉注射示例性候选抗体Hum-R37-2、Hum-R37-5、Hum-R37-8、hum_R54-3、hum_R54-4以及hum_R54-8，阳性对照抗体Hu01G06-127-IgG1，以及阴性对照抗体(来自舒泰神(北京)生物制药股份有限公司)，给药剂量为10mpk；正常小鼠组注射生理盐水。通过绘制小鼠体重变化率曲线来检测候选抗体的生物学活性。
结果如图5所示，示例性抗GDF15抗体Hum-R37-2、Hum-R37-5及Hum-R37-8均能够有效地恢复模型组小鼠的体重，且体内活性优于阳性对照抗体Hu01G06-127-IgG1，或与之相当。
示例性抗GDF15抗体hum_R54-3、hum_R54-4以及hum_R54-8均能够有效地恢复模型组小鼠的体重，且体内活性优于阳性对照抗体Hu01G06-127-IgG1，或与之相当(数据未显示)。

Claims (34)

  1. 一种分离的抗GDF15抗体，其中所述抗GDF15抗体包含：
    重链可变结构域(VH)，所述VH包含：
    重链互补决定区(HC-CDR)1，其包含X1YYMX2(SEQ ID NO:35)，其中X1为D或N，X2为S或T；
    HC-CDR2，其包含MISFSGTTX1ATWAKG(SEQ ID NO:36)，其中X1为H或Y；和
    HC-CDR3，其包含VVYAGWTYPLGI(SEQ ID NO:13)；以及
    轻链可变结构域(VL)，所述VL包含：
    轻链互补决定区(LC-CDR)1，其包含QASQSISSVLS(SEQ ID NO:18)；
    LC-CDR2，其包含EASX1X2AS(SEQ ID NO:37)，其中X1为I或T，X2为L或Q；和
    LC-CDR3，其包含QANYDVYNYGNP(SEQ ID NO:30)。
  2. 一种分离的抗GDF15抗体，其包含VH，
    所述VH包含：
    HC-CDR1，其包含SEQ ID NOs:1-2中任一所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；
    HC-CDR2，其包含SEQ ID NOs:7-8中任一所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；和
    HC-CDR3，其包含SEQ ID NO:13所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；以及
    VL，所述VL包含：
    LC-CDR1，其包含SEQ ID NO:18所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；
    LC-CDR2，其包含SEQ ID NOs:23-25中任一所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；和
    LC-CDR3，其包含SEQ ID NO:30所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代。
  3. 一种分离的抗GDF15抗体，其包含VH，所述VH包含如SEQ ID NOs:38-47中任一氨基酸序列所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，所 述VL包含如SEQ ID NOs:52-59中任一氨基酸序列所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
  4. 根据权利要求3中所述的分离的抗GDF15抗体，其包含：
    (i)VH，其包含如氨基酸序列SEQ ID NO:38所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:52所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；
    (ii)VH，其包含如氨基酸序列SEQ ID NO:45所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:56所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；
    (iii)VH，其包含如氨基酸序列SEQ ID NO:45所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:57所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；
    (iv)VH，其包含如氨基酸序列SEQ ID NO:46所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:58所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；或
    (v)VH，其包含如氨基酸序列SEQ ID NO:47所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:59所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
  5. 根据权利要求1-4中任一项所述的分离的抗GDF15抗体，其包含：
    (i)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:7，和HC-CDR3，其包含氨基酸序列SEQ ID NO:13，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:18，LC-CDR2，其包含氨基酸序列SEQ ID NO:23，和LC-CDR3，其包含氨基酸序列SEQ ID NO:30，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代；
    (ii)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:7，和HC-CDR3，其包含氨基酸序列SEQ ID NO:13，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ  ID NO:18，LC-CDR2，其包含氨基酸序列SEQ ID NO:24，和LC-CDR3，其包含氨基酸序列SEQ ID NO:30，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代；
    (iii)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:7，和HC-CDR3，其包含氨基酸序列SEQ ID NO:13，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:18，LC-CDR2，其包含氨基酸序列SEQ ID NO:25，和LC-CDR3，其包含氨基酸序列SEQ ID NO:30，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代；
    (iv)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:2，HC-CDR2，其包含氨基酸序列SEQ ID NO:7，和HC-CDR3，其包含氨基酸序列SEQ ID NO:13，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:18，LC-CDR2，其包含氨基酸序列SEQ ID NO:25，和LC-CDR3，其包含氨基酸序列SEQ ID NO:30，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代；或
    (v)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:1，HC-CDR2，其包含氨基酸序列SEQ ID NO:8，和HC-CDR3，其包含氨基酸序列SEQ ID NO:13，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:18，LC-CDR2，其包含氨基酸序列SEQ ID NO:25，和LC-CDR3，其包含氨基酸序列SEQ ID NO:30，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
  6. 根据权利要求1-5中任一项所述的分离的抗GDF15抗体，其包含：
    VH，其包含SEQ ID NOs:38-47中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:38-47中任一所示的氨基酸序列具有至少约80％序列同一性；以及VL，其包含SEQ ID NOs:52-59中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:52-59中任一所示的氨基酸序列具有至少约80％序列同一性。
  7. 根据权利要求6中所述的分离的抗GDF15抗体，其包含：
    (i)VH，其包含氨基酸序列SEQ ID NO:38或其变体，所述变体与氨基酸序列SEQ ID NO:38具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:52或其变体，所述变体与氨基酸序列SEQ ID NO:52具有至少约80％序列同一性；
    (ii)VH，其包含氨基酸序列SEQ ID NO:39或其变体，所述变体与氨基酸序列SEQ ID NO:39具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:53或其变体，所述变体与氨基酸序列SEQ ID NO:53具有至少约80％序列同一性；
    (iii)VH，其包含氨基酸序列SEQ ID NO:40或其变体，所述变体与氨基酸序列SEQ ID NO:40具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:53或其变体，所述变体与氨基酸序列SEQ ID NO:53具有至少约80％序列同一性；
    (iv)VH，其包含氨基酸序列SEQ ID NO:41或其变体，所述变体与氨基酸序列SEQ ID NO:41具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:53或其变体，所述变体与氨基酸序列SEQ ID NO:53具有至少约80％序列同一性；
    (v)VH，其包含氨基酸序列SEQ ID NO:42或其变体，所述变体与氨基酸序列SEQ ID NO:42具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:53或其变体，所述变体与氨基酸序列SEQ ID NO:53具有至少约80％序列同一性；
    (vi)VH，其包含氨基酸序列SEQ ID NO:43或其变体，所述变体与氨基酸序列SEQ ID NO:43具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:53或其变体，所述变体与氨基酸序列SEQ ID NO:53具有至少约80％序列同一性；
    (vii)VH，其包含氨基酸序列SEQ ID NO:44或其变体，所述变体与氨基酸序列SEQ ID NO:44具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:53或其变体，所述变体与氨基酸序列SEQ ID NO:53具有至少约80％序列同一性；
    (viii)VH，其包含氨基酸序列SEQ ID NO:39或其变体，所述变体与氨基酸序列SEQ ID NO:39具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:54或其变体，所述变体与氨基酸序列SEQ ID NO:54具有至少约80％序列同一性；
    (ix)VH，其包含氨基酸序列SEQ ID NO:40或其变体，所述变体与氨基酸序列SEQ ID NO:40具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:54或其变体，所述变体与氨基酸序列SEQ ID NO:54具有至少约80％序列同一性；
    (x)VH，其包含氨基酸序列SEQ ID NO:41或其变体，所述变体与氨基酸序列SEQ ID NO:41具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:54或其变体，所述变体与氨基酸序列SEQ ID NO:54具有至少约80％序列同一性；
    (xi)VH，其包含氨基酸序列SEQ ID NO:42或其变体，所述变体与氨基酸序列SEQ ID NO:42具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:54或其变体，所述变体与氨基酸序列SEQ ID NO:54具有至少约80％序列同一性；
    (xii)VH，其包含氨基酸序列SEQ ID NO:43或其变体，所述变体与氨基酸序列SEQ ID NO:43具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:54或其变体，所述变体与氨基酸序列SEQ ID NO:54具有至少约80％序列同一性；
    (xiii)VH，其包含氨基酸序列SEQ ID NO:44或其变体，所述变体与氨基酸序列SEQ ID NO:44具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:54或其变体，所述变体与氨基酸序列SEQ ID NO:54具有至少约80％序列同一性；
    (xiv)VH，其包含氨基酸序列SEQ ID NO:39或其变体，所述变体与氨基酸序列SEQ ID NO:39具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:55或其变体，所述变体与氨基酸序列SEQ ID NO:55具有至少约80％序列同一性；
    (xv)VH，其包含氨基酸序列SEQ ID NO:40或其变体，所述变体与氨基酸序列SEQ ID NO:40具有至少约80％序列同一性；以及VL，其包含氨基酸序列 SEQ ID NO:55或其变体，所述变体与氨基酸序列SEQ ID NO:55具有至少约80％序列同一性；
    (xvi)VH，其包含氨基酸序列SEQ ID NO:41或其变体，所述变体与氨基酸序列SEQ ID NO:41具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:55或其变体，所述变体与氨基酸序列SEQ ID NO:55具有至少约80％序列同一性；
    (xvii)VH，其包含氨基酸序列SEQ ID NO:42或其变体，所述变体与氨基酸序列SEQ ID NO:42具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:55或其变体，所述变体与氨基酸序列SEQ ID NO:55具有至少约80％序列同一性；
    (xviii)VH，其包含氨基酸序列SEQ ID NO:43或其变体，所述变体与氨基酸序列SEQ ID NO:43具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:55或其变体，所述变体与氨基酸序列SEQ ID NO:55具有至少约80％序列同一性；
    (xix)VH，其包含氨基酸序列SEQ ID NO:44或其变体，所述变体与氨基酸序列SEQ ID NO:44具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:55或其变体，所述变体与氨基酸序列SEQ ID NO:55具有至少约80％序列同一性；
    (xx)VH，其包含氨基酸序列SEQ ID NO:45或其变体，所述变体与氨基酸序列SEQ ID NO:45具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:56或其变体，所述变体与氨基酸序列SEQ ID NO:56具有至少约80％序列同一性；
    (xxi)VH，其包含氨基酸序列SEQ ID NO:45或其变体，所述变体与氨基酸序列SEQ ID NO:45具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:57或其变体，所述变体与氨基酸序列SEQ ID NO:57具有至少约80％序列同一性；
    (xxii)VH，其包含氨基酸序列SEQ ID NO:46或其变体，所述变体与氨基酸序列SEQ ID NO:46具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:58或其变体，所述变体与氨基酸序列SEQ ID NO:58具有至少约80％序列同一性；或
    (xxiii)VH，其包含氨基酸序列SEQ ID NO:47或其变体，所述变体与氨基酸序列SEQ ID NO:47具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:59或其变体，所述变体与氨基酸序列SEQ ID NO:59具有至少约80％序列同一性。
  8. 一种分离的抗GDF15抗体，其包含：
    (i)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:3，HC-CDR2，其包含氨基酸序列SEQ ID NO:9，和HC-CDR3，其包含氨基酸序列SEQ ID NO:14，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:19，LC-CDR2，其包含氨基酸序列SEQ ID NO:26，和LC-CDR3，其包含氨基酸序列SEQ ID NO:31，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代；
    (ii)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:4，HC-CDR2，其包含氨基酸序列SEQ ID NO:10，和HC-CDR3，其包含氨基酸序列SEQ ID NO:15，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:20，LC-CDR2，其包含氨基酸序列SEQ ID NO:27，和LC-CDR3，其包含氨基酸序列SEQ ID NO:32，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代；或
    (iii)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:5，HC-CDR2，其包含氨基酸序列SEQ ID NO:11，和HC-CDR3，其包含氨基酸序列SEQ ID NO:16，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:21，LC-CDR2，其包含氨基酸序列SEQ ID NO:28，和LC-CDR3，其包含氨基酸序列SEQ ID NO:33，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
  9. 根据权利要求8中所述的分离的抗GDF15抗体，其包含：
    VH，其包含SEQ ID NOs:48-50中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:48-50中任一所示的氨基酸序列具有至少约80％序列同一性；以及VL，其包含SEQ ID NOs:60-62中任一所示的氨基酸序列或其变体，所述 变体与SEQ ID NOs:60-62中任一所示的氨基酸序列具有至少约80％序列同一性。
  10. 根据权利要求8-9中任一项所述的分离的抗GDF15抗体，其包含：
    (i)VH，其包含SEQ ID NO:48所示的氨基酸序列或其变体，所述变体与SEQ ID NO:48所示的氨基酸序列具有至少约80％序列同一性；以及VL，其包含SEQ ID NO:60所示的氨基酸序列或其变体，所述变体与SEQ ID NO:60所示的氨基酸序列具有至少约80％序列同一性；
    (ii)VH，其包含SEQ ID NO:49所示的氨基酸序列或其变体，所述变体与SEQ ID NO:49所示的氨基酸序列具有至少约80％序列同一性；以及VL，其包含SEQ ID NO:61所示的氨基酸序列或其变体，所述变体与SEQ ID NO:61所示的氨基酸序列具有至少约80％序列同一性；或
    (iii)VH，其包含SEQ ID NO:50所示的氨基酸序列或其变体，所述变体与SEQ ID NO:50所示的氨基酸序列具有至少约80％序列同一性；以及VL，其包含SEQ ID NO:62所示的氨基酸序列或其变体，所述变体与SEQ ID NO:62所示的氨基酸序列具有至少约80％序列同一性。
  11. 根据权利要求8-10中任一项所述的分离的抗GDF15抗体，其包含VH，所述VH包含如SEQ ID NOs:48-50中任一氨基酸序列所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，所述VL包含如SEQ ID NOs:60-62中任一氨基酸序列所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
  12. 根据权利要求8-11中任一项所述的分离的抗GDF15抗体，其包含：
    (i)VH，其包含如氨基酸序列SEQ ID NO:48所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:60所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；
    (ii)VH，其包含如氨基酸序列SEQ ID NO:49所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:61所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；或
    (iii)VH，其包含如氨基酸序列SEQ ID NO:50所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:62所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
  13. 一种分离的抗GDF15抗体，其中所述抗GDF15抗体包含：
    重链可变结构域(VH)，所述VH包含：
    重链互补决定区(HC-CDR)1，其包含SYDMT(SEQ ID NO:6)；
    HC-CDR2，其包含IIX1X2SGX3TYYASWAKG(SEQ ID NO:79)，其中X1为N或S,X2为G,N,或S,以及X3为N或S；和
    HC-CDR3，其包含GILVYADYGDHNL(SEQ ID NO:17)；以及
    轻链可变结构域(VL)，所述VL包含：
    轻链互补决定区(LC-CDR)1，其包含QASEDIYTNLA(SEQ ID NO:22)；
    LC-CDR2，其包含AASTLAS(SEQ ID NO:29)；和
    LC-CDR3，其包含LGVYTYISAX1GA(SEQ ID NO:81)，其中X1为D或E。
  14. 一种分离的抗GDF15抗体，其包含：
    VH，所述VH包含：HC-CDR1，其包含SEQ ID NO:6所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；HC-CDR2，其包含SEQ ID NOs:12，75-78中任一所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；和HC-CDR3，其包含SEQ ID NO:17所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含SEQ ID NO:22所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；LC-CDR2，其包含SEQ ID NO:29所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代；和LC-CDR3，其包含SEQ ID NOs:34或80中任一所示的氨基酸序列或其变体，所述变体包含至多约3个氨基酸的取代。
  15. 一种分离的抗GDF15抗体，其包含VH，所述VH包含如SEQ ID NOs:51,82-89中任一氨基酸序列所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，所述VL包含如SEQ ID NOs:63,90-91中任一氨基酸序列所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
  16. 根据权利要求15中所述的分离的抗GDF15抗体，其包含：
    (i)VH，其包含如氨基酸序列SEQ ID NO:51所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:63所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；
    (ii)VH，其包含如氨基酸序列SEQ ID NO:82所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:90所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；
    (iii)VH，其包含如氨基酸序列SEQ ID NO:83所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:90所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；
    (iv)VH，其包含如氨基酸序列SEQ ID NO:84所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:90所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3；或
    (v)VH，其包含如氨基酸序列SEQ ID NO:85所示的VH包含的HC-CDR1、HC-CDR2和HC-CDR3；以及VL，其包含如氨基酸序列SEQ ID NO:90所示的VL包含的LC-CDR1、LC-CDR2和LC-CDR3。
  17. 根据权利要求13-16中任一项所述的分离的抗GDF15抗体，其包含：
    (i)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:12，和HC-CDR3，其包含氨基酸序列SEQ ID NO:17，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:22，LC-CDR2，其包含氨基酸序列SEQ ID NO:29，和LC-CDR3，其包含氨基酸序列SEQ ID NO:34，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代；
    (ii)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:75，和HC-CDR3，其包含氨基酸序列SEQ ID NO:17，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:22，LC-CDR2，其包含氨基酸序列SEQ ID NO:29，和LC-CDR3，其包含氨基酸序列SEQ ID NO:80，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代；
    (iii)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:76，和HC-CDR3，其包含氨基酸序列SEQ ID NO:17，或者所述VH的变体，其HC-CDRs中包含至多约5个氨 基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:22，LC-CDR2，其包含氨基酸序列SEQ ID NO:29，和LC-CDR3，其包含氨基酸序列SEQ ID NO:80，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代；
    (iv)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:77，和HC-CDR3，其包含氨基酸序列SEQ ID NO:17，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:22，LC-CDR2，其包含氨基酸序列SEQ ID NO:29，和LC-CDR3，其包含氨基酸序列SEQ ID NO:80，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代；或
    (v)VH，所述VH包含：HC-CDR1，其包含氨基酸序列SEQ ID NO:6，HC-CDR2，其包含氨基酸序列SEQ ID NO:78，和HC-CDR3，其包含氨基酸序列SEQ ID NO:17，或者所述VH的变体，其HC-CDRs中包含至多约5个氨基酸的取代；以及VL，所述VL包含：LC-CDR1，其包含氨基酸序列SEQ ID NO:22，LC-CDR2，其包含氨基酸序列SEQ ID NO:29，和LC-CDR3，其包含氨基酸序列SEQ ID NO:80，或者所述VL的变体，其LC-CDRs中包含至多约5个氨基酸的取代。
  18. 根据权利要求13-17中任一项所述的分离的抗GDF15抗体，其包含：
    VH，其包含SEQ ID NOs:51,82-89中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:51,82-89中任一所示的氨基酸序列具有至少约80％序列同一性；以及VL，其包含SEQ ID NOs:63,90-91中任一所示的氨基酸序列或其变体，所述变体与SEQ ID NOs:63,90-91中任一所示的氨基酸序列具有至少约80％序列同一性。
  19. 根据权利要求18中所述的分离的抗GDF15抗体，其包含：
    (i)VH，其包含氨基酸序列SEQ ID NO:51或其变体，所述变体与氨基酸序列SEQ ID NO:51具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:63或其变体，所述变体与氨基酸序列SEQ ID NO:63具有至少约80％序列同一性；
    (ii)VH，其包含氨基酸序列SEQ ID NO:82或其变体，所述变体与氨基酸序列SEQ ID NO:82具有至少约80％序列同一性；以及VL，其包含氨基酸序列 SEQ ID NO:90或其变体，所述变体与氨基酸序列SEQ ID NO:90具有至少约80％序列同一性；
    (iii)VH，其包含氨基酸序列SEQ ID NO:83或其变体，所述变体与氨基酸序列SEQ ID NO:83具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:90或其变体，所述变体与氨基酸序列SEQ ID NO:90具有至少约80％序列同一性；
    (iv)VH，其包含氨基酸序列SEQ ID NO:84或其变体，所述变体与氨基酸序列SEQ ID NO:84具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:90或其变体，所述变体与氨基酸序列SEQ ID NO:90具有至少约80％序列同一性；
    (v)VH，其包含氨基酸序列SEQ ID NO:85或其变体，所述变体与氨基酸序列SEQ ID NO:85具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:90或其变体，所述变体与氨基酸序列SEQ ID NO:90具有至少约80％序列同一性；
    (vi)VH，其包含氨基酸序列SEQ ID NO:86或其变体，所述变体与氨基酸序列SEQ ID NO:86具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:91或其变体，所述变体与氨基酸序列SEQ ID NO:91具有至少约80％序列同一性；
    (vii)VH，其包含氨基酸序列SEQ ID NO:87或其变体，所述变体与氨基酸序列SEQ ID NO:87具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:91或其变体，所述变体与氨基酸序列SEQ ID NO:91具有至少约80％序列同一性；
    (viii)VH，其包含氨基酸序列SEQ ID NO:88或其变体，所述变体与氨基酸序列SEQ ID NO:88具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:91或其变体，所述变体与氨基酸序列SEQ ID NO:91具有至少约80％序列同一性；或
    (ix)VH，其包含氨基酸序列SEQ ID NO:89或其变体，所述变体与氨基酸序列SEQ ID NO:89具有至少约80％序列同一性；以及VL，其包含氨基酸序列SEQ ID NO:91或其变体，所述变体与氨基酸序列SEQ ID NO:91具有至少约80％序列同一性。
  20. 根据权利要求1-19中任一项所述的分离的抗GDF15抗体，其中所述抗GDF15抗体与人GDF15结合的Kd值为约0.1pM至约10nM。
  21. 一种分离的抗GDF15抗体，其与权利要求1-20中任一项所述的分离的抗GDF15抗体竞争与GDF15的特异性结合，或与权利要求1-20中任一项所述的分离的抗GDF15抗体特异性地结合相同的表位。
  22. 根据权利要求1-21中任一项的分离的抗GDF15抗体，其中所述抗GDF15抗体包含Fc片段。
  23. 根据权利要求22中的分离的抗GDF15抗体，其中所述抗GDF15抗体是全长的IgA、IgD、IgE、IgG或IgM抗体。
  24. 根据权利要求23中的分离的抗GDF15抗体，其中所述抗GDF15抗体是全长的IgG1、IgG2、IgG3或IgG4抗体。
  25. 根据权利要求1-24中任一项的分离的抗GDF15抗体，其中所述抗GDF15抗体是嵌合的、人的或人源化的抗体。
  26. 根据权利要求1-21中任一项的分离的抗GDF15抗体，其中所述抗GDF15抗体是抗原结合片段，所述抗原结合片段选自Fab、Fab’、F(ab)’2、Fab’-SH、单链Fv(scFv)、Fv片段、dAb、Fd、纳米抗体(nanobody)、双链抗体(diabody)和线性抗体。
  27. 一种分离的编码权利要求1-26中任一项所述的抗GDF15抗体的核酸分子。
  28. 一种包含权利要求27中所述的核酸分子的载体。
  29. 一种分离的宿主细胞，其包含权利要求1-26中任一项所述的抗GDF15抗体、权利要求27中所述的核酸分子或权利要求28中所述的载体。
  30. 一种制备抗GDF15抗体的方法，其包含：
    a)在能有效表达抗GDF15抗体的条件下培养权利要求29中所述的宿主细胞；和
    b)从宿主细胞中获得表达的抗GDF15抗体。
  31. 一种药物组合物，其包含权利要求1-26中任一项所述的抗GDF15抗体、权利要求27中所述的核酸分子、权利要求28中所述的载体、权利要求29中所述的分离的宿主细胞或由权利要求30中所述方法制备得到的抗体，以及药学上可接受的载体。
  32. 权利要求1-26中任一项所述的抗体、权利要求27中所述的核酸分子、权利要求28中所述的载体、权利要求29中所述的宿主细胞、由权利要求30中所述方法制 备得到的抗体、或权利要求31中所述的药物组合物在制备治疗有此需求的个体疾病或病症的药物中的用途。
  33. 根据权利要求32中的用途，其中所述疾病或病症是与GDF15信号通路失调导致的疾病和/或病症，例如癌症、恶液质和/或代谢性疾病。
  34. 根据权利要求33中的用途，其中所述疾病或病症选自癌症(如脑癌、黑素瘤、肺癌、胃肠道肿瘤、结肠癌、胰腺癌、前列腺癌、乳腺癌、口腔癌、肝癌、白血病、霍奇金淋巴瘤，非霍奇金淋巴瘤、膀胱癌、子宫颈癌、子宫体癌、睾丸癌，甲状腺癌、肾癌、胆囊癌、多发性骨髓瘤、鼻咽癌、喉癌、咽癌，食道癌等)，恶液质，肾衰竭、脓毒症、AIDS、慢性阻塞性肺病引起的恶液质，恶液质相关的体重减少，放疗、化疗引起的恶心呕吐，晚期慢性小管间质性肾炎，孕吐，肝硬化，肌少症，代谢性疾病(如脂肪和能量代谢失衡、调节食欲、调节体重)。
PCT/CN2023/092690 2022-05-09 2023-05-08 特异性识别gdf15的抗体及其应用 WO2023217068A1 (zh)

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