Methods of reducing weight loss using anti-gdf15 antibodies

Abstract

Provided herein are methods of reducing weight loss in a subject having cancer comprising administering to the subject one or more 12.5-800 mg doses of an anti-GDF15 antibody. Also provided are methods of reducing weight loss in a subject having cancer receiving standard-of-care chemotherapy comprising administering to the subject an anti-GDF15 antibody.

Description

[0001] Related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 585,792, filed September 27, 2023, the entirety of which is hereby incorporated by reference.

[0003] sequence list

[0004] The following sequence list XML content is incorporated herein by reference in its entirety: Computer-readable form of sequence lists (CRF) (filename: sequence_listing_406767-AVO-049WO_2024-09-26.XML, created: September 26, 2024, size: 94,208 bytes). Technical Field

[0005] This disclosure relates to anti-GDF15 antibodies and methods of using them. Background Technology

[0006] Cachexia is a complex metabolic syndrome characterized by significant involuntary weight loss, primarily due to the wasting of muscle and adipose tissue, along with severe inflammation and anemia. This wasting condition is characterized by involuntary weight loss, leading to progressive weakness, muscle atrophy, treatment resistance, and death. Weight loss is thought to result from energy imbalances caused by reduced food intake and a shift from anabolism to catabolism. The combined effects of these metabolic changes are loss of skeletal muscle mass, muscle strength and function, and increased mortality. Cachexia is associated not only with cancer, chronic kidney disease, and heart failure, but also with other underlying chronic diseases such as rheumatoid arthritis, chronic obstructive pulmonary disease, and other conditions.

[0007] In all these diseases, the presence of cachexia is associated with increased mortality. It is estimated that up to 80% of cancer patients develop cachexia during the course of their disease, and 20% to 30% of cancer-related deaths are attributed to cachexia. The prevalence of cachexia depends on the type of cancer: 50% to 80% of patients with prostate, lung, colorectal, head and neck, stomach, esophageal, and pancreatic cancer develop cachexia during the course of their disease. Given the limited effectiveness of current treatments that traditionally focus on nutritional support, the prevalence and mortality associated with cachexia represent a significant unmet therapeutic need.

[0008] GDF15 is an inflammatory cytokine involved in stress response and body weight regulation. The mature form of GDF15 is a 25-kDa disulfide-linked dimer belonging to the transforming growth factor β superfamily. GDF15 has been shown to be significantly overexpressed by tumors in patients with colorectal cancer (CRC), prostate cancer, metastatic breast cancer, and other malignancies. Long-term elevated circulating GDF15 levels are associated with cachexia in cancer patients. GDF15 is a promising intervention target for cachexia. Summary of the Invention

[0009] This disclosure provides a method for reducing weight loss in subjects by administering anti-GDF antibodies. Specifically, this disclosure provides a method for reducing weight loss in subjects receiving standard-of-care chemotherapy.

[0010] On one hand, this article provides a method for reducing weight loss in subjects with cancer, which involves administering 12.5–800 mg of anti-GDF15 antibody to the subjects.

[0011] In some embodiments, the anti-GDF15 antibody comprises CDRH1, CDRH2, and CDRH3 of VH, wherein the VH comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 67-84, and CDRH1, CDRH2, and CDRH3 of VL, wherein the VL comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 58-66.

[0012] In some embodiments, CDRH1, CDRH2 and CDRH3 each comprise an amino acid sequence selected from the group consisting of: SEQ ID NO: 1, 4 and 13; 1, 5 and 13; 1, 6 and 13; 1, 7 and 13; 1, 8 and 13; 1, 9 and 13; 2, 10 and 14; 2, 11 and 14; and 3, 12 and 15.

[0013] In some embodiments, CDRL1, CDRL2, and CDRL3 each comprise an amino acid sequence selected from the group consisting of: SEQ ID NO: 16, 18, and 21; 16, 18, and 22; 17, 19, and 23; and 17, 20, and 24.

[0014] In some embodiments, CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 each comprise an amino acid sequence selected from the group consisting of: SEQ ID NO: 1, 4, 13, 16, 18, and 21; 1, 4, 13, 16, 18, and 22; 1, 4, 13, 17, 19, and 23; 1, 4, 13, 17, 20, and 24; 1, 5, 13, 16, 18, and 21; 1, 5, 13, 16, 18, and 22; 1, 5, 13, 17, 19, and 23; 1, 5, 13, 17, 20, and 24; 1, 6, 13, 16, 18, and 21 ...8, 19, and 22; 1, 6, 18, 19, and 23; 1, 6, 18, 19, and 23; 1, 6, 18, 19, and 23; 1, 6, 18, 19, and 23; 1 , 13, 16, 18 and 22; 1, 6, 13, 17, 19 and 23; 1, 6, 13, 17, 20 and 24; 1, 7, 13, 16, 18 and 21; 1, 7, 13, 16, 18 and 22; 1, 7, 13, 17, 19 and 23; 1, 7, 13, 17, 20 and 24; 1, 8, 13, 16, 18 and 21; 1, 8, 13, 16, 18 and 22; 1, 8, 13, 17, 19 and 23; 1, 8, 13, 17, 20 and 24; 1, 9, 13, 16, 18 and 21; 1, 9, 13, 16, 18 and 22; 1, 9, 13, 17, 19 and 23; 1, 9, 13, 17, 20 and 24; 2, 10, 14, 16, 18 and 21; 2, 10, 14, 16, 18 and 22; 2, 10, 14, 17, 19 and 23; 2, 10, 14 17, 20 and 24; 2, 11, 14, 16, 18 and 21; 2, 11, 14, 16, 18 and 22; 2, 11, 14, 17, 19 and 23; 2, 11, 14, 17, 20 and 24; 3, 12, 15, 16, 18 and 21; 3, 12, 15, 16, 18 and 22; 3, 12, 15, 17, 19 and 23; and 3, 12, 15, 17, 20 and 24.

[0015] In some embodiments, the anti-GDF15 antibody comprises a VH, said VH containing an amino acid sequence that is at least 95% identical to the amino acid sequence selected from the group consisting of SEQ ID NO: 67-84.

[0016] In some embodiments, the anti-GDF15 antibody comprises a VL containing an amino acid sequence that is at least 95% identical to the amino acid sequence selected from the group consisting of SEQ ID NO: 58-66.

[0017] In some embodiments, the anti-GDF15 antibody comprises VH and VL, wherein each VH and VL comprises an amino acid sequence that is at least 95% identical to an amino acid sequence selected from the group consisting of: SEQ ID NO: 58 and 67, 59 and 68, 59 and 69, 59 and 70, 59 and 71, 59 and 72, 59 and 73, 59 and 74, 60 and 70, 60 and 71, 60 and 72, 60 and 73, 60 and 74, 61 and 70, 61 and 71, 61 and 72, 61 and 73, 61 and 74, 61 and 75, 62 and 76, 61 and 77, 61 and 78, 62 and 78, 63 and 79, 64 and 80, 64 and 81, 65 and 82, 65 and 79, 63 and 82, 66 and 83, and 66 and 84.

[0018] In some embodiments, the anti-GDF15 antibody comprises VH and VL, wherein VH and VL each comprise an amino acid sequence selected from the group consisting of: SEQ ID NO: 58 and 67, 59 and 68, 59 and 69, 59 and 70, 59 and 71, 59 and 72, 59 and 73, 59 and 74, 60 and 70, 60 and 71, 60 and 72, 60 and 73, 60 and 74, 61 and 70, 61 and 71, 61 and 72, 61 and 73, 61 and 74, 61 and 75, 62 and 76, 61 and 77, 61 and 78, 62 and 78, 63 and 79, 64 and 80, 64 and 81, 65 and 82, 65 and 79, 63 and 82, 66 and 83, and 66 and 84.

[0019] In some implementations, the anti-GDF15 antibody is administered weekly or every two weeks. In other implementations, the anti-GDF15 antibody is administered every seven days or every fourteen days.

[0020] In some embodiments, the anti-GDF15 antibody is administered intravenously. In other embodiments, the anti-GDF15 antibody is administered subcutaneously.

[0021] In some embodiments, the anti-GDF15 antibody is administered at a dose of approximately 12.5 mg, approximately 25 mg, approximately 50 mg, approximately 100 mg, approximately 200 mg, approximately 400 mg, or approximately 800 mg weekly or every two weeks.

[0022] In some implementations, the cancer is selected from the group consisting of: colorectal cancer, pancreatic cancer, prostate cancer, lung cancer, ovarian cancer, and breast cancer. In some implementations, the cancer is metastatic cancer.

[0023] In some implementations, the subject's serum GDF15 level is elevated. In some implementations, the subject's serum GDF15 level is >1200 pg / mL.

[0024] In some implementations, the anti-GDF15 antibody is administered to the subject concurrently or sequentially in combination with another therapeutic agent. In some implementations, the other therapeutic agent is a standard-of-care chemotherapy agent. In some implementations, the other therapeutic agent is FOLFOX, FOLFOXIRI, FOLFIRINOX, bevacizumab, or any combination thereof.

[0025] In some embodiments, the subject regained lost weight after administration of the anti-GDF15 antibody. In some embodiments, at least 5% of the lost weight was regained. In some embodiments, the subject's weight was maintained for at least one month after administration of the anti-GDF15 antibody. In some embodiments, the subject's weight was maintained within 5% of the subject's weight at the time of the first administration of the anti-GDF15 antibody. In some embodiments, the rate of weight loss was slowed. In some embodiments, the rate of weight loss was slowed by at least 5% after the first administration of the anti-GDF15 antibody.

[0026] In another aspect, this article provides the use of anti-GDF15 antibodies to reduce weight loss in subjects with cancer, which includes administering 12.5–800 mg of anti-GDF15 antibody to the subject.

[0027] In another aspect, this article provides the use of anti-GDF15 antibodies in the preparation of medicaments for reducing weight loss in subjects with cancer, which includes administering 12.5–800 mg of anti-GDF15 antibodies to the subjects. Attached Figure Description

[0028] Figure 1 The study design of a phase 1b dose escalation study of AV-380 in combination with standard-of-care chemotherapy in patients with metastatic cancer who had cachexia and elevated GDF15 levels is shown. Detailed Implementation

[0029] This disclosure provides a method for reducing weight loss in subjects by administering anti-GDF antibodies. Specifically, this disclosure provides a method for reducing weight loss in subjects receiving standard-of-care chemotherapy.

[0030] definition

[0031] As used herein, the term "antibody" includes full-length antibodies, antigen-binding fragments of full-length antibodies, and molecules containing antibody CDR, VH region, and / or VL region. Examples of antibodies include, but are not limited to, monoclonal antibodies, recombinant antibodies, monospecific antibodies, multispecific antibodies (including bispecific antibodies), human antibodies, humanized antibodies, chimeric antibodies, immunoglobulins, synthetic antibodies, tetrameric antibodies composed of two heavy chains and two light chains, antibody light chain monomers, antibody heavy chain monomers, antibody light chain dimers, antibody heavy chain dimers, antibody light chain-antibody heavy chain pairs, intracellular antibodies, heteroconjugated antibodies, antibody-drug conjugates, single-domain antibodies (sdAbs), monovalent antibodies, single-chain antibodies or single-chain Fvs (scFvs), camelified antibodies, affinity molecules, VHH fragments, Fab fragments, F(ab')2 fragments, disulfide-linked Fvs (sdFvs), anti-idiotypic (anti-Id) antibodies (including, for example, anti-anti-Id antibodies), and antigen-binding fragments of any of the above antibodies. Antibodies can be any type of immunoglobulin molecule (e.g., IgG, IgE, IgM, IgD, IgA, or IgY), any class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, or IgA2), or any subclass (e.g., IgG). 2a or IgG 2b ) or species (e.g., mouse IgG) 2a or IgG 2b In some implementations, the antibody described herein is an IgG1 antibody.

[0032] As used herein, the terms “antigen-binding domain,” “antigen-binding region,” “antigen-binding fragment,” and similar terms refer to any polypeptide that specifically binds to an antigen. Examples of antigen-binding domains include antibody-derived polypeptides such as Fab fragments, F(ab')2 fragments, disulfide-linked Fv (sdFv), single-chain Fv (scFv), CDR, VH domains, VL domains, single-domain antibodies (sdAb), VHH fragments, camelid antibodies, and any of the aforementioned antigen-binding fragments. The terminology also covers synthetic antigen-binding proteins or antibody mimics, such as, for example, anticalcitonins and DARPins.

[0033] As used herein, the terms “variable region” and “variable domain” are used interchangeably and are generally applicable in the art. A variable region typically refers to a portion of an antibody, generally a portion of a light or heavy chain, typically about 110 to 120 amino acids from the amino terminus in a mature heavy chain and about 90 to 115 amino acids from the amino terminus in a mature light chain. These amino acids vary considerably in sequence between antibodies and are responsible for the binding and specificity of a particular antibody to its specific antigen. Sequence variations are concentrated in regions called complementarity-determining regions (CDRs), while highly conserved regions within a variable domain are called framework regions (FRs). For example, generally, each heavy chain variable region has three CDRs (e.g., HCDR1, HCDR2, and HCDR3), and each light chain variable region also has three CDRs (LCDR1, LCDR2, and LCDR3). While not wishing to be bound by any particular mechanism or theory, it is generally accepted that the CDRs of both the light and heavy chains are primarily responsible for antibody-antigen interactions and specificity. In some embodiments, the variable region is a human variable region.

[0034] The terms “VL” and “VL domain” are used interchangeably to refer to the variable region of the light chain of an antibody.

[0035] The terms "VH" and "VH domain" are used interchangeably to refer to the variable region of the heavy chain of an antibody.

[0036] As used herein, the terms “constant region” or “constant domain” are used interchangeably and have the meanings commonly understood in the art. A constant region is an antibody portion, such as the carboxyl-terminal portion of the light and / or heavy chain, that does not directly participate in antibody-antigen binding but can exhibit various effector functions, such as interacting with Fc receptors. Compared to the variable domains of immunoglobulins, the constant regions of immunoglobulin molecules typically have a more conserved amino acid sequence.

[0037] As used herein, the term "heavy chain" when referring to antibodies can refer to any different type, such as α, δ, ε, γ, and μ based on constant domain amino acid sequences that produce IgA, IgD, IgE, IgG, and IgM antibodies, including subclasses of IgG such as IgG1, IgG2, IgG3, and IgG4. In a specific embodiment, the heavy chain is the human heavy chain.

[0038] As used herein, the term "light chain" when referring to an antibody can refer to any different type, such as kappa (κ) or lambda (λ) based on a constant domain amino acid sequence. Light chain amino acid sequences are well known in the art. In this particular embodiment, the light chain is a human light chain.

[0039] As used herein, the term "Fc region" refers to the portion of an immunoglobulin formed by the Fc domains of its two heavy chains. The Fc region can be a wild-type Fc region (natural Fc region) or a variant Fc region. The natural Fc region is a homodimer. The Fc region can be derived from any natural immunoglobulin. In some embodiments, the Fc region is formed by the constant region of the IgA, IgD, IgE, or IgG heavy chain. In some embodiments, the Fc region is formed by the constant region of the IgG heavy chain. In some embodiments, the IgG heavy chain is the constant region of the IgG1, IgG2, IgG3, or IgG4 heavy chain. In some embodiments, the Fc region is formed by the constant region of the IgG1 heavy chain.

[0040] As used herein, the term "variant Fc region" refers to an Fc region variant that has one or more alterations relative to the native Fc region. Alterations may include amino acid substitutions, additions and / or deletions, additional linkages, and / or changes to the native glycan. The term encompasses heterodimeric Fc regions, where each constituent Fc domain is distinct. The term also encompasses single-chain Fc regions, where the constituent Fc domains are linked together by linker portions.

[0041] As used herein, the term "Fc domain" refers to a portion of an antibody's CH2 and CH3 domains contained within a single immunoglobulin heavy chain. In some embodiments, the Fc domain includes a portion of a hinge region (e.g., an upper hinge region, a middle hinge region, and / or a lower hinge region), a CH2 domain, and a CH3 domain.

[0042] As used herein, the term "hinge region" refers to the portion of a heavy-chain molecule that connects the CH1 and CH2 domains. This hinge region contains approximately 25 amino acid residues and is flexible, thus allowing the two N-terminal antigen-binding regions to move independently. The hinge region can be divided into three distinct domains: the upper hinge domain, the middle hinge domain, and the lower hinge domain.

[0043] As used herein, the term “EU position” refers to the amino acid position in the EU numbering rules for the Fc region as described by Edelman, GM et al., Proc. Natl. Acad. USA, 63, 78-85 (1969) and Kabat et al., in “Sequences of Proteins of Immunological Interest,” US Dept. Health and Human Services, 5th edition, 1991.

[0044] As used herein, the term "affinity" or "binding affinity" refers to the strength of the binding interaction between two molecules, such as the binding interaction between an antibody and an antigen. Unless otherwise stated, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of molecule X for its partner Y can generally be determined by the equilibrium dissociation constant (K0). D Affinity can be expressed in various ways known in the art, including but not limited to the equilibrium dissociation constant (K). D ) and equilibrium association constant (K A K D By k off / k on The quotient is calculated, and K A By k on / k off The quotient is calculated from k. on This refers to, for example, the association rate constant between an antibody and an antigen, and k off This refers to, for example, the dissociation of antibodies and antigens. on and k off It can be determined by techniques known to those skilled in the art, such as BIAcore. ® Or KinExA.

[0045] As used herein, "epitope" is a term in the art and refers to a localized region on an antigen that an antibody can specifically bind to. For example, an epitope can be an adjacent amino acid of a polypeptide (linear or adjacent epitope), or an epitope can consist of two or more non-adjacent regions of one or more polypeptides (conformational epitope, nonlinear epitope, discontinuous epitope, or non-adjacent epitope). In some embodiments, the antibody-binding epitope can be determined by, for example, NMR spectroscopy, X-ray diffraction crystallography, ELISA assays, hydrogen / deuterium exchange coupled with mass spectrometry (e.g., liquid chromatography-electrospray mass spectrometry), array-based oligopeptide scanning assays, and / or mutagenesis mapping (e.g., site-directed mutagenesis mapping). For X-ray crystallography, crystallization can be performed using any method known in the art (e.g., Giege R et al., (1994) Acta Crystallogr D Biol Crystallogr 50(Pt4): 339-350; McPherson A (1990) Eur J Biochem 189: 1-23; Chayen NE (1997) Structure 5: 1269-1274; McPherson A (1976) J Biol Chem 251: 6300-6303). Antibodies: Antigen crystals can be studied using well-known X-ray diffraction techniques and refined using computer software such as X-PLOR (Yale University, 1992, published by Molecular Simulations, Inc.; see, for example, Meth Enzymol (1985) Vols. 114 and 115, edited by Wyckoff HW et al.; US 2004 / 0014194) and BUSTER (Bricogne G (1993) Acta Crystallogr D Biol Crystallogr 49(Pt 1): 37-60; Bricogne G (1997) MethEnzymol 276A: 361-423, edited by Carter CW; Roversi P et al., (2000) Acta Crystallogr DBiol Crystallogr 56(Pt 10): 1316-1323). Mutagenesis mapping studies can be performed using any method known to those skilled in the art. For descriptions of mutagenesis techniques, see, for example, Champe M et al., (1995) J Biol Chem270: 1388-1394 and Cunningham BC and Wells JA (1989) Science 244:1081-1085, including alanine scanning mutagenesis.In one specific implementation, the AlphaFold multimer algorithm is used to predict the epitopes of the antibody.

[0046] As used herein, the term "specific binding" refers to the specificity of a binding molecule (e.g., an antibody) to an antigen, as understood by those skilled in the art. A binding molecule that specifically binds to an antigen typically has an equilibrium dissociation constant (K0) associated with the antigen. D Less than 1×10 −6 M, as measured by, for example, ELISA, surface plasmon resonance, or other suitable assays known to those skilled in the art. Those skilled in the art will understand that, in some embodiments, the binding molecule can specifically bind to different antigens, for example, different antigens having a common epitope recognized by the binding molecule.

[0047] As used herein, the term “GDF15” (also known as “growth differentiation factor-15” or “GDF-15”) refers to a member of the transforming growth factor-β (TGF-β) protein superfamily. Other names for “GDF15” include macrophage inhibitory cytokine 1 (or MIC1), NSAID activating gene 1 protein (or NAG1), NSAID regulatory gene 1 protein (or NRG-1), placental TGF-β (or PTGFB), placental bone morphogenetic protein (or PLAB), and prostate differentiation factor (or PDF).

[0048] Mathematical algorithms can be used to determine the "percentage of identity" between two sequences (e.g., amino acid sequences or nucleic acid sequences). A specific, non-limiting example of a mathematical algorithm for comparing two sequences is the algorithm in Karlin S & Altschul SF, (1990) PNAS 87: 2264-2268, modified as in Karlin S and Altschul SF, (1993) PNAS 90: 5873-5877, each of which is incorporated herein by reference in its entirety. This algorithm is incorporated into the NBLAST and XBLAST procedures in Altschul SF et al., (1990) J Mol Biol 215: 403, which is also incorporated herein by reference in its entirety. BLAST nucleotide searches can be performed using NBLAST nucleotide procedure parameter settings (e.g., score = 100, word length = 12) to obtain nucleotide sequences homologous to the nucleic acid molecules described herein. BLAST protein searches can be performed using XBLAST program parameter settings (e.g., score = 50, word length = 3) to obtain amino acid sequences homologous to the protein molecules described herein. For obtaining vacancy alignments for comparison, Gapped BLAST can be used as described in Altschul SF et al., (1997) Nuc Acids Res 25: 3389-3402, which is incorporated herein by reference in its entirety. Alternatively, iterative searches can be performed using PSI BLAST, which detects long-distance relationships between molecules. Ibid. When using BLAST, Gapped BLAST, and PSI BLAST programs, the default parameters of the respective programs (e.g., the default parameters for XBLAST and NBLAST) can be used (see, for example, the website of the National Center for Biotechnology Information (NCBI), ncbi.nlm.nih.gov). Another specific, non-limiting example of a mathematical algorithm for sequence comparison is the algorithm of Myers and Miller, (1988) CABIOS 4:11-17, which is incorporated herein by reference in its entirety. This algorithm is incorporated into the ALIGN program (version 2.0), which is part of the GCG sequence alignment software package. When comparing amino acid sequences using the ALIGN program, a PAM120 weighted residue table, a vacancy length penalty of 12, and a vacancy penalty of 4 can be used.

[0049] Similar techniques to those described above can be used to determine the percentage of identity between two sequences, regardless of whether gaps are allowed. When calculating the percentage of identity, typically only exact matches are counted.

[0050] As used herein, with respect to antibodies or polynucleotides, the term "isolated" refers to an antibody or polynucleotide isolated from one or more contaminants (e.g., polypeptides, polynucleotides, lipids, or carbohydrates) present in the natural source of the antibody or polynucleotide. All examples of "isolated antibodies" described herein are also contemplated as antibodies that may (but do not have to) be isolated. All examples of "isolated polynucleotides" described herein are also contemplated as polynucleotides that may (but do not have to) be isolated. All examples of "antibodies" described herein are also contemplated as antibodies that may (but do not have to) be isolated. All examples of "polynucleotides" described herein are also contemplated as polynucleotides that may (but do not have to) be isolated.

[0051] As used herein, the terms “treat,” “treating,” and “treatment” refer to the treatment or preventative measures described herein. A “treatment” method involves administering a peptide to a subject who has a disease or condition, or is susceptible to such a disease or condition, to prevent, cure, delay, reduce, alleviate, or relapse the severity of the disease or condition, or improve one or more of its symptoms, or to prolong the subject’s life beyond their expected lifespan without such treatment.

[0052] As used in this article, the term "effective amount" in the context of administering a therapy to a subject refers to the amount of therapy that achieves the desired preventive or therapeutic effect.

[0053] As used herein, the term "subject" includes any human or non-human animal. In one embodiment, the subject is a human or non-human mammal. In another embodiment, the subject is a human.

[0054] As used herein, the terms “about” or “approximately” when referring to measurable values ​​(such as doses) cover variations of ±20%, ±15%, ±10%, ±5%, ±1%, or ±0.1% of a given value or range, provided that such variation is suitable for the methods disclosed herein.

[0055] GDF15 regulator

[0056] As used herein, “GDF15 modulator” should be understood to mean an agent that reduces or inhibits GDF15 activity or GDF15 pathway activity, which may be due to a decrease in the expression, amount, biological activity, or function of GDF15 or the GDF15 pathway. GDF15 modulators or modulating agents that may be used in the practice of this invention may include anti-GDF15 antibodies, anti-GDF15 receptor antibodies, soluble GDF15 mimics or analogs (which prevent GDF15 from binding to its homologous binding partner), and soluble GDF15 receptor mimics or analogs (which prevent GDF15 from binding to its homologous binding partner). Other exemplary GDF15 modulators include small molecule inhibitors of GDF15 or the GDF15 receptor, interfering nucleic acids (e.g., interfering RNA or antisense nucleic acids, such as antisense DNA or RNA), which interfere with the expression of endogenous GDF15 or its homologous receptor.

[0057] Antibodies against GDF15, their GDF15-binding fragments, and methods of using them have been described in U.S. Patent Nos. 8,192,735 and WO 2014 / 100689 (corresponding to U.S. Patent Publication No. US 2014-0193427-A1) and International Patent Applications Nos. PCT / US2015 / 036790 and PCT / US2015 / 036794. These documents are hereby incorporated in their entirety, including their descriptions of GDF15, GDF15 modulators (e.g., GDF15 inhibitors), GDF15 antibodies, methods of generating and using such modulators and antibodies, and their descriptions of compositions, formulations, excipients and carriers, therapeutically effective amounts, dosage forms, and routes of administration.

[0058] In a preferred embodiment, the GDF15 modulator may comprise a humanized or human anti-GDF15 antibody.

[0059] In one aspect, the anti-GDF15 antibody described herein comprises a heavy chain variable region (VH), which includes CDRH1, CDRH2, and CDRH3. In some embodiments, the anti-GDF15 antibody comprises any one of the nine sets of CDRH1, CDRH2, and CDRH3 sequences listed in Table 1.

[0060] In another aspect, the anti-GDF15 antibody described herein comprises a light chain variable region (VL) comprising CDRL1, CDRL2, and CDRL3. In some embodiments, the anti-GDF15 antibody comprises any one of the nine sets of CDRL1, CDRL2, and CDRL3 sequences listed in Table 2.

[0061] Table 1. VH CDR Sequences

[0062] <![CDATA[CDR H1 ]]> <![CDATA[CDR H2 ]]> <![CDATA[CDR H3 ]]> 1 DYNMD (SEQ ID NO:1) QINPNNGGIFFNQKFKG (SEQ ID NO:4) EAITTVGAMDY (SEQ ID NO:13) 2 DYNMD (SEQ ID NO:1) QINPNNGGIFFNQKFQG (SEQ ID NO:5) EAITTVGAMDY (SEQ ID NO:13) 3 DYNMD (SEQ ID NO:1) QINPYNHLIFFNQKFQG (SEQ ID NO:6) EAITTVGAMDY (SEQ ID NO:13) 4 DYNMD (SEQ ID NO:1) QINPNNGLIFFNQKFQG (SEQ ID NO:7) EAITTVGAMDY (SEQ ID NO:13) 5 DYNMD (SEQ ID NO:1) QINPNNGLIFFNQKFKG (SEQ ID NO:8) EAITTVGAMDY (SEQ ID NO:13) 6 DYNMD (SEQ ID NO:1) QINPYNHLIFFNQKFKG (SEQ ID NO:9) EAITTVGAMDY (SEQ ID NO:13) 7 TYGMGVS (SEQ ID NO:2) HIYWDDDKRYNPSLKS (SEQ ID NO:10 RGYDDYWGY (SEQ ID NO:14) 8 TYGMGVS (SEQ ID NO:2) HIYWDDDKRYNPSLKT (SEQ ID NO:11) RGYDDYWGY (SEQ ID NO:14) 9 TYGMGVG (SEQ ID NO:3) DIWWDDDKYYNPSLKS (SEQ ID NO:12) RGHYSAMDY (SEQ ID NO:15)

[0063] Table 2. VL CDR Sequences

[0064] <![CDATA[CDRL1]]> <![CDATA[CDRL2]]> <![CDATA[CDRL3]]> 1 RTSENLHNYLA (SEQ ID NO:16) DAKTLAD (SEQ ID NO:18) QHFWSSPYT (SEQ ID NO:21) 2 RTSENLHNYLA (SEQ ID NO:16) DAKTLAD (SEQ ID NO:18) QHFWSDPYT (SEQ ID NO:22) 3 KASQNVGTNVA (SEQ ID NO:17) SASYRYS (SEQ ID NO:19) QQYNNYPLT (SEQ ID NO:23) 4 KASQNVGTNVA (SEQ ID NO:17) SPSYRYS (SEQ ID NO:20) QQYNSYPHT (SEQ ID NO:24)

[0065] In some embodiments, this document provides an anti-GDF15 antibody comprising a VH that includes one, two, or all three VH CDRs of the antibodies in Table 1 (e.g., VH CDRs in a row of Table 1).

[0066] In some embodiments, this document provides an anti-GDF15 antibody comprising a VL containing one, two, or all three VL CDRs of the antibodies in Table 2 (e.g., VH CDRs in a row of Table 2).

[0067] Exemplary anti-GDF15 antibodies, including 01G06, 03G05, 04F08, 06C11, 08G01, 14F11, 17B11, and their human or humanized forms, are described in U.S. Patent Publication No. US 2014-0193427-A1. In some embodiments, the antibodies disclosed herein (e.g., 01G06, 03G05, 04F08, 06C11, 08G01, 14F11, or 17B11, or their humanized forms) are used to reduce weight loss in subjects with cancer.

[0068] In a preferred embodiment, the anti-GDF15 antibody that can be used in the practice of this invention is referred to as 01G06 in U.S. Patent Application No. 14 / 137,415. The humanized forms of the 01G06 antibody and their respective heavy and light chain variable regions are listed below. Exemplary humanized anti-GDF15 antibodies include: Hu01G06-1; Hu01G06-46; Hu01G06-52; Hu01G06-100; Hu01G06-101; Hu01G06-102; Hu01G06-103; Hu01G06-104; Hu01G06-105; Hu01G06-106; Hu01G06-107; Hu01G06-108; Hu01G06-109; Hu01G06-110; Hu01G06 -111; Hu01G06-112; Hu01G06-113; Hu01G06-114; Hu01G06-122; Hu01G06-127; Hu01G06-135; Hu01G06-138; Hu01G06-146; Hu06C11-1; Hu06C11-27; Hu06C11-30; Hu14F11-1; Hu14F11-23; Hu14F11-24; Hu14F11-39; and Hu14F11-47. The amino acid sequences of the heavy and light chains of each of the aforementioned antibodies are listed in Table 3 below.

[0069] Table 3. Heavy and light chain sequences

[0070] Antibody Name Light Chain Heavy Chain 01G06 (Mouse) SEQ ID NO:25 SEQ ID NO:37 Hu01G06-1 SEQ ID NO:26 SEQ ID NO:38 Hu01G06-46 SEQ ID NO:27 SEQ ID NO:39 Hu01G06-52 SEQ ID NO:27 SEQ ID NO:40 Hu01G06-100 SEQ ID NO:27 SEQ ID NO:41 Hu01G06-101 SEQ ID NO:27 SEQ ID NO:42 Hu01G06-102 SEQ ID NO:27 SEQ ID NO:43 Hu01G06-103 SEQ ID NO:27 SEQ ID NO:44 Hu01G06-104 SEQ ID NO:27 SEQ ID NO:45 Hu01G06-105 SEQ ID NO:28 SEQ ID NO:41 Hu01G06-106 SEQ ID NO:28 SEQ ID NO:42 Hu01G06-107 SEQ ID NO:28 SEQ ID NO:43 Hu01G06-108 SEQ ID NO:28 SEQ ID NO:44 Hu01G06-109 SEQ ID NO:28 SEQ ID NO:45 Hu01G06-110 SEQ ID NO:29 SEQ ID NO:41 Hu01G06-111 SEQ ID NO:29 SEQ ID NO:42 Hu01G06-112 SEQ ID NO:29 SEQ ID NO:43 Hu01G06-113 SEQ ID NO:29 SEQ ID NO:44 Hu01G06-114 SEQ ID NO:29 SEQ ID NO:45 Hu01G06-122 SEQ ID NO:29 SEQ ID NO:46 Hu01G06-127 SEQ ID NO:30 SEQ ID NO:47 Hu01G06-135 SEQ ID NO:29 SEQ ID NO:48 Hu01G06-138 SEQ ID NO:29 SEQ ID NO:49 Hu01G06-146 SEQ ID NO:30 SEQ ID NO:49 06C11 (mouse) SEQ ID NO:31 SEQ ID NO:50 Hu06C11-1 SEQ ID NO:32 SEQ ID NO:38 Hu06C11-27 SEQ ID NO:33 SEQ ID NO:51 Hu06C11-30 SEQ ID NO:33 SEQ ID NO:52 14F11 (mouse) SEQ ID NO:34 SEQ ID NO:53 Hu14F11-1 SEQ ID NO:35 SEQ ID NO:54 Hu14F11-23 SEQ ID NO:35 SEQ ID NO:55 Hu14F11-24 SEQ ID NO:32 SEQ ID NO:54 Hu14F11-39 SEQ ID NO:36 SEQ ID NO:56 Hu14F11-47 SEQ ID NO:36 SEQ ID NO:57

[0071] SEQ ID NO:25

[0072]

[0073] SEQ ID NO:26

[0074]

[0075] SEQ ID NO:27

[0076]

[0077] SEQ ID NO:29

[0078]

[0079] SEQ ID NO:28

[0080]

[0081] SEQ ID NO:32

[0082]

[0083] SEQ ID NO:33

[0084]

[0085] SEQ ID NO:35

[0086]

[0087] SEQ ID NO:36

[0088]

[0089] SEQ ID NO:37

[0090]

[0091] SEQ ID NO:30

[0092]

[0093]

[0094] SEQ ID NO:38

[0095]

[0096] SEQ ID NO:39

[0097]

[0098] SEQ ID NO:40

[0099]

[0100] SEQ ID NO:41

[0101]

[0102] SEQ ID NO:43

[0103]

[0104] SEQ ID NO:42

[0105]

[0106] SEQ ID NO:44

[0107]

[0108] SEQ ID NO:45

[0109]

[0110] SEQ ID NO:46

[0111]

[0112] SEQ ID NO:47

[0113]

[0114] SEQ ID NO:48

[0115]

[0116]

[0117] SEQ ID NO:49

[0118]

[0119] SEQ ID NO:38

[0120]

[0121] SEQ ID NO:51

[0122]

[0123] SEQ ID NO:52

[0124]

[0125] SEQ ID NO:54

[0126]

[0127]

[0128] SEQ ID NO:55

[0129]

[0130] SEQ ID NO:56

[0131]

[0132] SEQ ID NO:57

[0133]

[0134] SEQ ID NO:50

[0135]

[0136] SEQ ID NO:31

[0137]

[0138] SEQ ID NO:53

[0139]

[0140]

[0141] SEQ ID NO:34

[0142]

[0143] The amino acid sequences of the VH and VL domains of each of the aforementioned antibodies are listed in Table 4 below.

[0144] Table 4. VL and VH sequences

[0145] Antibody Name VL VH 01G06 (Mouse) SEQ ID NO:58 SEQ ID NO:67 Hu01G06-1 SEQ ID NO:58 SEQ ID NO:67 Hu01G06-46 SEQ ID NO:59 SEQ ID NO:68 Hu01G06-52 SEQ ID NO:59 SEQ ID NO:69 Hu01G06-100 SEQ ID NO:59 SEQ ID NO:70 Hu01G06-101 SEQ ID NO:59 SEQ ID NO:71 Hu01G06-102 SEQ ID NO:59 SEQ ID NO:72 Hu01G06-103 SEQ ID NO:59 SEQ ID NO:73 Hu01G06-104 SEQ ID NO:59 SEQ ID NO:74 Hu01G06-105 SEQ ID NO:60 SEQ ID NO:70 Hu01G06-106 SEQ ID NO:60 SEQ ID NO:71 Hu01G06-107 SEQ ID NO:60 SEQ ID NO:72 Hu01G06-108 SEQ ID NO:60 SEQ ID NO:73 Hu01G06-109 SEQ ID NO:60 SEQ ID NO:74 Hu01G06-110 SEQ ID NO:61 SEQ ID NO:70 Hu01G06-111 SEQ ID NO:61 SEQ ID NO:71 Hu01G06-112 SEQ ID NO:61 SEQ ID NO:72 Hu01G06-113 SEQ ID NO:61 SEQ ID NO:73 Hu01G06-114 SEQ ID NO:61 SEQ ID NO:74 Hu01G06-122 SEQ ID NO:61 SEQ ID NO:75 Hu01G06-127 SEQ ID NO:62 SEQ ID NO:76 Hu01G06-135 SEQ ID NO:61 SEQ ID NO:77 Hu01G06-138 SEQ ID NO:61 SEQ ID NO:78 Hu01G06-146 SEQ ID NO:62 SEQ ID NO:78 06C11 (Rat) SEQ ID NO:63 SEQ ID NO:79 Hu06C11-1 SEQ ID NO:63 SEQ ID NO:79 Hu06C11-27 SEQ ID NO:64 SEQ ID NO:80 Hu06C11-30 SEQ ID NO:64 SEQ ID NO:81 14F11 (Rat) SEQ ID NO:65 SEQ ID NO:82 Hu14F11-1 SEQ ID NO:65 SEQ ID NO:82 Hu14F11-23 SEQ ID NO:65 SEQ ID NO:79 Hu14F11-24 SEQ ID NO:63 SEQ ID NO:82 Hu14F11-39 SEQ ID NO:66 SEQ ID NO:83 Hu14F11-47 SEQ ID NO:66 SEQ ID NO:84

[0146] SEQ ID NO:58

[0147]

[0148] SEQ ID NO:59

[0149]

[0150] SEQ ID NO:60

[0151]

[0152] SEQ ID NO:61

[0153]

[0154] SEQ ID NO:62

[0155]

[0156] SEQ ID NO:63

[0157]

[0158] SEQ ID NO:64

[0159]

[0160] SEQ ID NO:65

[0161]

[0162] SEQ ID NO:66

[0163]

[0164] SEQ ID NO:67

[0165]

[0166] SEQ ID NO:68

[0167]

[0168] SEQ ID NO:69

[0169]

[0170] SEQ ID NO:70

[0171]

[0172] SEQ ID NO:71

[0173]

[0174] SEQ ID NO:72

[0175]

[0176] SEQ ID NO:73

[0177]

[0178] SEQ ID NO:74

[0179]

[0180] SEQ ID NO:75

[0181]

[0182] SEQ ID NO:76

[0183]

[0184]

[0185] SEQ ID NO:77

[0186]

[0187] SEQ ID NO:78

[0188]

[0189] SEQ ID NO:79

[0190]

[0191] SEQ ID NO:80

[0192]

[0193] SEQ ID NO:81

[0194]

[0195] SEQ ID NO:82

[0196]

[0197] SEQ ID NO:83

[0198]

[0199] SEQ ID NO:84

[0200]

[0201] In some embodiments, this document provides an anti-GDF15 antibody comprising: 01G06; Hu01G06-1; Hu01G06-46; Hu01G06-52; Hu01G06-100; Hu01G06-101; Hu01G06-102; Hu01G06-103; Hu01G06-104; Hu01G06-105; Hu01G06-106; Hu01G06-107; Hu01G06-108; Hu01G06-109; Hu01G06-110; Hu01G0 VH CDR and VL CDR of any one of the following: 6-111; Hu01G06-112; Hu01G06-113; Hu01G06-114; Hu01G06-122; Hu01G06-127; Hu01G06-135; Hu01G06-138; Hu01G06-146; 06C11; Hu06C11-1; Hu06C11-27; Hu06C11-30; 14F11; Hu14F11-1; Hu14F11-23; Hu14F11-24; Hu14F11-39; and Hu14F11-47.

[0202] In one particular embodiment, the anti-GDF15 antibody described herein comprises VH, said VH comprising antibody 01G06; Hu01G06-1; Hu01G06-46; Hu01G06-52; Hu01G06-100; Hu01G06-101; Hu01G06-102; Hu01G06-103; Hu01G06-104; Hu01G06-105; Hu01G06-106; Hu01G06-107; Hu01G06-108; Hu01G06-109; Hu01G06-110; Hu01G06-111 CDRH1, CDRH2 and CDRH3 of any one of Hu01G06-112; Hu01G06-113; Hu01G06-114; Hu01G06-122; Hu01G06-127; Hu01G06-135; Hu01G06-138; Hu01G06-146; 06C11; Hu06C11-1; Hu06C11-27; Hu06C11-30; 14F11; Hu14F11-1; Hu14F11-23; Hu14F11-24; Hu14F11-39; and Hu14F11-47.

[0203] In one particular embodiment, the anti-GDF15 antibody described herein comprises VL, said VL comprising antibody 01G06; Hu01G06-1; Hu01G06-46; Hu01G06-52; Hu01G06-100; Hu01G06-101; Hu01G06-102; Hu01G06-103; Hu01G06-104; Hu01G06-105; Hu01G06-106; Hu01G06-107; Hu01G06-108; Hu01G06-109; Hu01G06-110; Hu01G06-111 CDRL1, CDRL2 and CDRL3 of any one of Hu01G06-112; Hu01G06-113; Hu01G06-114; Hu01G06-122; Hu01G06-127; Hu01G06-135; Hu01G06-138; Hu01G06-146; 06C11; Hu06C11-1; Hu06C11-27; Hu06C11-30; 14F11; Hu14F11-1; Hu14F11-23; Hu14F11-24; Hu14F11-39; and Hu14F11-47.

[0204] In one particular embodiment, the anti-GDF15 antibody described herein comprises: (i) a VH, said VH comprising antibody 01G06; Hu01G06-1; Hu01G06-46; Hu01G06-52; Hu01G06-100; Hu01G06-101; Hu01G06-102; Hu01G06-103; Hu01G06-104; Hu01G06-105; Hu01G06-106; Hu01G06-107; Hu01G06-108; Hu01G06-109; Hu01G06-110; Hu01G06-111; Hu01G06-112; Hu0 CDRH1, CDRH2, and CDRH3 of any one of 1G06-113; Hu01G06-114; Hu01G06-122; Hu01G06-127; Hu01G06-135; Hu01G06-138; Hu01G06-146; 06C11; Hu06C11-1; Hu06C11-27; Hu06C11-30; 14F11; Hu14F11-1; Hu14F11-23; Hu14F11-24; Hu14F11-39; and Hu14F11-47, and (ii) VL, the VL antibody 01G06; Hu01G06-1; Hu01G06-46; Hu01G06-52; Hu01G06-100; Hu01G06-101; Hu01G06-102; Hu01G06-103; Hu01G06 Hu01G06-105 CDRL1, CDRL2 and CDRL3 of any one of u01G06-113; Hu01G06-114; Hu01G06-122; Hu01G06-127; Hu01G06-135; Hu01G06-138; Hu01G06-146; 06C11; Hu06C11-1; Hu06C11-27; Hu06C11-30; 14F11; Hu14F11-1; Hu14F11-23; Hu14F11-24; Hu14F11-39; and Hu14F11-47.

[0205] In some embodiments, the anti-GDF15 antibody comprises a VH domain containing or consisting of an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to, or constitutes, the amino acid sequence of the VH domain of the antibodies listed in Table 4. In one specific embodiment, the anti-GDF15 antibody comprises a VH domain containing or consisting of an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to, or constitutes, the amino acid sequence of the VH domain of any of SEQ ID NO: 67-84.

[0206] In some embodiments, the anti-GDF15 antibody comprises a VH domain, which comprises or is composed of the amino acid sequences of the VH domains of the antibodies listed in Table 4. In one specific embodiment, the anti-GDF15 antibody comprises a VH domain, which comprises or is composed of the amino acid sequences listed in any of SEQ ID NO: 67-84.

[0207] In some embodiments, the anti-GDF15 antibody comprises a VL domain containing or consisting of an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to, or consists of, the amino acid sequence of the VL domain of the antibodies listed in Table 4. In one specific embodiment, the anti-GDF15 antibody comprises a VL domain containing or consisting of an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to, or consists of, the amino acid sequence of the VL domain listed in any of SEQ ID NO: 58-66.

[0208] In some embodiments, the anti-GDF15 antibody comprises a VL domain, which comprises or is composed of the amino acid sequences of the VL domains of the antibodies listed in Table 4. In one specific embodiment, the anti-GDF15 antibody comprises a VL domain, which comprises or is composed of the amino acid sequences listed in any of SEQ ID NO: 58-66.

[0209] In some embodiments, the anti-GDF15 antibody comprises a VH domain and a VL domain, wherein the VH domain and VL domain comprise or consist of the amino acid sequences of the VH domain and VL domain of the antibodies listed in Table 4 or amino acid sequences that are at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to them (e.g., the VH domain and VL domain in a row of Table 4). In one specific embodiment, the anti-GDF15 antibody comprises a VH domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 67 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto; and a VL domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 58 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto (e.g., 01G06 or Hu01G06-1). In one specific embodiment, the anti-GDF15 antibody comprises a VH domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 68 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto; and a VL domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 59 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto (e.g., Hu01G06-46). In one specific embodiment, the anti-GDF15 antibody comprises a VH domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 69 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto; and a VL domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 59 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto (e.g., Hu01G06-52). In one specific embodiment, the anti-GDF15 antibody comprises a VH domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 70 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto; and a VL domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 59 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto (e.g., Hu01G01-100).In one specific embodiment, the anti-GDF15 antibody comprises a VH domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 71 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto; and a VL domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 59 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto (e.g., Hu01G06-101). In one specific embodiment, the anti-GDF15 antibody comprises a VH domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 72 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto; and a VL domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 59 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto (e.g., Hu01G06-102). In one specific embodiment, the anti-GDF15 antibody comprises a VH domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 73 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto; and a VL domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 59 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto (e.g., Hu01G06-103). In one specific embodiment, the anti-GDF15 antibody comprises a VH domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 74 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto; and a VL domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 59 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto (e.g., Hu01G06-104).In one specific embodiment, the anti-GDF15 antibody comprises a VH domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 70 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto; and a VL domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 60 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto (e.g., Hu01G06-105). In one specific embodiment, the anti-GDF15 antibody comprises a VH domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 71 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto; and a VL domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 60 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto (e.g., Hu01G06-106). In one specific embodiment, the anti-GDF15 antibody comprises a VH domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 72 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto; and a VL domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 60 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto (e.g., Hu01G06-107). In one specific embodiment, the anti-GDF15 antibody comprises a VH domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 73 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto; and a VL domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 60 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto (e.g., Hu01G06-108).In one specific embodiment, the anti-GDF15 antibody comprises a VH domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 74 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto; and a VL domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 60 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto (e.g., Hu01G06-109). In one specific embodiment, the anti-GDF15 antibody comprises a VH domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 70 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto; and a VL domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 61 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto (e.g., Hu01G06-110). In one specific embodiment, the anti-GDF15 antibody comprises a VH domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 71 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto; and a VL domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 61 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto (e.g., Hu01G06-111). In one specific embodiment, the anti-GDF15 antibody comprises a VH domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 72 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto; and a VL domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 61 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto (e.g., Hu01G06-112).In one specific embodiment, the anti-GDF15 antibody comprises a VH domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 73 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto; and a VL domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 61 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto (e.g., Hu01G06-113). In one specific embodiment, the anti-GDF15 antibody comprises a VH domain comprising or consisting of an amino acid sequence listed in SEQ ID NO:74 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto; and a VL domain comprising or consisting of an amino acid sequence listed in SEQ ID NO:61 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto (e.g., Hu01G06-114). In one specific embodiment, the anti-GDF15 antibody comprises a VH domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 75 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto; and a VL domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 61 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto (e.g., Hu01G06-122). In one specific embodiment, the anti-GDF15 antibody comprises a VH domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 76 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto; and a VL domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 62 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto (e.g., Hu01G06-127).In one specific embodiment, the anti-GDF15 antibody comprises a VH domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 77 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto; and a VL domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 61 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto (e.g., Hu01G06-135). In one specific embodiment, the anti-GDF15 antibody comprises a VH domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 78 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto; and a VL domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 61 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto (e.g., Hu01G06-138). In one specific embodiment, the anti-GDF15 antibody comprises a VH domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 78 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto; and a VL domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 62 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto (e.g., Hu01G06-146). In one specific embodiment, the anti-GDF15 antibody comprises a VH domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 79 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto; and a VL domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 63 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto (e.g., 06C11 or Hu06C11-1).In one specific embodiment, the anti-GDF15 antibody comprises a VH domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 80 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto; and a VL domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 64 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto (e.g., Hu06C11-27). In one specific embodiment, the anti-GDF15 antibody comprises a VH domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 81 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto; and a VL domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 64 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto (e.g., Hu06C11-30). In one specific embodiment, the anti-GDF15 antibody comprises a VH domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 82 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto; and a VL domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 65 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto (e.g., 14F11 or Hu14F11-1). In one specific embodiment, the anti-GDF15 antibody comprises a VH domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 79 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto; and a VL domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 65 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto (e.g., Hu14F11-23).In one specific embodiment, the anti-GDF15 antibody comprises a VH domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 82 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto; and a VL domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 63 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto (e.g., Hu14F11-24). In one specific embodiment, the anti-GDF15 antibody comprises a VH domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 83 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto; and a VL domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 66 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto (e.g., Hu14F11-39). In one specific embodiment, the anti-GDF15 antibody comprises a VH domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 84 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto; and a VL domain comprising or consisting of an amino acid sequence listed in SEQ ID NO: 66 or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto (e.g., Hu14F11-47).

[0210] In some respects, the antibodies described herein may be described solely by their VL domain, or solely by their VH domain, or solely by their three VL CDRs, or solely by their three VH CDRs. See, for example, Rader C et al., (1998) PNAS 95:8910-8915, which is incorporated herein by reference in its entirety, describing the humanization of mouse anti-αvβ3 antibodies by identifying complementary light or heavy chains, respectively, from human light or heavy chain libraries, resulting in humanized antibody variants with affinity as high as or higher than that of the original antibody. See also Clackson T et al., (1991) Nature 352: 624-628, which is incorporated herein by reference in its entirety, describing a method for generating antibodies that bind to specific antigens by using specific VL domains (or VH domains) and screening libraries for complementary variable domains. The screening yielded 14 new mates targeting a specific VH domain and 13 new mates targeting a specific VL domain, all of which are strong binding agents, as determined by ELISA. See also Kim SJ and Hong HJ, (2007) J Microbiol 45: 572-577, which is incorporated herein by reference in its entirety, describing a method for generating antibodies that bind to a specific antigen by using a specific VH domain and screening libraries (e.g., human VL libraries) for complementary VL domains; the selected VL domains, in turn, can be used to guide the selection of additional complementary (e.g., human) VH domains.

[0211] The individual CDR of the antibody disclosed herein can be determined according to any CDR numbering scheme known in the art.

[0212] In some implementations, one or more CDRs of the antibodies disclosed herein may be determined according to Kabat et al., J. Biol. Chem. 252, 6609-6616 (1977) and Kabat et al., Sequences of protein of immunological interest (1991), each of which is incorporated herein by reference in its entirety.

[0213] In some embodiments, the antibodies provided herein comprise CDRH1, CDRH2, and / or CDRH3 of the VH amino acid sequence as listed in any of SEQ ID NO: 67-84 as determined by the Kabat numbering scheme. In some embodiments, the antibodies provided herein comprise CDRL1, CDRL2, and / or CDRL3 of the VL amino acid sequence as listed in any of SEQ ID NO: 58-66 as determined by the Kabat numbering scheme.

[0214] In some implementations, one or more CDRs of the antibodies disclosed herein may be determined according to the Chothia numbering scheme, which refers to the location of the immunoglobulin structural loop (see, for example, Chothia C and Lesk AM, (1987), J Mol Biol 196: 901-917; Al-Lazikani B et al., (1997) J Mol Biol 273: 927-948; Chothia C et al., (1992) J Mol Biol 227: 799-817; Tramontano A et al., (1990) J Mol Biol 215(1): 175-82; and U.S. Patent No. 7,709,226, all of which are incorporated herein by reference in their entirety).

[0215] In some embodiments, the antibodies provided herein comprise CDRH1, CDRH2, and / or CDRH3 of the VH amino acid sequence as listed in any of SEQ ID NOs: 67-84 as determined by the Chothia numbering system. In some embodiments, the antibodies provided herein comprise CDRL1, CDRL2, and / or CDRL3 of the VL amino acid sequence as listed in any of SEQ ID NOs: 58-66 as determined by the Chothia numbering system.

[0216] In some implementations, one or more CDRs of the antibodies disclosed herein may be determined according to MacCallum RM et al., (1996) J Mol Biol 262: 732-745, which is incorporated herein by reference in its entirety. See also, for example, Martin A. “Protein Sequence and Structure Analysis of Antibody Variable Domains”, in Antibody Engineering, edited by Kontermann and Dübel, Chapter 31, pp. 422-439, Springer-Verlag, Berlin (2001), which is incorporated herein by reference in its entirety.

[0217] In some embodiments, the antibodies provided herein comprise CDRH1, CDRH2, and / or CDRH3 of the VH amino acid sequence as listed in any of SEQ ID NOs: 67-84 as determined by the MacCallum numbering system. In some embodiments, the antibodies provided herein comprise CDRL1, CDRL2, and / or CDRL3 of the VL amino acid sequence as listed in any of SEQ ID NOs: 58-66 as determined by the MacCallum numbering system.

[0218] In some implementations, the CDR of the antibodies disclosed herein may be determined according to the IMGT numbering system, as described in the following references: Lefranc MP, (1999) The Immunologist 7: 132-136; Lefranc MP et al., (1999) Nucleic Acids Res 27: 209-212; and Lefranc MP et al., (2009) Nucleic Acids Res 37: D1006-D1012, each of which is incorporated herein by reference in its entirety.

[0219] In some embodiments, the antibodies provided herein comprise CDRH1, CDRH2, and / or CDRH3 of the VH amino acid sequence as listed in any of SEQ ID NO: 67-84 as determined by the IMGT numbering system. In some embodiments, the antibodies provided herein comprise CDRL1, CDRL2, and / or CDRL3 of the VL amino acid sequence as listed in any of SEQ ID NO: 58-66 as determined by the IMGT numbering system.

[0220] In some implementations, the CDR of the antibody disclosed herein may be determined according to the AbM numbering scheme, which refers to the AbM hypervariable region, representing a compromise between the Kabat CDR and the Chothia structural loop, and is used by the AbM antibody modeling software of Oxford Molecular Group, Inc., which is incorporated herein by reference in its entirety.

[0221] In some embodiments, the antibodies provided herein comprise CDRH1, CDRH2, and / or CDRH3 of the VH amino acid sequence as listed in any of SEQ ID NO: 67-84 as determined by the AbM numbering scheme. In some embodiments, the antibodies provided herein comprise CDRL1, CDRL2, and / or CDRL3 of the VL amino acid sequence as listed in any of SEQ ID NO: 58-66 as determined by the AbM numbering scheme.

[0222] In some implementations, the CDR of the antibody disclosed herein may be determined according to the AHo numbering system, as described in Honegger and Plückthun, A., J. Mol. Biol. 309:657-670 (2001), which is incorporated herein by reference in its entirety.

[0223] In some embodiments, the antibodies provided herein comprise CDRH1, CDRH2, and / or CDRH3 of the VH amino acid sequence as listed in any of SEQ ID NO: 67-84 as determined by the AHo numbering system. In some embodiments, the antibodies provided herein comprise CDRL1, CDRL2, and / or CDRL3 of the VL amino acid sequence as listed in any of SEQ ID NO: 58-66 as determined by the AHo numbering system.

[0224] In some embodiments, the individual CDRs of the antibodies disclosed herein are determined independently according to one of the Kabat, Chothia, MacCallum, IMGT, AHo, or AbM numbering schemes, or by structural analysis of the antibody, wherein the structural analysis identifies residues in the variable region predicted to contact the GDF15 epitope region.

[0225] In some embodiments, this disclosure provides an anti-GDF15 antibody comprising a VH comprising the CDRH1, CDRH2, and CDRH3 amino acid sequences of the VH amino acid sequence listed in any of SEQ ID NO: 67-84, and a VL comprising the CDRL1, CDRL2, and CDRL3 amino acid sequences of the VL amino acid sequence listed in any of SEQ ID NO: 58-66, wherein each CDR is independently determined according to one of the Kabat, Chothia, MacCallum, IMGT, AHo, or AbM numbering schemes, or determined by structural analysis of the antibody, wherein the structural analysis identifies residues in the variable region predicted to contact the GDF15 epitope region.

[0226] In some embodiments, this disclosure provides an anti-GDF15 antibody comprising VH comprising the CDRH1, CDRH2, and CDRH3 amino acid sequences of the VH amino acid sequence listed in any of SEQ ID NO: 67-84, and VL comprising the CDRL1, CDRL2, and CDRL3 amino acid sequences of the VL amino acid sequence listed in any of SEQ ID NO: 58-66, wherein the VH and VL amino acid sequences are derived from the same antibody (i.e., as shown in Table 4), and wherein each CDR is independently determined according to one of the numbering schemes Kabat, Chothia, MacCallum, IMGT, AHo, or AbM, or determined by structural analysis of the antibody, wherein the structural analysis identifies residues in the variable region predicted to contact the GDF15 epitope region.

[0227] In some embodiments, this disclosure provides an anti-GDF15 antibody, wherein the antibody comprises the following components, respectively listed in SEQ ID NO: 67 and 58; SEQ ID NO: 68 and 59; SEQ ID NO: 69 and 59; SEQ ID NO: 70 and 59; SEQ ID NO: 71 and 59; SEQ ID NO: 72 and 59; SEQ ID NO: 73 and 59; SEQ ID NO: 74 and 59; SEQ ID NO: 70 and 60; SEQ ID NO: 71 and 60; SEQ ID NO: 72 and 60; SEQ ID NO: 73 and 60; SEQ ID NO: 74 and 60; SEQ ID NO: 70 and 61; SEQ ID NO: 71 and 61; SEQ ID NO: 72 and 61; SEQ ID NO: 73 and 61; SEQ ID NO: 74 and 61; SEQ ID NO: 75 and 61; SEQ ID NO: 76 and 62; SEQ ID NO: SEQ ID NO: 77 and 61; SEQ ID NO: 78 and 61; SEQ ID NO: 78 and 62; SEQ ID NO: 79 and 63; SEQ ID NO: 80 and 64; SEQ ID NO: 81 and 64; SEQ ID NO: 82 and 65; SEQ ID NO: 79 and 65; SEQ ID NO: 82 and 63; SEQ ID NO: 83 and 66; or the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences of VH and VL amino acid sequences in SEQ ID NO: 84 and 66.

[0228] In one specific embodiment, the position of one or more CDRs along the VH (e.g., CDR1, CDR2, or CDR3) and / or VL (e.g., CDR1, CDR2, or CDR3) regions of the antibody described herein may be altered by one, two, three, four, five, or six amino acid positions, provided that specific binding to GDF15 is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%). For example, in one embodiment, the position of a CDR of any antibody described herein may be defined by shifting the N-terminal and / or C-terminal boundary of the CDR relative to the CDR position of any antibody described herein by one, two, three, four, five, or six amino acids, provided that specific binding to GDF15 is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%). In another embodiment, one or more CDRs may vary in length (e.g., shorter or longer) along the VH (e.g., CDR1, CDR2, or CDR3) and / or VL (e.g., CDR1, CDR2, or CDR3) regions of the antibody described herein by one, two, three, four, five, or more amino acids, as long as specific binding to GDF15 is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%).

[0229] In one embodiment, CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and / or CDRL3 described herein may be one, two, three, four, five, or more amino acids shorter than one or more CDRs described herein (e.g., SEQ ID NO: 1-24), provided that specific binding to GDF15 is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%). In another embodiment, CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and / or CDRL3 described herein may be one, two, three, four, five, or more amino acids longer than one or more CDRs described herein (e.g., SEQ ID NO: 1-24), provided that specific binding to GDF15 is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%). In another embodiment, the amino terminus of CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and / or CDRL3 described herein may be extended by one, two, three, four, five, or more amino acids compared to one or more CDRs described herein (e.g., SEQ ID NO: 1-24), provided that specific binding to GDF15 is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%). In another embodiment, the carboxyl terminus of CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and / or CDRL3 described herein may be extended by one, two, three, four, five, or more amino acids compared to one or more CDRs described herein (e.g., SEQ ID NO: 1-24), provided that specific binding to GDF15 is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%). In another embodiment, the amino terminus of CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and / or CDRL3 described herein may be shortened by one, two, three, four, five or more amino acids compared to one or more CDRs described herein (e.g., SEQ ID NO: 1-24), as long as the specific binding to GDF15 is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%).In one embodiment, the carboxyl terminus of CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and / or CDRL3 described herein may be shortened by one, two, three, four, five, or more amino acids compared to one or more CDRs described herein (e.g., SEQ ID NO: 1-24), as long as specific binding to GDF15 is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%). Any method known in the art can be used to determine whether specific binding to GDF15 is maintained.

[0230] In a specific embodiment, this document provides an antibody comprising an antibody light chain and a heavy chain, for example, a light chain and a heavy chain separately. Regarding the light chain, in one specific embodiment, the light chain of the antibody described herein is a kappa light chain. In another specific embodiment, the light chain of the antibody described herein is a lambda light chain. In yet another specific embodiment, the light chain of the antibody described herein is a human kappa light chain or a human lambda light chain. In one particular embodiment, the antibody described herein comprises a light chain wherein the amino acid sequence of the VL domain comprises any amino acid sequence described herein (e.g., SEQ ID NO: 58-66), and wherein the constant region of the light chain comprises the amino acid sequence of the constant region of a human kappa light chain. In another particular embodiment, the antibody described herein comprises a light chain wherein the amino acid sequence of the VL domain may comprise any amino acid sequence described herein (e.g., SEQ ID NO: 58-66), and wherein the constant region of the light chain comprises the amino acid sequence of the constant region of a human lambda light chain. Non-limiting examples of human constant region sequences have been described in the art, see, for example, U.S. Patent No. 5,693,780 and Kabat EA et al., (1991), ibid.

[0231] In some embodiments, this disclosure provides an anti-GDF15 antibody comprising a light chain constant region comprising the amino acid sequences shown in Table 5. In some embodiments, the light chain constant region comprises the amino acid sequence of SEQ ID NO: 85 or 86. In some embodiments, the light chain constant region consists of the amino acid sequence of SEQ ID NO: 85 or 86.

[0232] Table 5. Amino acid sequences of the light chain constant region

[0233] describe amino acid sequence SEQ ID Kappa light chain constant region RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 85 Lambda light chain constant region GQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 86

[0234] In one particular embodiment, the anti-GDF15 antibody described herein comprises a light chain comprising or consisting of an amino acid sequence selected from or composed of the group consisting of SEQ ID NO: 25-36.

[0235] Regarding the heavy chain, in one specific embodiment, the heavy chain of the antibody described herein may be an alpha (α), delta (δ), epsilon (ε), gamma (γ), or mu (μ) heavy chain. In another specific embodiment, the heavy chain of the described antibody may comprise a human alpha (α), delta (δ), epsilon (ε), gamma (γ), or mu (μ) heavy chain. In one specific embodiment, the antibody described herein comprises a heavy chain wherein the amino acid sequence of the VH domain may comprise any of the amino acid sequences described herein (e.g., any of SEQ ID NO: 67-84), and wherein the constant region of the heavy chain comprises the amino acid sequence of the constant region of a human gamma (γ) heavy chain. In one specific embodiment, the antibody described herein comprises a heavy chain wherein the amino acid sequence of the VH domain is selected from the group consisting of SEQ ID NO: 67-84, and wherein the constant region of the heavy chain comprises amino acids of human heavy chains described herein or known in the art. Non-limiting examples of human constant region sequences have been described in the art, see, for example, U.S. Patent No. 5,693,780 and Kabat EA et al., (1991), ibid.

[0236] In one particular embodiment, the anti-GDF15 antibody described herein comprises a heavy chain comprising or consisting of an amino acid sequence selected from or composed of the group consisting of SEQ ID NO: 37-57.

[0237] In one specific embodiment, the anti-GDF15 antibody described herein comprises a VH domain and a VL domain, the VH domain and the VL domain comprising any amino acid sequence described herein, and wherein the constant region comprises the amino acid sequence of the constant region of an IgG, IgE, IgM, IgD, IgA, or IgY immunoglobulin molecule or a human IgG, IgE, IgM, IgD, IgA, or IgY immunoglobulin molecule. In another specific embodiment, the anti-GDF15 antibody described herein comprises a VH domain and a VL domain, the VH domain comprising any amino acid sequence described herein, and wherein the constant region comprises the amino acid sequence of the constant region of an IgG, IgE, IgM, IgD, IgA, or IgY immunoglobulin molecule, any class of immunoglobulin molecules (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) or any subclass (e.g., IgG2a and IgG2b). In one particular embodiment, the constant region comprises the amino acid sequence of the constant region of human IgG, IgE, IgM, IgD, IgA or IgY immunoglobulin molecules, any class of immunoglobulin molecules (e.g. IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or any subclass (e.g. IgG2a and IgG2b).

[0238] In another specific embodiment, the anti-GDF15 antibody described herein comprises a VH domain and a VL domain, the VH domain and VL domain comprising any of the amino acid sequences described herein, and wherein the constant region comprises the amino acid sequence of the constant region of human IgG1 (e.g., allotype G1m3, G1m17,1, or G1m17,1,2) or human IgG4. In a particular embodiment, the anti-GDF15 antibody described herein comprises a VH domain and a VL domain, the VH domain and VL domain comprising any of the amino acid sequences described herein, and wherein the constant region comprises the amino acid sequence of the constant region of human IgG1. Non-limiting examples of human constant regions are described in the art, see, for example, Kabat EA et al., (1991), ibid.

[0239] In another embodiment, the anti-GDF15 antibody described herein comprises a light chain containing an amino acid sequence selected from the group consisting of SEQ ID NO: 25-36 and a heavy chain containing an amino acid sequence selected from the group consisting of SEQ ID NO: 37-57. In some embodiments, this disclosure provides an anti-GDF15 antibody, wherein the antibody comprises a light chain containing an amino acid sequence listed in SEQ ID NO: 25 and a heavy chain containing an amino acid sequence listed in SEQ ID NO: 37. In some embodiments, this disclosure provides an anti-GDF15 antibody, wherein the antibody comprises a light chain containing an amino acid sequence listed in SEQ ID NO: 26 and a heavy chain containing an amino acid sequence listed in SEQ ID NO: 38. In some embodiments, this disclosure provides an anti-GDF15 antibody, wherein the antibody comprises a light chain containing an amino acid sequence listed in SEQ ID NO: 27 and a heavy chain containing an amino acid sequence listed in SEQ ID NO: 39. In some embodiments, this disclosure provides an anti-GDF15 antibody, wherein the antibody comprises a light chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 27 and a heavy chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 40. In some embodiments, this disclosure provides an anti-GDF15 antibody, wherein the antibody comprises a light chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 27 and a heavy chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 41. In some embodiments, this disclosure provides an anti-GDF15 antibody, wherein the antibody comprises a light chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 27 and a heavy chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 42. In some embodiments, this disclosure provides an anti-GDF15 antibody, wherein the antibody comprises a light chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 27 and a heavy chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 43. In some embodiments, this disclosure provides an anti-GDF15 antibody, wherein the antibody comprises a light chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 27 and a heavy chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 44.In some embodiments, this disclosure provides an anti-GDF15 antibody, wherein the antibody comprises a light chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 27 and a heavy chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 45. In some embodiments, this disclosure provides an anti-GDF15 antibody, wherein the antibody comprises a light chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 28 and a heavy chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 41. In some embodiments, this disclosure provides an anti-GDF15 antibody, wherein the antibody comprises a light chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 28 and a heavy chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 42. In some embodiments, this disclosure provides an anti-GDF15 antibody, wherein the antibody comprises a light chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 28 and a heavy chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 43. In some embodiments, this disclosure provides an anti-GDF15 antibody, wherein the antibody comprises a light chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 28 and a heavy chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 44. In some embodiments, this disclosure provides an anti-GDF15 antibody, wherein the antibody comprises a light chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 28 and a heavy chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 45. In some embodiments, this disclosure provides an anti-GDF15 antibody, wherein the antibody comprises a light chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 29 and a heavy chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 41. In some embodiments, this disclosure provides an anti-GDF15 antibody, wherein the antibody comprises a light chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 29 and a heavy chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 42. In some embodiments, this disclosure provides an anti-GDF15 antibody, wherein the antibody comprises a light chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 29 and a heavy chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 43. In some embodiments, this disclosure provides an anti-GDF15 antibody, wherein the antibody comprises a light chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 29 and a heavy chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 44.In some embodiments, this disclosure provides an anti-GDF15 antibody, wherein the antibody comprises a light chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 29 and a heavy chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 45. In some embodiments, this disclosure provides an anti-GDF15 antibody, wherein the antibody comprises a light chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 29 and a heavy chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 46. In some embodiments, this disclosure provides an anti-GDF15 antibody, wherein the antibody comprises a light chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 30 and a heavy chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 47. In some embodiments, this disclosure provides an anti-GDF15 antibody, wherein the antibody comprises a light chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 29 and a heavy chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 48. In some embodiments, this disclosure provides an anti-GDF15 antibody, wherein the antibody comprises a light chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 29 and a heavy chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 49. In some embodiments, this disclosure provides an anti-GDF15 antibody, wherein the antibody comprises a light chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 30 and a heavy chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 49. In some embodiments, this disclosure provides an anti-GDF15 antibody, wherein the antibody comprises a light chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 31 and a heavy chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 50. In some embodiments, this disclosure provides an anti-GDF15 antibody, wherein the antibody comprises a light chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 32 and a heavy chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 38. In some embodiments, this disclosure provides an anti-GDF15 antibody, wherein the antibody comprises a light chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 33 and a heavy chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 51. In some embodiments, this disclosure provides an anti-GDF15 antibody, wherein the antibody comprises a light chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 33 and a heavy chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 52.In some embodiments, this disclosure provides an anti-GDF15 antibody, wherein the antibody comprises a light chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 34 and a heavy chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 53. In some embodiments, this disclosure provides an anti-GDF15 antibody, wherein the antibody comprises a light chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 35 and a heavy chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 54. In some embodiments, this disclosure provides an anti-GDF15 antibody, wherein the antibody comprises a light chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 35 and a heavy chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 55. In some embodiments, this disclosure provides an anti-GDF15 antibody, wherein the antibody comprises a light chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 32 and a heavy chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 54. In some embodiments, this disclosure provides an anti-GDF15 antibody, wherein the antibody comprises a light chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 36 and a heavy chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 56. In some embodiments, this disclosure provides an anti-GDF15 antibody, wherein the antibody comprises a light chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 36 and a heavy chain containing or consisting of the amino acid sequence listed in SEQ ID NO: 57.

[0240] In some embodiments, one, two or more mutations (e.g., amino acid substitutions) are introduced into the Fc region of the antibody described herein (e.g., the CH2 domain (residues 231-340 of human IgG1) and / or the CH3 domain (residues 341-447 of human IgG1) and / or the hinge region, numbered according to the Kabat numbering system (e.g., the EU index in Kabat)) to alter one or more functional properties of the antibody, such as serum half-life, complement fixation, Fc receptor binding, and / or antigen-dependent cytotoxicity.

[0241] In some embodiments, one, two, or more mutations (e.g., amino acid substitutions) are introduced into the hinge region of the Fc region (CH1 domain) to alter the number of cysteine ​​residues in the hinge region (e.g., increase or decrease), as described in U.S. Patent No. 5,677,425. The number of cysteine ​​residues in the hinge region of the CH1 domain may be altered, for example, to facilitate the assembly of the light and heavy chains, or to alter (e.g., increase or decrease) the stability of the antibody.

[0242] In some embodiments, one, two, or more mutations (e.g., amino acid substitutions) are introduced into the Fc region of the antibody described herein (e.g., the CH2 domain (residues 231-340 of human IgG1) and / or the CH3 domain (residues 341-447 of human IgG1) and / or the hinge region, numbered according to the Kabat numbering system (e.g., the EU index in Kabat)) to increase or decrease the antibody's affinity for Fc receptors (e.g., activated Fc receptors) on the surface of effector cells. Those skilled in the art are aware of mutations in the Fc region of antibodies that decrease or increase the antibody's affinity for Fc receptors, and techniques for introducing such mutations into Fc receptors. Examples of mutations in the Fc receptor of antibodies that can alter the affinity of antibodies for the Fc receptor are described in the following literature: see, for example, Smith P et al., (2012) PNAS 109: 6181-6186, U.S. Patent No. 6,737,056 and International Publications Nos. WO02 / 060919, WO 98 / 23289; and WO 97 / 34631, which are incorporated herein by reference.

[0243] In one specific embodiment, one, two, or more amino acid mutations (i.e., substitution, insertion, or deletion) are introduced into the constant domain of IgG or its FcRn-binding fragment (preferably an Fc or hinged Fc domain fragment) to alter (e.g., reduce or increase) the half-life of the antibody in vivo. Examples of mutations that alter (e.g., reduce or increase) the half-life of the antibody in vivo can be found, for example, International Publications WO 02 / 060919; WO 98 / 23289; and WO 97 / 34631; and U.S. Patents 5,869,046, 6,121,022, 6,277,375, and 6,165,745. In some embodiments, one, two, or more amino acid mutations (i.e., substitution, insertion, or deletion) are introduced into the constant domain of IgG or its FcRn-binding fragment (preferably an Fc or hinged Fc domain fragment) to reduce the half-life of the antibody in vivo. In other embodiments, one, two, or more amino acid mutations (i.e., substitutions, insertions, or deletions) are introduced into the IgG constant domain or its FcRn binding fragment (preferably an Fc or hinge Fc domain fragment) to increase the antibody's half-life in vivo. In one specific embodiment, the antibody may have one or more amino acid mutations (e.g., substitutions) in the second constant (CH2) domain (residues 231-340 of human IgG1) and / or the third constant (CH3) domain (residues 341-447 of human IgG1), numbered according to the EU index in Kabat (Kabat EA et al., (1991) ibid.). In one specific embodiment, the IgG1 constant region of the antibody described herein comprises: methionine (M) substituted for tyrosine (Y) at position 252, serine (S) substituted for threonine (T) at position 254, and threonine (T) substituted for glutamic acid (E) at position 256, according to the EU index number, as described in Kabat. See U.S. Patent No. 7,658,921, which is incorporated herein by reference. This mutant IgG, known as the “YTE mutant,” has been shown to exhibit a fourfold increase in half-life compared to the wild-type version of the same antibody (see Dall'Acqua WF et al., (2006) J Biol Chem 281: 23514-24). In some embodiments, the antibody comprises a constant IgG domain containing one, two, three, or more amino acid substitutions at positions 251-257, 285-290, 308-314, 385-389, and 428-436, according to EU index numbers, as described in Kabat.

[0244] In another embodiment, one, two, or more amino acids are substituted into the Fc region of the IgG constant domain to alter the effector function of the antibody. For example, one or more amino acids selected from amino acid residues 234, 235, 236, 237, 297, 318, 320, and 322 (according to EU index numbers, as described in Kabat) can be substituted with different amino acid residues, thereby altering the antibody's affinity for the effector ligand while retaining the antigen-binding ability of the parent antibody. The effector ligand whose affinity is altered can be an Fc receptor or a C1 component of complement. This method is described in more detail in U.S. Patent Nos. 5,624,821 and 5,648,260. In some embodiments, deletion or inactivation of the constant domain (through point mutations or other means) can reduce Fc receptor binding of circulating antibodies, thereby increasing tumor localization. For a description of mutations that delete or inactivate the constant domain, thereby increasing tumor localization, see, for example, U.S. Patent Nos. 5,585,097 and 8,591,886. In some embodiments, one or more amino acid substitutions may be introduced into the Fc region of the antibody described herein to remove potential glycosylation sites on the Fc region, which may reduce Fc receptor binding (see, for example, Shields RL et al., (2001) J Biol Chem276:6591-604). In various embodiments, one or more of the following mutations may be made into the constant region of the antibody described herein: N297A substitution; N297Q substitution; L235A and L237A substitution; L234A and L235A substitution; E233P substitution; L234V substitution; L235A substitution; C236 deletion; P238A substitution; D265A substitution; A327Q substitution; or P329A substitution, according to the EU index number, as described in Kabat.

[0245] In one specific embodiment, the antibody described herein comprises a constant domain of IgG1 having N297A or N297Q amino acid substitutions.

[0246] In some embodiments, one or more amino acid residues selected from amino acid residues 329, 331, and 322 (according to EU index numbers, as described in Kabat) in the constant region of the antibody described herein may be replaced with different amino acid residues, thereby altering C1q binding and / or reducing or eliminating complement-dependent cytotoxicity (CDC). This method is described in more detail in U.S. Patent No. 6,194,551 (Idusogie et al.). In some embodiments, altering one or more amino acid residues at positions 231 to 238 of the N-terminal region of the CH2 domain of the antibody described herein alters the antibody's ability to fix complement. This method is described in more detail in International Publication No. WO 94 / 29351. In some embodiments, the Fc region of the antibody described herein is modified by mutating one or more amino acids at the following positions (e.g., introducing amino acid substitutions) to enhance the antibody's ability to mediate antibody-dependent cytotoxicity (ADCC) and / or increase the antibody's affinity for the Fcγ receptor: 238, 239, 248, 249, 252, 254, 255, 256, 258, 265, 267, 268, 269, 270, 272, 276, 278, 280, 283, 285, 286, 289, 290, 29 2, 293, 294, 295, 296, 298, 301, 303, 305, 307, 309, 312, 315, 320, 322, 324, 326, 327, 329, 330, 331, 333, 334, 335, 337, 338, 340, 360, 373, 376, 378, 382, ​​388, 389, 398, 414, 416, 419, 430, 434, 435, 437, 438, or 439, according to EU index numbers, as described in Kabat. International Publication WO 00 / 42072 provides a more detailed description of this method.

[0247] In some embodiments, the antibody described herein comprises the constant region of an IgG4 antibody and proline is replaced with serine at amino acid residue 228 of the heavy chain (according to the EU index number, as described in Kabat).

[0248] It has been reported that antibodies with reduced fucosylation content have increased affinity for Fc receptors, such as, for example, FcγRIIIa. Therefore, in some embodiments, the antibodies described herein have reduced or no fucosylation content. Such antibodies can be prepared using techniques known to those skilled in the art. For example, the antibodies can be expressed in cells lacking or devoid of fucosylation capacity. In one specific example, a cell line with both alleles of α1,6-fucosyltransferase knocked out can be used to produce antibodies with reduced fucosylation content. The Potelligent® system (Lonza) is an example of such a system, which can be used to produce antibodies with reduced fucosylation content. Alternatively, antibodies with reduced or no fucosylation content can be produced, for example, by: (i) culturing cells under conditions that prevent or reduce fucosylation; (ii) removing fucosylation post-translationally (e.g., with fucosidase); (iii) adding the desired carbohydrate post-translationally, for example, after recombinant expression of a non-glycosylated glycoprotein; or (iv) purifying the glycoprotein for selection against non-fucosylated antibodies. For methods for generating antibodies with no or reduced fucose content, see, for example, Longmore GD and Schachter H (1982) Carbohydr Res 100: 365-92 and Imai-Nishiya H et al., (2007) BMCBiotechnol. 7: 84.

[0249] In some embodiments, the antibodies described herein have increased affinity for CD32B (also known as FcγRIIB or FCGR2B), for example, compared to antibodies having a wild-type Fc region (e.g., IgG1 Fc). In some embodiments, the antibodies described herein have selectively increased affinity for CD32B (FcγRIIB) relative to their affinity for CD32A (FcγRIIA) and CD16 (FcγRIIIA). For example, sequence alterations leading to increased affinity for CD32B are provided in Mimoto et al., Protein Engineering, Design & Selection 10: 589-598 (2013), Chu et al., Molecular Immunology 45: 3926-3933 (2008), and Strohl, Current Opinion in Biology 20: 685-691 (2009), each of which is incorporated herein by reference in its entirety. In some embodiments, antibodies with increased affinity for CD32B include a heavy chain constant region, for example, an IgG1 constant region containing mutations selected from the group consisting of: G236D, P238D, S239D, S267E, L328F, L328E, arginine inserted after position 236, and combinations thereof, according to EU index numbers (Kabat et al., Sequences of Proteins of Immunological Interest, US Department of Health and Human Services, Bethesda (1991)). In some embodiments, antibodies with increased affinity for CD32B include a heavy chain constant region, for example, an IgG1 constant region containing S267E and L328F substitutions. In some embodiments, antibodies with increased affinity for CD32B include a heavy chain constant region, for example, an IgG1 constant region containing P238D and L328E substitutions. In some embodiments, the antibody with increased affinity for CD32B comprises a heavy chain constant region, for example, an IgG1 constant region comprising P238D substitution and substitutions selected from the group consisting of E233D, G237D, H268D, P271G, A330R, and combinations thereof. In some embodiments, the antibody with increased affinity for CD32B comprises a heavy chain constant region, for example, an IgG1 constant region comprising P238D, E233D, G237D, H268D, P271G, and A330R substitutions. In some embodiments, the antibody with increased affinity for CD32B comprises a heavy chain constant region, for example, an IgG1 constant region comprising G236D and S267E.In some embodiments, the antibody with increased affinity for CD32B includes a heavy chain constant region, for example, an IgG1 constant region comprising S239D and S267E. In some embodiments, the antibody with increased affinity for CD32B includes a heavy chain constant region, for example, an IgG1 constant region comprising S267E and L328F. In some embodiments, the antibody with increased affinity for CD32B includes a heavy chain constant region, for example, an IgG1 constant region comprising an arginine residue inserted after position 236 and L328R.

[0250] In another aspect, the antibodies provided herein bind to the same or overlapping epitopes of GDF15 as the antibodies described herein (e.g., 01G06; Hu01G06-1; Hu01G06-46; Hu01G06-52; Hu01G06-100; Hu01G06-101; Hu01G06-102; Hu01G06-103; Hu01G06-104; Hu01G06-105; Hu01G06-106; Hu01G06-107; Hu01G06-108; Hu01G06-109; Hu01G06-11). 0; Hu01G06-111; Hu01G06-112; Hu01G06-113; Hu01G06-114; Hu01G06-122; Hu01G06-127; Hu01G06-135; Hu01G06-138; Hu01G06-146; 06C11; Hu06C11-1; Hu06C11-27; Hu06C11-30; 14F11; Hu14F11-1; Hu14F11-23; Hu14F11-24; Hu14F11-39; or Hu14F11-47). In some embodiments, the antibody binds to an epitope that overlaps with an epitope of an antibody comprising any of the six CDRs defined by the Kabat, Chothia, IMGT, or combined Kabat / Chothia methods, any one of the antibodies described in Tables 3 and 4. In some embodiments, the epitope of the antibody can be determined by, for example, NMR spectroscopy, X-ray diffraction crystallography, ELISA assays, hydrogen / deuterium exchange coupled with mass spectrometry (e.g., liquid chromatography-electrospray mass spectrometry), array-based oligopeptide scanning assays, and / or mutagenesis mapping (e.g., site-directed mutagenesis mapping). For X-ray crystallography, crystallization can be performed using any method known in the art (e.g., Giege R et al., (1994) Acta Crystallogr D Biol Crystallogr 50 (Pt 4): 339-350; McPherson A (1990) Eur J Biochem 189:1-23; Chayen NE (1997) Structure 5: 1269-1274; McPherson A (1976) J Biol Chem 251:6300-6303).Antibodies: Antigen crystals can be studied using well-known X-ray diffraction techniques and refined using computer software such as X-PLOR (Yale University, 1992, published by Molecular Simulations, Inc.; see, for example, Meth Enzymol (1985) Vols. 114 and 115, edited by Wyckoff HW et al.; U.S. Patent Application No. 2004 / 0014194) and BUSTER (Bricogne G (1993) Acta Crystallogr D Biol Crystallogr 49(Pt 1): 37-60; Bricogne G (1997) Meth Enzymol 276A: 361-423, edited by Carter CW; Roversi P et al., (2000) Acta Crystallogr D Biol Crystallogr 56(Pt 10): 1316-1323). Mutagenesis mapping studies can be performed using any method known to those skilled in the art. For descriptions of mutagenesis techniques, see, for example, Champe M et al., (1995) ibid. and Cunningham BC and Wells JA (1989) ibid., including alanine scanning mutagenesis.

[0251] In addition, conventional techniques such as immunoassays can be used to identify antibodies that recognize and bind to the same or overlapping epitopes of GDF15, for example, by demonstrating the ability of one antibody to block the binding of another antibody to the target antigen, i.e., a competitive binding assay. Competitive binding assays can also be used to determine whether the binding specificity of two antibodies to an epitope is similar. Competitive binding can be determined in the assay of the specific binding of the immunoglobulin-inhibiting reference antibody to a common antigen, such as GDF15. Several types of competitive binding assays are known, such as: solid-phase direct or indirect radioimmunoassay (RIA), solid-phase direct or indirect enzyme immunoassay (EIA), sandwich competitive assay (see Stahli C et al., (1983) Methods Enzymol9: 242-253); solid-phase direct biotin-avidin EIA (see Kirkland TN et al., (1986) J Immunol137: 3614-9); solid-phase direct labeling assay, solid-phase direct labeling sandwich assay (see Harlow E and Lane D, (1988) Antibodies: A Laboratory Manual, Cold Spring Harbor Press); solid-phase direct labeling RIA using I-125 labeling (see Morel GA et al., (1988) Mol Immunol 25(1): 7-15); solid-phase direct biotin-avidin EIA (see Cheung RC et al., (1990) Virology 176: 546-52); and directly labeled MA (see Moldenhauer G et al., (1990) Scand J Immunol 32: 77-82). Typically, this assay involves using a purified antigen (e.g., GDF15) bound to a solid surface or cells carrying any of these antigens, an unlabeled test immunoglobulin, and a labeled reference immunoglobulin. Competitive inhibition can be measured by determining the amount of label bound to the solid surface or cells in the presence of the test immunoglobulin. Typically, an excess of the test immunoglobulin is present. Typically, when an excess of the competitive antibody is present, it inhibits the specific binding of the reference antibody to the common antigen by at least 50-55%, 55-60%, 60-65%, 65-70%, 70-75%, or more. Competitive binding assays can use labeled antigens or labeled antibodies, configured in a variety of different forms. In a common version of this assay, the antigen is immobilized on a 96-well plate. Radiolabeling or enzyme labeling is then used to measure the ability of the unlabeled antibody to block the binding of the labeled antibody to the antigen.For further details, see, for example, Wagener C et al., (1983) J Immunol 130: 2308-2315; Wagener C et al., (1984) J Immunol Methods 68: 269-274; Kuroki M et al., (1990) Cancer Res 50:4872-4879; Kuroki M et al., (1992) Immunol Invest 21: 523-538; Kuroki M et al., (1992) Hybridoma 11: 391-407, and Antibodies: A Laboratory Manual, edited by Harlow E and Lane D, ibid., pp. 386-389.

[0252] In one implementation, surface plasmon resonance (BIAcore) is used. ® Competitive assays can be performed, for example, by a “tandem method” such as that described by Abdiche YN et al., (2009) Analytical Biochem 386: 172-180, in which the GDF15 antigen is immobilized on a chip surface, such as a CMS sensor chip, and then an anti-GDF15 antibody is run on the chip. To determine whether an antibody competes with the anti-GDF15 antibody described herein, the anti-GDF15 antibody is first run on the chip surface to saturation, and then a potentially competitive antibody is added. Binding of the competitive antibody can then be determined and quantified relative to a non-competitive control.

[0253] In some respects, competitive binding assays can be used to determine whether an antibody is competitively blocked by another antibody, for example, in a dose-dependent manner, when two antibodies recognize the same or spatially overlapping epitopes in a competitive binding assay (such as a competitive ELISA assay, which may use labeled antigens or labeled antibodies configured in a variety of different forms), and the antibody binds to an epitope that is substantially the same as or overlaps with that of a reference antibody. In one particular implementation, the antibodies described herein (e.g., 01G06; Hu01G06-1; Hu01G06-46; Hu01G06-52; Hu01G06-100; Hu01G06-101; Hu01G06-102; Hu01G06-103; Hu01G06-104; Hu01G06-105; Hu01G06-106; Hu01G06-107; Hu01G06-108; Hu01G06-109; Hu01G06-110; Hu01G06-111; Hu01G06) may be used. -112; Hu01G06-113; Hu01G06-114; Hu01G06-122; Hu01G06-127; Hu01G06-135; Hu01G06-138; Hu01G06-146; 06C11; Hu06C11-1; Hu06C11-27; Hu06C11-30; 14F11; Hu14F11-1; Hu14F11-23; Hu14F11-24; Hu14F11-39; or Hu14F11-47), or their chimeric antibodies or Fab antibodies, or VH containing the antibodies described herein. Antibodies against CDR and VLCDR (e.g., 01G06; Hu01G06-1; Hu01G06-46; Hu01G06-52; Hu01G06-100; Hu01G06-101; Hu01G06-102; Hu01G06-103; Hu01G06-104; Hu01G06-105; Hu01G06-106; Hu01G06-107; Hu01G06-108; Hu01G06-109; Hu01G06-110; Hu01G06-111; Hu01G The antibodies (06-112; Hu01G06-113; Hu01G06-114; Hu01G06-122; Hu01G06-127; Hu01G06-135; Hu01G06-138; Hu01G06-146; 06C11; Hu06C11-1; Hu06C11-27; Hu06C11-30; 14F11; Hu14F11-1; Hu14F11-23; Hu14F11-24; Hu14F11-39; and Hu14F11-47) were tested in a competitive binding assay.

[0254] In another aspect, this article provides antibodies similar to those described herein (e.g., 01G06; Hu01G06-1; Hu01G06-46; Hu01G06-52; Hu01G06-100; Hu01G06-101; Hu01G06-102; Hu01G06-103; Hu01G06-104; Hu01G06-105; Hu01G06-106; Hu01G06-107; Hu01G06-108; Hu01G06-109; Hu01G06-110; Hu01G06-111; Hu01G06-112; Hu01G06-113; Hu01G06). -114; Hu01G06-122; Hu01G06-127; Hu01G06-135; Hu01G06-138; Hu01G06-146; 06C11; Hu06C11-1; Hu06C11-27; Hu06C11-30; 14F11; Hu14F11-1; Hu14F11-23; Hu14F11-24; Hu14F11-39; or Hu14F11-47) antibodies that competitively (e.g., in a dose-dependent manner) bind to GDF15, as determined using assays known to those skilled in the art or described herein (e.g., competitive ELISA assays or surface plasmon resonance). In some implementations, the antibody competitively binds to GDF15 with an antibody containing six CDRs, wherein the CDRs are defined by any of the Kabat, Chothia, IMGT, or combined Kabat / Chothia methods of any of the antibodies described in Tables 3 and 4.

[0255] In another aspect, this article provides competitive inhibition (e.g., in a dose-dependent manner) of the antibodies described herein (e.g., Hu01G06; Hu01G06-1; Hu01G06-46; Hu01G06-52; Hu01G06-100; Hu01G06-101; Hu01G06-102; Hu01G06-103; Hu01G06-104; Hu01G06-105; Hu01G06-106; Hu01G06-107; Hu01G06-108; Hu01G06-109; Hu01G06-110; Hu01G06-111; Hu01G06-112; Hu01G06). -113; Hu01G06-114; Hu01G06-122; Hu01G06-127; Hu01G06-135; Hu01G06-138; Hu01G06-146; 06C11; Hu06C11-1; Hu06C11-27; Hu06C11-30; 14F11; Hu14F11-1; Hu14F11-23; Hu14F11-24; Hu14F11-39; or Hu14F11-47) antibodies that bind to GDF15, as determined using an assay known to those skilled in the art or described herein (e.g., a competitive ELISA assay or a suspension array or surface plasmon resonance assay). In certain embodiments, such competitive blocking antibodies activate, induce, or enhance the activity of one or more GDF15 molecules. In some implementations, the antibody competitively inhibits an antibody comprising six CDRs, wherein the CDRs are defined by any of the Kabat, Chothia, IMGT, or combined Kabat / Chothia methods of any of the antibodies described in Tables 3 and 4.Specifically, this document provides an antibody that interacts with an antibody containing the amino acid sequence described herein (e.g., antibody 01G06; Hu01G06-1; Hu01G06-46; Hu01G06-52; Hu01G06-100; Hu01G06-101; Hu01G06-102; Hu01G06-103; Hu01G06-104; Hu01G06-105; Hu01G06-106; Hu01G06-107; Hu01G06-108; Hu01G06-109; Hu01G06-110; Hu01G06-111; Hu01G06-112; Hu01G06-113; Hu01G06-1). 14; Hu01G06-122; Hu01G06-127; Hu01G06-135; Hu01G06-138; Hu01G06-146; 06C11; Hu06C11-1; Hu06C11-27; Hu06C11-30; 14F11; Hu14F11-1; Hu14F11-23; Hu14F11-24; Hu14F11-39; or the VL and / or VH amino acid sequences of Hu14F11-47) competitively (e.g., in a dose-dependent manner) specifically bind to GDF15, as known to those skilled in the art or described herein (e.g., ELISA competitive assay or suspension array or surface plasmon resonance assay).

[0256] In a specific aspect, this document provides an antibody that specifically binds to GDF15 in a competitive (e.g., dose-dependent) manner against antibodies comprising a VH domain having an amino acid sequence selected from the group consisting of SEQ ID NO: 67-84 and a VL domain having an amino acid sequence selected from the group consisting of SEQ ID NO: 58-66.

[0257] In a specific respect, this article provides an antibody that competes (e.g., in a dose-dependent manner) for specific binding to GDF15 with antibodies comprising: (i) a VH domain comprising CDRH1, CDRH2, and CDRH3 having the amino acid sequences of the VH CDRs of the antibodies listed in Table 1; and (ii) a VL domain comprising CDRL1, CDRL2, and CDRL3 having the amino acid sequences of the VL CDRs of the antibodies listed in Table 2.

[0258] In one specific embodiment, the antibody described herein is an antibody that is competitively blocked (e.g., in a dose-dependent manner) specifically bound to GDF15 by an antibody comprising a VH domain having an amino acid sequence selected from the group consisting of SEQ ID NO: 67-84 and a VL domain having an amino acid sequence selected from the group consisting of SEQ ID NO: 58-66.

[0259] In another specific embodiment, the antibody described herein is an antibody that is competitively blocked (e.g., in a dose-dependent manner) by comprising: (i) a VH domain comprising CDRH1, CDRH2, and CDRH3 having the amino acid sequence of the CDR of the antibodies listed in Table 1 (e.g., the VH CDR of the specific antibodies mentioned by name in Table 1); and (ii) a VL domain comprising CDRL1, CDRL2, and CDRL3 having the amino acid sequence of the CDR of the antibodies listed in Table 2 (e.g., the VL CDR of the specific antibodies mentioned by name in Table 2).

[0260] In a specific respect, this document provides an antibody that specifically binds to antibodies containing the amino acid sequence described herein (see, for example, Tables 1-4) (e.g., antibody 01G06; Hu01G06-1; Hu01G06-46; Hu01G06-52; Hu01G06-100; Hu01G06-101; Hu01G06-102; Hu01G06-103; Hu01G06-104; Hu01G06-105; Hu01G06-106; Hu01G06-107; Hu01G06-108; Hu01G06-109; Hu01G06-110; Hu01G06-111; Hu01G06-1). 12; Hu01G06-113; Hu01G06-114; Hu01G06-122; Hu01G06-127; Hu01G06-135; Hu01G06-138; Hu01G06-146; 06C11; Hu06C11-1; Hu06C11-27; Hu06C11-30; 14F11; Hu14F11-1; Hu14F11-23; Hu14F11-24; Hu14F11-39; or any one of Hu14F11-47) are identical epitopes. Assays known to those skilled in the art or described herein (e.g., X-ray crystallography, ELISA assays, etc.) can be used to determine whether two antibodies bind to the same epitope.

[0261] In one specific embodiment, the antibodies described herein specifically bind to antibodies comprising a VH domain having an amino acid sequence selected from the group consisting of SEQ ID NO: 67-84 and a VL domain having an amino acid sequence selected from the group consisting of SEQ ID NO: 58-66 (e.g., antibody 01G06; Hu01G06-1; Hu01G06-46; Hu01G06-52; Hu01G06-100; Hu01G06-101; Hu01G06-102; Hu01G06-103; Hu01G06-104; Hu01G06-105; Hu01G06-106; Hu01G06-107; Hu01G06-108; Hu01G06-109; Hu01G06-110; Hu01G06-1). 11; Hu01G06-112; Hu01G06-113; Hu01G06-114; Hu01G06-122; Hu01G06-127; Hu01G06-135; Hu01G06-138; Hu01G06-146; 06C11; Hu06C11-1; Hu06C11-27; Hu06C11-30; 14F11; Hu14F11-1; Hu14F11-23; Hu14F11-24; Hu14F11-39; or any one of Hu14F11-47) are the same epitopes.

[0262] In another specific embodiment, the antibody described herein specifically binds to the same epitopes as an antibody comprising: (i) a VH domain comprising CDRH1, CDRH2, and CDRH3 having the amino acid sequences of the CDRs listed in Table 1, and (ii) a VL domain comprising CDRL1, CDRL2, and CDRL3 having the amino acid sequences of the CDRs listed in Table 2.

[0263] Antibodies may be neutralizing antibodies that reduce GDF15 activity. For example, antibodies are used in in vivo assays (see Johnen et al., 2007). (13:1333-1340) The antibody can reduce GDF15 activity by at least 10%, preferably 20%, 30%, or 40%, and more preferably at least about 50%, 60%, 80%, or 90%, compared to GDF15 activity measured under the same conditions without the antibody. The antibody can selectively and / or significantly reduce or inhibit the binding of GDF15 to its endogenous receptor. As used herein, the term “significantly reduce or inhibit” the binding of GDF15 to its receptor should be understood to mean that, in the absence of the antibody, the antibody has an inhibitory potency or percentage of inhibition of GDF15 binding of at least 10%, preferably 20%, 30%, or 40%, and more preferably at least about 50%, 60%, 80%, or 90% of GDF15 [serum level / activity]. The binding can be measured using a direct or sandwich enzyme-linked immunosorbent assay (ELISA), such as, for example, Tsai et al., 2013. As described in , 8:e55174. As used herein, the term “selectively” in the case of antibodies binding to GDF15 or the GDF15 receptor should be understood to mean that when the antibody binds to GDF15 or the GDF15 receptor, its binding affinity is at least two, three, four, five, or ten times that of a functionally unrelated protein or another member of the TGF-β superfamily or the receptor of a member of the TGF-β superfamily.

[0264] Methods for reducing or eliminating the antigenicity of antibodies and antibody fragments are known in the art. When antibodies are intended for use in humans, it is preferable to "humanize" the antibodies to reduce or eliminate their antigenicity in the human body. Preferably, each humanized antibody has the same or substantially the same affinity for the antigen as its derived non-humanized mouse antibody.

[0265] In one humanization method, chimeric proteins were produced in which the mouse immunoglobulin constant region was replaced by the human immunoglobulin constant region. See, for example, Morrison et al., 1984. 81:6851-6855, Neuberger et al., 1984, 312:604-608; U.S. Patent No. 6,893,625 (Robinson); No. 5,500,362 (Robinson); and No. 4,816,567 (Cabilly).

[0266] In a method called CDR transplantation, the CDRs of the light and heavy chain variable regions are transplanted into the framework of another species. For example, mouse CDRs can be transplanted into human FRs. In some embodiments, the CDRs of the light and heavy chain variable regions of the anti-GDF15 antibody are transplanted into human FRs or co-human FRs. To generate co-human FRs, FRs from several human heavy or light chain amino acid sequences are aligned to identify common amino acid sequences. CDR transplantation is described in the following: U.S. Patents 7,022,500 (Queen), 6,982,321 (Winter), 6,180,370 (Queen), 6,054,297 (Carter), 5,693,762 (Queen), 5,859,205 (Adair), 5,693,761 (Queen), 5,565,332 (Hoogenboom), 5,585,089 (Queen), and 5,530,101 (Queen); Jones et al., 1986, 321: 522-525; Riechmann et al., 1988, 332: 323-327; Verhoeyen et al., 1988, 239: 1534-1536; and Winter, 1998, 430: 92-94.

[0267] In a method called "SUPERHUMANIZATION™", human CDR sequences are selected from human germline genes based on the structural similarity between human CDRs and the CDRs of the mouse antibody to be humanized. See, for example, U.S. Patent No. 6,881,557 (Foote); and Tan et al., 2002. 169:1119-1125.

[0268] Other methods to reduce immunogenicity include "remodeling," "hyperchidization," and "decorative / surface remodeling." See, for example, Vaswami et al., 1998. 81:105; Roguska et al., 1996, 9:895-904; and U.S. Patent No. 6,072,035 (Hardman). In the matte / surface remodeling method, surface-accessible amino acid residues in mouse antibodies are replaced with amino acid residues more common at the same positions in human antibodies. For example, this type of antibody surface remodeling is described in U.S. Patent No. 5,639,641 (Pedersen).

[0269] Another method for converting mouse antibodies into a form suitable for human medical use is called ACTIVMAB. TM The technology (Vaccinex, Inc., Rochester, NY) relates to the expression of antibodies in mammalian cells based on vaccinia virus vectors. It is claimed to produce high levels of combinatorial diversity of IgG heavy and light chains. See, for example, U.S. Patent Nos. 6,706,477 (Zauderer); 6,800,442 (Zauderer); and 6,872,518 (Zauderer).

[0270] Another method for converting mouse antibodies into a form suitable for human use is a technique commercially practiced by KaloBiosPharmaceuticals, Inc. (Palo Alto, CA). This technique involves using a proprietary human “recipient” library to generate an “epitope-focused” library for antibody selection.

[0271] Another method for modifying mouse antibodies to suit human medical use is HUMAN ENGINEERING. TM The technology is commercialized by XOMA (US) LLC. See, for example, PCT Publication WO 93 / 11794 and U.S. Patent Nos. 5,766,886 (Studnicka); 5,770,196 (Studnicka); 5,821,123 (Studnicka); and 5,869,619 (Studnicka).

[0272] Any suitable method, including any of the methods mentioned above, can be used to reduce or eliminate the human immunogenicity of antibodies.

[0273] Furthermore, fully human antibodies can be generated in mice. Fully human mAbs lacking any non-human sequences can be prepared from human immunoglobulin transgenic mice using techniques cited below: e.g., Lonberg et al. 368:856-859, 1994; Fishwild et al., 14:845-851, 1996, and Mendez et al., 15:146-156, 1997. Fully human mAbs can also be prepared and optimized from phage display libraries using techniques cited below, such as those used by Knappik et al. 296:57-86, 2000; and Krebs et al., J. Immunol. Meth. 254:67-84 2001).

[0274] In some embodiments, the antibodies disclosed herein are conjugated to cytotoxic agents, cell inhibitors, toxins, radionuclides, or detectable markers. In some embodiments, the cytotoxic agent is capable of inducing cell death or destruction upon contact with it. In some embodiments, the cell inhibitor is capable of preventing or significantly reducing the proliferation of cells upon contact with it and / or inhibiting their activity or function. In some embodiments, the cytotoxic agent or cell inhibitor is a chemotherapeutic agent. In some embodiments, the radionuclide is selected from the group consisting of isotopes. 3 H, 14 C 32 P, 35 S, 36 Cl、 51 Cr 57 Co、 58 Co、 59 Fe、 67 Cu、 90 Y、 99 Tc, 111 In、 117 Lu、 121 I, 124 I, 125 I, 131 I, 198 Au、 211 At、 213 Bi、 225 Ac and 186 Re. In some implementations, the detectable marker may contain a fluorescent portion or a click chemical handle.

[0275] Pharmaceutical Composition

[0276] The compositions provided herein comprise antibodies of the desired purity described herein, wherein the antibodies are in physiologically acceptable carriers, excipients, or stabilizers (Remington's Pharmaceutical Sciences (1990) Mack Publishing Co., Easton, PA). Acceptable carriers, excipients, or stabilizers are non-toxic to recipients at the doses and concentrations used and include buffers such as phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyl dimethyl benzyl ammonium chloride; hexamethyl diammonium chloride; benzalkonium chloride; benzyl chloride; phenol, butyl or benzyl alcohol; alkyl esters of p-hydroxybenzoate, such as methylparaben or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); and low molecular weight (less than about 10 residues). Polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; 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 (e.g., Zn-protein complexes); and / or nonionic surfactants, such as TWEEN. TM PLURONICS TM Or polyethylene glycol (PEG). In one specific embodiment, the pharmaceutical composition comprises the antibody described herein, and optionally one or more other preventive or therapeutic agents, said pharmaceutical composition being in a pharmaceutically acceptable carrier. In one specific embodiment, the pharmaceutical composition comprises an effective amount of the antibody described herein, and optionally one or more other preventive or therapeutic agents, said pharmaceutical composition being in a pharmaceutically acceptable carrier. Examples of preventive or therapeutic agents are provided throughout this disclosure. In some embodiments, the antibody is the only active ingredient contained in the pharmaceutical composition. The pharmaceutical compositions described herein can be used to reduce weight loss in subjects with cancer.

[0277] Pharmaceutically acceptable carriers used in parenteral preparations include aqueous media, non-aqueous media, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifiers, sequestering agents, or chelating agents, and other pharmaceutically acceptable substances. Examples of aqueous media include sodium chloride injection, Ringer's solution, isotonic glucose injection, sterile water injection, and glucose and lactated Ringer's solution. Non-aqueous parenteral media include plant-derived fixed oils, cottonseed oil, corn oil, sesame oil, and peanut oil. Antimicrobial agents at antibacterial or antifungal concentrations may be added to parenteral preparations packaged in multi-dose containers. These parenteral preparations include phenol or cresol, mercury compounds, benzyl alcohol, chlorobutanol, methylparaben and propylparaben, thimerosal, benzalkonium chloride, and benzyl chloride. Isotonic agents include sodium chloride and glucose. Buffers include phosphates and citrates. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspensors and dispersants include sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Emulsifiers include polysorbate 80 (TWEEN® 80). Metal ion chelators or chelating agents include EDTA. Drug carriers also include ethanol, polyethylene glycol, and propylene glycol (for water-soluble media); and sodium hydroxide, hydrochloric acid, citric acid, or lactic acid (for pH adjustment).

[0278] The pharmaceutical composition can be formulated for any route of administration to a subject. Specific examples of routes of administration include intranasal, oral, pulmonary, transdermal, intradermal, and parenteral administration. Parenteral administration, characterized by subcutaneous, intramuscular, or intravenous injection, is also considered herein. The injection can be prepared in a conventional form, which may be a liquid solution or suspension, a solid form suitable for dissolution or suspension in a liquid prior to injection, or an emulsion. The injection, solution, and emulsion also contain one or more excipients. Suitable excipients are, for example, water, saline, glucose, glycerol, or ethanol. Furthermore, if desired, the pharmaceutical composition to be administered may also contain small amounts of non-toxic excipients, such as wetting agents or emulsifiers, pH buffers, stabilizers, solubilizers, and other such agents, such as, for example, sodium acetate, sorbitol monolaurate, triethanolamine oleate, and cyclodextrin.

[0279] Antibody preparations for parenteral administration include injectable sterile solutions, sterile dried soluble products (such as lyophilized powders), products that can be combined with solvents before use (including subcutaneous tablets), injectable sterile suspensions, sterile dried insoluble products that can be combined with media before use, and sterile emulsions. Solutions can be aqueous or non-aqueous.

[0280] If administered intravenously, suitable carriers include physiological saline or phosphate-buffered saline (PBS), as well as solutions containing thickeners and solubilizers, such as glucose, polyethylene glycol, and polypropylene glycol, and mixtures thereof.

[0281] Prepare the antibody-containing topical mixture as described above for both local and systemic application. The resulting mixture may be a solution, suspension, emulsion, etc., and may be formulated into creams, gels, ointments, lotions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, rinses, sprays, suppositories, bandages, skin patches, or any other formulation suitable for topical application.

[0282] The antibodies described herein can be formulated as aerosols for external application, such as by inhalation (see, for example, U.S. Patents 4,044,126, 4,414,209, and 4,364,923, which describe aerosols for delivering steroids used to treat inflammatory conditions, particularly asthma). These formulations for application to the respiratory tract can be in the form of aerosols or solutions for nebulizer use, or as fine powders for nasal inhalation, alone or in combination with an inert carrier such as lactose. In this case, in one embodiment, the particle diameter of the formulation will be less than 50 micrometers; in another embodiment, less than 10 micrometers.

[0283] The antibodies described herein can be formulated for topical or external application, such as for skin and mucous membranes (e.g., eyes), in gel, cream, and lotion form, and for application to the eyes, or for intracranial or intraspinal application. External application is considered for transdermal delivery and application to the eyes or mucous membranes, or for inhalation therapy. Antibody nasal solutions can also be administered alone, or in combination with pharmaceutically acceptable excipients.

[0284] Transdermal patches, including iontophoresis and electrophoresis devices, are well known to those skilled in the art and can be used to administer antibodies. Such patches are disclosed, for example, in U.S. Patent Nos. 6,267,983, 6,261,595, 6,256,533, 6,167,301, 6,024,975, 6,010,715, 5,985,317, 5,983,134, 5,948,433, and 5,860,957.

[0285] In some embodiments, the pharmaceutical composition comprising the antibody described herein is a lyophilized powder that can be reconstituted into solutions, emulsions, and other mixtures for administration. It can also be reconstituted and formulated into a solid or gel. The lyophilized powder is prepared by dissolving the antibody described herein or a pharmaceutically acceptable derivative thereof in a suitable solvent. In some embodiments, the lyophilized powder is sterile. The solvent may contain excipients that improve the stability of the powder or a reconstituted solution prepared from the powder, or other pharmacological components. Excipients that may be used include, but are not limited to, glucose, sorbitol, fructose, corn syrup, xylitol, glycerol, glucose, sucrose, or other suitable agents. The solvent may also contain a buffer, such as citrate, sodium phosphate, or potassium phosphate, or other such buffers known to those skilled in the art, and in one embodiment, its pH is close to neutral. The solution is then sterilely filtered and lyophilized under standard conditions known to those skilled in the art to obtain the desired formulation. In one embodiment, the resulting solution is aliquoted into vials for lyophilization. Each vial will contain a single or multiple doses of the compound. The lyophilized powder can be stored under suitable conditions, such as between about 4°C and room temperature. This lyophilized powder is reconstituted with water for injection to obtain a formulation suitable for parenteral administration. For reconstitution, the lyophilized powder is added to sterile water or another suitable carrier. The precise amount depends on the compound selected. This amount can be determined empirically.

[0286] The antibodies described herein and other compositions provided herein can also be formulated to target specific tissues, receptors, or other sites in the body of a subject to be treated. Many such targeting methods are well known to those skilled in the art. This document contemplates the application of all such targeting methods to the compositions of the invention. Non-limiting examples of targeting methods can be found, for example, in U.S. Patent Nos. 6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082, 6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542, and 5,709,874. In one specific embodiment, the antibody described herein targets a tumor.

[0287] Compositions intended for in vivo administration can typically be sterile. This is easily achieved through filtration, for example, via a sterile filter membrane.

[0288] Generally, the therapeutically effective amount of the active ingredient ranges from 0.1 mg / kg to 100 mg / kg, for example, 1 mg / kg to 100 mg / kg, or 1 mg / kg to 10 mg / kg. The dosage administered will depend on various variables, such as the type and extent of the disease or indication to be treated, the patient's overall health condition, the antibody's potency in vivo, the drug formulation, and the route of administration. To rapidly achieve the desired blood or tissue levels, the initial dose may be increased above the upper limit. Alternatively, the initial dose may be less than the optimal dose, with the daily dose gradually increased during treatment. Human dosing can be optimized, for example, designed as 0.5 mg / kg to 20 mg / kg in a standard Phase I dose-escalation study. Dosing frequency can vary depending on factors such as the route of administration, dosage, the antibody's serum half-life, and the disease being treated. Exemplary dosing frequencies are once daily, once weekly, and once every two weeks.

[0289] The optimal effective amount of the composition can be determined empirically and will depend on the type and severity of the disease, route of administration, disease progression and health status, and the subject's weight and body area. Such determinations are within the skill of those skilled in the art. Dosage examples of GDF15 modulator molecules that can be used in the methods described herein include, but are not limited to, effective amounts in any of the following dosage ranges: about 0.01 μg / kg to about 300 mg / kg, or about 0.1 μg / kg to about 40 mg / kg, or about 1 μg / kg to about 20 mg / kg, or about 1 μg / kg to about 10 mg / kg. For example, when administered subcutaneously, the composition can be administered in low microgram ranges, including, for example, about 0.1 μg / kg or less, about 0.05 μg / kg or less, or 0.01 μg / kg or less.

[0290] In some embodiments, the amount of GDF15 modifier administered to the subject is from about 10 μg to about 500 mg per dose, including, for example, any one of about 10 μg to about 50 μg, about 50 μg to about 100 μg, about 100 μg to about 200 μg, about 200 μg to about 300 μg, about 300 μg to about 500 μg, about 500 μg to about 1 mg, about 1 mg to about 10 mg, about 10 mg to about 50 mg, about 50 mg to about 100 mg, about 100 mg to about 200 mg, about 200 mg to about 300 mg, about 300 mg to about 400 mg, or about 400 mg to about 500 mg. In some embodiments, the GDF15 modifier is administered at doses of about 0.025 mg to about 4 mg, about 0.035 mg to about 2 mg, about 0.05 mg to about 2 mg, about 0.1 mg to about 2 mg, about 0.2 mg to about 1 mg, or about 0.2 mg to about 0.8 mg of the GDF15 modifier. In one embodiment, 0.5 mg of the GDF15 modifier is applied topically. In some other embodiments, about 0.05 mg to about 2 mg, about 0.2 mg to about 2 mg, about 0.05 mg to about 1.5 mg, about 0.15 mg to about 1.5 mg, about 0.4 mg to about 1 mg, or about 0.5 mg to about 0.8 mg of the GDF15 modifier is applied topically.

[0291] In some embodiments, the anti-GDF15 antibody described herein is administered to the subject at a dose of about 12.5 mg to about 800 mg. In some embodiments, the anti-GDF15 antibody described herein is administered to the subject at a dose of about 12.5 mg to about 200 mg. In some embodiments, the anti-GDF15 antibody described herein is administered to the subject at a dose of about 50 mg to about 800 mg.

[0292] In some embodiments, the anti-GDF15 antibody described herein is administered to the subject at a dose of 12.5 mg to 800 mg. In some embodiments, the anti-GDF15 antibody described herein is administered to the subject at a dose of 12.5 mg to 200 mg. In some embodiments, the anti-GDF15 antibody described herein is administered to the subject at a dose of 50 mg to 800 mg.

[0293] In some embodiments, the anti-GDF15 antibody described herein is administered to the subject at doses of about 12.5 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, or about 800 mg. In some embodiments, the anti-GDF15 antibody described herein is administered to subjects at doses of 12.5 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, or 800 mg.

[0294] In some embodiments, the anti-GDF15 antibody is administered intravenously. In some embodiments, the anti-GDF15 antibody is administered intravenously once weekly or every 2 weeks. In some embodiments, the anti-GDF15 antibody is administered intravenously once every 7 days or every 14 days.

[0295] In some embodiments, the anti-GDF15 antibody is administered subcutaneously. In some embodiments, the anti-GDF15 antibody is administered subcutaneously once a week or every 2 weeks. In some embodiments, the anti-GDF15 antibody is administered subcutaneously once every 7 days or every 14 days.

[0296] Treatment

[0297] In one aspect, a method for reducing weight loss in subjects suffering from cancer is provided, comprising administering to the subject an effective amount of an anti-GDF15 antibody according to the present disclosure or a pharmaceutical composition containing said antibody.

[0298] In some embodiments, the subject recovers lost weight after administration of one or more effective doses of the anti-GDF15 antibody or a pharmaceutical composition containing said antibody. In some embodiments, at least 5% of the lost weight is recovered. In some embodiments, the subject's weight is maintained for at least one month after administration of one or more effective doses of the anti-GDF15 antibody or a pharmaceutical composition containing said antibody. In some embodiments, the subject's weight is maintained within 5% of the weight at the time of the first administration of the anti-GDF15 antibody or a pharmaceutical composition containing said antibody. In some embodiments, the rate of weight loss in the subject is slowed after administration of one or more effective doses of the anti-GDF15 antibody or a pharmaceutical composition containing said antibody. In some embodiments, the rate of weight loss in the subject is slowed by at least 5% after the first administration of the anti-GDF15 antibody or a pharmaceutical composition containing said antibody.

[0299] In some implementations, the cancer is a solid tumor. In some implementations, the cancer is a liquid tumor. In some implementations, the cancer is a metastatic cancer. In some implementations, the cancer is selected from the group consisting of: lung cancer, liver cancer, ovarian cancer, kidney cancer, prostate cancer, testicular cancer, uterine cancer, gallbladder cancer, sarcoma, Ewing sarcoma, thyroid cancer, melanoma, skin cancer, pancreatic cancer, stomach cancer, gastrointestinal / gastric (GIST) cancer, lymphoma, head and neck cancer, glioma or brain cancer, colon cancer, rectal cancer, colorectal cancer, breast cancer, renal cell carcinoma or kidney cancer. In some implementations, lung cancer is non-small cell lung cancer.

[0300] In some implementations, the subjects were diagnosed with cachexia. In some implementations, the subjects were diagnosed with cachexia as defined by the following Fearon criteria: (i) a weight loss of >5% in the past 6 months (without simple starvation), or (ii) a BMI <20 kg / m². 2 And any degree of weight loss >2%, or (iii) sarcopenia and any degree of weight loss >2%. In some embodiments, the subject has cancer anorexia-cachexia syndrome. In some embodiments, the subject has chemotherapy-induced cachexia. In some embodiments, the subject has both cancer anorexia-cachexia syndrome and chemotherapy-induced cachexia.

[0301] In some embodiments, the subject's serum GDF15 level is elevated. In some embodiments, the subject's serum GDF15 level is >1200 pg / mL. The serum GDF15 level can be determined by any known method, such as the method described in the examples herein.

[0302] In some implementations, the subject's Eastern Cooperative Oncology Group (ECOG) activity status is 0 or 1. An ECOG activity status of 0 indicates that the subject is fully active and able to perform all pre-illness activities without restriction. An ECOG activity status score of 1 indicates that the subject is limited in strenuous physical activity but can walk and perform light physical or sedentary work (e.g., light housework or office work).

[0303] In some implementations, these methods are also provided in combination with other adjuvant therapies, such as anti-VEGF therapy, PDL blockade therapy, anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, CTLA4 blockade therapy, anti-CTLA-4 antibody, generalized checkpoint blockade therapy that blocks inhibitory molecules on T cells, adoptive T-cell therapy, CAR-T cell therapy, dendritic cell therapy or other cell therapies, and conventional chemotherapy.

[0304] In one implementation, the anti-GDF15 antibody is administered to a subject in combination with another therapeutic agent. As used herein, the term "combination" means the use of more than one therapy (e.g., one or more preventive and / or therapeutic agents). The use of the term "combination" does not limit the order or route of administration of the therapy to a subject with a disease or condition. The first therapy (e.g., preventative and / or therapeutic agent) may be administered to a subject suffering from a disease or condition or its symptoms before (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks prior), simultaneously with, or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks later). In some embodiments, the therapy (e.g., a dose) administered to the subject in combination with the anti-GDF15 antibody is administered in the same composition (e.g., a pharmaceutical composition). In other embodiments, the therapy (e.g., a dose) administered to the subject in combination with the anti-GDF15 antibody is administered in a different composition (e.g., two or more pharmaceutical compositions). The two formulations may be administered at the same or different times and / or via the same or different routes of administration.

[0305] In one embodiment, the additional therapeutic agent is a tissue damage enhancer. Non-limiting examples of tissue damage enhancers include chemotherapeutic agents, radiotherapy, and antibody-drug conjugates (ADCs). In some embodiments, another therapeutic agent is a standard-of-care chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is a platinum-based drug, such as, for example, carboplatin, oxaliplatin, cisplatin, nedaplatin, triplatin tetranitrate, lobaplatin, phenanthriplatin, picoplatin, and satraplatin. In some embodiments, the chemotherapeutic agent is a pyrimidine analogue, such as, for example, fluorouracil, fluorouridine, 6-azauracil, cytarabine, and gemcitabine. In some embodiments, the chemotherapeutic agent is a topoisomerase inhibitor, such as, for example, irinotecan and topotecan. In some implementations, the chemotherapeutic agent is a taxane, such as, for example, paclitaxel (TAXOL). ® ), albumin-bound paclitaxel (Abraxane) ® ), docetaxel, and cabazitaxel.

[0306] In some embodiments, the additional therapeutic agents are FOLFOX (leucovorin, fluorouracil, and oxaliplatin), FOLFOXIRI (leucovorin, fluorouracil, oxaliplatin, and irinotecan hydrochloride), FOLFIRINOX (leucovorin, fluorouracil, irinotecan hydrochloride, and oxaliplatin), bevacizumab, or any combination thereof. In some embodiments, the additional therapeutic agent is a combination of FOLFOX and bevacizumab. In some embodiments, the additional therapeutic agent is a combination of FOLFOXIRI and bevacizumab. In some embodiments, the chemotherapy agent is a combination of gemcitabine and paclitaxel. In some embodiments, the chemotherapy agent is a combination of gemcitabine and albumin-bound paclitaxel.

[0307] Example

[0308] The following examples are provided by way of illustration, not by way of limitation.

[0309] Example 1: A Phase 1 dose escalation study of AV-380 in combination with standard-of-care chemotherapy in patients with metastatic cancer and cachexia and elevated GDF15 levels.

[0310] Cachexia is a complex metabolic syndrome characterized by significant involuntary weight loss, primarily due to the wasting of muscle and fat tissue, along with severe inflammation and anemia. This wasting condition is characterized by involuntary weight loss, leading to progressive weakness, muscle atrophy, resistance to treatment, and ultimately death.

[0311] It is estimated that cachexia affects more than 5 million people in the United States (von Haehling and Anker, J Cachexia Sarcopenia Muscle. 2014; 5(4):261-3). Given the limited effectiveness of current treatments that traditionally focus on nutritional support, the prevalence and mortality rates of cachexia represent a significant unmet medical need.

[0312] Long-term elevation of circulating growth differentiation factor-15 (GDF-15) (an inflammatory cytokine involved in stress response and weight regulation) is associated with cachexia in cancer patients (Johnen et al., Nat Med 2007;13:1333-40). Furthermore, GDF-15 has been shown to be significantly overexpressed in tumors in patients with the following conditions: colorectal cancer (CRC) (Mehta et al., J Natl Cancer Inst 2014; 106(4):dju016; Brown et al., Clin Cancer Res 2003;9(7):2642-50; Welsh et al., Proc Natl Acad Sci USA 2003; 100(6):3410-5), prostate cancer (Brown et al., Clin Cancer Res 2006; 12:89-96; Rasiah et al., Cancer Epidemiol Biomarkers Prev 2006; 14(4):711-6; Wakchoure et al., Prostate 2009; 69:625-61), metastatic breast cancer (Ganapathy et al., Mol Cancer 2010; 9:122), and other malignancies (Lerner et al., J Cachexia Sarcopenia Muscle. Sep 2016; 7(4):467-82. doi: 10.1002 / jcsm.12077. Epub Oct 29 2015; Lerner et al., J Cachexia Sarcopenia Muscle. Dec 2015; 6(4):317-24. doi: 10.1002 / jcsm.12033. Epub April 30 2015; Lerner et al., Oncol Lett. Nov 2016; 12(5):4219-23. doi: 10.3892 / ol.2016.5183. Epub Sep 23 2016).

[0313] In non-clinical tumor models, GDF-15 levels were consistently elevated in mice carrying cachexia tumors, while they were very low or undetectable in non-cachexia controls. Treatment with humanized GDF-15 neutralizing antibodies reversed the cachexia phenotype without affecting tumor growth kinetics or proliferation rate.

[0314] AV-380 is an antibody that binds to GDF-15 with high affinity, thereby clearing it from circulation. In animal cancer models, it has been shown to reverse weight loss and increase muscle recovery, and was well-tolerated in a phase 1 study without serious adverse events (AEs). This study aims to determine whether adding AV-380 to standard-of-care (SoC) chemotherapy could provide additional clinically meaningful benefits to patients with metastatic cancer suffering from cachexia.

[0315] The primary objective of this study is to refine the dosage and schedule of AV-380 and to determine its adverse events (AEs), pharmacokinetic (PK), and pharmacodynamic (PD) profiles in patients with metastatic cancer who are receiving standard of care (SoC) chemotherapy for metastatic cancer and have cachexia (as defined by the Fearon criteria) and elevated serum GDF15 (>1200 pg / mL). Secondary objectives of this study are to evaluate validated measures of cachexia in patients with metastatic cancer receiving AV-380 and to determine its immunogenic potential. Exploratory objectives of this study are to determine the benefit / risk of combining AV-380 with SoC chemotherapy and to evaluate exploratory biomarkers.

[0316] This is an open-label, dose-escalation, multicenter phase 1b study (NCT05865535). Five escalation-dose cohorts of AV-380 (50, 100, 200, 400, and 800 mg intravenously) are planned, with 4–6 patients per cohort, enrolled according to a standard 3+3 design. If the lowest dose cohort is successful, dose reduction will be implemented, and may include 25 mg and 12.5 mg dose levels to replace the 800 mg and 400 mg cohorts. The study is divided into 28-day treatment cycles, with cycle 1 being a single-dose phase of AV-380 and cycle 2 initiating a multi-dose phase with AV-380 administered every 14 days. Figure 1 Patients will continue to be enrolled until they begin second-line systemic anticancer therapy, experience unacceptable toxicities related to AV-380, complete four cycles of AV-380, withdraw consent, or the sponsor terminates the study. Statistical analyses are performed by cohort and summarized in a descriptive manner.

[0317] Eligible participants must be ≥18 years old, histologically confirmed with metastatic colorectal or pancreatic cancer, currently receiving first-line SoC chemotherapy, have cachexia as defined by the Fearon criteria, have a life expectancy ≥3 months, GDF15 >1200 pg / mL, and an ECOG activity status of 0 or 1. The Fearon criteria are: (i) a weight loss of >5% in the past 6 months (without simple starvation), or (ii) a BMI <20 kg / m². 2Any degree of weight loss >2%, or (iii) sarcopenia with any degree of weight loss >2%. Patients with significant clinical manifestations of any allergic condition, skin condition, liver condition, kidney condition, blood condition, lung condition, metabolic condition, cardiovascular condition, gastrointestinal condition, neurological condition, or psychiatric condition; known brain metastases or intracranial / epidural disease (unless treated with radiation therapy and / or surgery and stable for ≥2 weeks prior to study treatment); severe cardiovascular disease, including myocardial infarction within 3 months prior to protocol initiation; corrected QT interval (QTcF) >460 ms calculated according to the Fridricia formula during the screening period prior to the first dose of study treatment; uncontrolled pleural or pericardial effusion; receiving parenteral nutrition at screening; or non-cancer-related cachexia were excluded.

[0318] The primary endpoints were adverse event (AE) characteristics, serum pharmacokinetic parameters, and serum GDF15 levels; secondary endpoints included weight / BMI assessment, cachexia markers, and anti-AV-380 antibody; and exploratory endpoints included best objective response (BOR) and biomarkers. Best objective response (BOR) was defined as the proportion of patients achieving a complete response (CR) or partial response (PR) as determined by the investigators based on RECIST 1.1.

[0319] ***

[0320] The scope of this invention is not limited to the specific embodiments described herein. In fact, various modifications to the invention, other than those described, will be apparent to those skilled in the art from the foregoing description and drawings. Such modifications are intended to fall within the scope of the appended claims.

Claims

1. A method for reducing weight loss in a subject with cancer, comprising administering 12.5-800 mg of an anti-GDF15 antibody to the subject.

2. The method of claim 1, wherein the anti-GDF15 antibody comprises CDRH1, CDRH2 and CDRH3 of VH, wherein VH comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 67-84, and CDRH1, CDRH2 and CDRH3 of VL, wherein VL comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 58-66.

3. The method of claim 2, wherein CDRH1, CDRH2 and CDRH3 each comprise an amino acid sequence selected from the group consisting of: SEQ ID NO: 1, 4 and 13; 1, 5 and 13; 1, 6 and 13; 1, 7 and 13; 1, 8 and 13; 1, 9 and 13; 2, 10 and 14; 2, 11 and 14; and 3, 12 and 15.

4. The method of claim 2 or 3, wherein CDRL1, CDRL2 and CDRL3 each comprise an amino acid sequence selected from the group consisting of: SEQ ID NO: 16, 18 and 21; 16, 18 and 22; 17, 19 and 23; and 17, 20 and 24.

5. The method of any one of claims 2-4, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 each comprise an amino acid sequence selected from the group consisting of: SEQ ID NO: 1, 4, 13, 16, 18, and 21; 1, 4, 13, 16, 18, and 22; 1, 4, 13, 17, 19, and 23; 1, 4, 13, 17, 20, and 24; 1, 5, 13, 16, 18, and 21; 1, 5, 13, 16, 18, and 22; 1, 5, 13, 17, 19, and 23; 1, 5, 13, 17, 20, and 24; 1, 6, 13, 16, 18, and 21 ...8, 19, and 22; 1, 6, 18, 19, and 23; 1, 6, 18, 19, and 23; 1, 6, 18, 19, and 23; 1, 6, 18 , 13, 16, 18 and 22; 1, 6, 13, 17, 19 and 23; 1, 6, 13, 17, 20 and 24; 1, 7, 13, 16, 18 and 21; 1, 7, 13, 16, 18 and 22; 1, 7, 13, 17, 19 and 23; 1, 7, 13, 17, 20 and 24; 1, 8, 13, 16, 18 and 21; 1, 8, 13, 16, 18 and 22; 1, 8, 13, 17, 19 and 23; 1, 8, 13, 17, 20 and 24; 1, 9, 13, 16, 18 and 21; 1, 9, 13, 16, 18 and 22; 1, 9, 13, 17, 19 and 23; 1, 9, 13, 17, 20 and 24; 2, 10, 14, 16, 18 and 21; 2, 10, 14, 16, 18 and 22; 2, 10, 14, 17, 19 and 23; 2, 10, 14 17, 20 and 24; 2, 11, 14, 16, 18 and 21; 2, 11, 14, 16, 18 and 22; 2, 11, 14, 17, 19 and 23; 2, 11, 14, 17, 20 and 24; 3, 12, 15, 16, 18 and 21; 3, 12, 15, 16, 18 and 22; 3, 12, 15, 17, 19 and 23; and 3, 12, 15, 17, 20 and 24.

6. The method of any one of claims 1-5, wherein the anti-GDF15 antibody comprises VH, the VH comprising an amino acid sequence that is at least 95% identical to the amino acid sequence selected from the group consisting of SEQ ID NO: 67-84.

7. The method of any one of claims 1-6, wherein the anti-GDF15 antibody comprises VH, the VH comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 67-84.

8. The method of any one of claims 1-7, wherein the anti-GDF15 antibody comprises a VL, the VL comprising an amino acid sequence that is at least 95% identical to the amino acid sequence selected from the group consisting of SEQ ID NO: 58-66.

9. The method of any one of claims 1-8, wherein the anti-GDF15 antibody comprises a VL, the VL comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 58-66.

10. The method of any one of claims 1-9, wherein the anti-GDF15 antibody comprises VH and VL, wherein VH and VL each comprise an amino acid sequence that is at least 95% identical to an amino acid sequence selected from the group consisting of: SEQ ID NO: 58 and 67, 59 and 68, 59 and 69, 59 and 70, 59 and 71, 59 and 72, 59 and 73, 59 and 74, 60 and 70, 60 and 71, 60 and 72, 60 and 73, 60 and 74, 61 and 70, 61 and 71, 61 and 72, 61 and 73, 61 and 74, 61 and 75, 62 and 76, 61 and 77, 61 and 78, 62 and 78, 63 and 79, 64 and 80, 64 and 81, 65 and 82, 65 and 79, 63 and 82, 66 and 83, and 66 and 84.

11. The method of any one of claims 1-10, wherein the anti-GDF15 antibody comprises VH and VL, wherein VH and VL each comprise an amino acid sequence selected from the group consisting of: SEQ ID NO: 58 and 67, 59 and 68, 59 and 69, 59 and 70, 59 and 71, 59 and 72, 59 and 73, 59 and 74, 60 and 70, 60 and 71, 60 and 72, 60 and 73, 60 and 74, 61 and 70, 61 and 71, 61 and 72, 61 and 73, 61 and 74, 61 and 75, 62 and 76, 61 and 77, 61 and 78, 62 and 78, 63 and 79, 64 and 80, 64 and 81, 65 and 82, 65 and 79, 63 and 82, 66 and 83, and 66 and 84.

12. The method of any one of claims 1-11, wherein the anti-GDF15 antibody is administered once weekly or every two weeks.

13. The method of any one of claims 1-12, wherein the anti-GDF15 antibody is administered once every 7 days or every 14 days.

14. The method of any one of claims 1-13, wherein the anti-GDF15 antibody is administered intravenously.

15. The method of any one of claims 1-13, wherein the anti-GDF15 antibody is administered subcutaneously.

16. The method of any one of claims 1-15, wherein the anti-GDF15 antibody is administered at a dose of about 12.5 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, about 400 mg, or about 800 mg per week or every two weeks.

17. The method of any one of claims 1-16, wherein the anti-GDF15 antibody is administered at a dose of 12.5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 400 mg or 800 mg per week or every 2 weeks.

18. The method of any one of claims 1-17, wherein the cancer is selected from the group consisting of: colorectal cancer, pancreatic cancer, prostate cancer, lung cancer, ovarian cancer, and breast cancer.

19. The method of any one of claims 1-18, wherein the cancer is a metastatic cancer.

20. The method of any one of claims 1-19, wherein the subject has elevated serum GDF15 levels.

21. The method of any one of claims 1-20, wherein the subject's serum GDF15 level is >1200 pg / mL.

22. The method of any one of claims 1-21, wherein the anti-GDF15 antibody is administered to the subject simultaneously or sequentially in combination with another therapeutic agent.

23. The method of claim 22, wherein the other therapeutic agent is a standard chemotherapy agent.

24. The method of claim 22, wherein the other therapeutic agent is FOLFOX, FOLFOXIRI, FOLFIRINOX, bevacizumab, or any combination thereof.

25. The method of any one of claims 1-24, wherein the subject regained lost weight after administration of the anti-GDF15 antibody.

26. The method of claim 25, wherein at least 5% of the lost body weight is recovered.

27. The method of any one of claims 1-24, wherein the subject's weight was maintained for at least one month after administration of the anti-GDF15 antibody.

28. The method of claim 27, wherein the subject's weight is maintained within 5% of the subject's weight at the time the subject first received the anti-GDF15 antibody.

29. The method of any one of claims 1-24, wherein the rate of weight loss of the subject is slowed down.

30. The method of claim 29, wherein after the first administration of the anti-GDF15 antibody, the rate of weight loss of the subject is slowed by at least 5%.

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