Anti-GDF15 Antibodies, Compositions, and Uses Thereof

Abstract

Provided herein are antibody agents that specifically bind to GDF15, as well as compositions that include the GDF15 antibody agents, and methods for making and using them.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 231,484, filed August 10, 2021, and U.S. Provisional Patent Application No. 63 / 292,880, filed December 22, 2021, the entire contents of each of which are incorporated herein by reference. [Background technology]

[0002] Growth differentiation factor 15 (GDF15) is a member of the transforming growth factor beta (TGFb) superfamily. GDF15 expression is typically low in cells and can be upregulated in response to stimuli such as inflammation. Summary of the Invention

[0003] The present disclosure provides novel high-affinity GDF15 antibody agents. Among other things, the provided agents can be used, for example, to bind to GDF15 and / or reduce the activity and / or levels of GDF15 (e.g., free and / or active GDF15) in relevant systems (e.g., in vitro, in cells, in tissues, and / or in subjects).

[0004] For example, in some embodiments, the present disclosure provides novel GDF15 antibody agents having improved binding rate, binding affinity, pharmacokinetics, and / or function, e.g., compared to anti-GDF15 antibodies known in the art. In some embodiments, the GDF15 antibody agents disclosed herein bind to GDF15 with high specificity. In some embodiments, the provided GDF15 antibody agents may exhibit preferential binding to GDF15 relative to one or more TGF-beta family members other than GDF15. In some such embodiments, preferential binding may be assessed, for example, by simultaneously contacting the GDF15 antibody agent with GDF15 and one or more other TGF-beta family members. Alternatively or additionally, in some embodiments, preferential binding may be assessed in comparison to a suitable reference GDF15 antibody agent (e.g., as described in one or more of WO2014049087, WO21544855, WO2017055613, US2020 / 0055930A1, or U.S. Patent No. 9,175,076), and may reflect, for example, a higher level of binding to GDF15 relative to one or more other TGF-beta family members than observed with the reference antibody.

[0005] In some embodiments, the GDF15 antibody agents disclosed herein inhibit the activity of GDF15 and / or reduce the level of GDF15 (e.g., free and / or active GDF15) when administered to a cell, tissue, or subject. In some embodiments, the GDF15 antibody agents disclosed herein can be used to prevent and / or treat a condition or disease associated with increased GDF15, such as nausea, vomiting, cancer, anorexia, immunosuppression, fibrosis, senescence, aging, mitochondrial dysfunction, chronic kidney disease, chronic heart failure, COPD, failure to thrive (FTT), cytokine storm, cytokine release syndrome (CRS), cyclic vomiting syndrome (CVS), cannabinoid hyperemesis syndrome (CHS), migraine-associated nausea / vomiting (MAN / V), etc. In some embodiments, the GDF15 antibody agents disclosed herein can be used to prevent and / or treat symptoms of conditions or diseases associated with increased GDF15 (e.g., symptoms including nausea, vomiting, weight loss, anorexia, fatigue, muscle loss, immunosuppression, fibrosis, senescence, aging, mitochondrial dysfunction, failure to thrive (FTT), cytokine storm, cytokine release syndrome (CRS), etc. Among other things, the present disclosure provides compositions comprising new and improved GDF15 antibody agents, as well as methods of making and using the same.

[0006] The present disclosure provides antibody agents comprising a polypeptide that binds to human growth differentiation factor 15 (GDF15), the polypeptide comprising at least one light chain complementarity determining region (LC CDR) and / or at least one heavy chain complementarity determining region (HC CDR).

[0007] In some embodiments, a GDF15 antibody agent comprises one, two, or three of LC CDR1, LC CDR2, and LC CDR3. In some embodiments, a GDF15 antibody agent comprising LC CDR1, LC CDR2, and / or LC CDR3 can specifically bind to GDF15.

[0008] In some embodiments, a GDF15 antibody agent comprises one, two, or three of HC CDR1, HC CDR2, and HC CDR3. In some embodiments, a GDF15 antibody agent comprising HC CDR1, HC CDR2, and / or HC CDR3 can specifically bind to GDF15.

[0009] In some embodiments, a GDF15 antibody agent comprises one, two, or three of LC CDR1, LC CDR2, and LC CDR3, and one, two, or three of HC CDR1, HC CDR2, and HC CDR3. In some embodiments, a GDF15 antibody agent comprising LC CDR1, LC CDR2, and / or LC CDR3, and HC CDR1, HC CDR2, and / or HC CDR3, can specifically bind to GDF15.

[0010] In some embodiments, the GDF15 antibody agent is selected from the group consisting of: (a) an LC CDR1 sequence provided in Table 1, e.g., any one of SEQ ID NOs: 92, 101, 117, 125, 129, 137, 212; a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity to an LC CDR1 sequence provided in Table 1, e.g., any one of SEQ ID NOs: 92, 101, 117, 125, 129, 137, 212; or a sequence having at least 5, 10, or 20 substitutions to an LC CDR1 sequence provided in Table 1, e.g., any one of SEQ ID NOs: 92, 101, 117, 125, 129, 137, 212; a CDR2 sequence, e.g., any one of SEQ ID NOs: 93, 102, or 130; a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity to an LC CDR2 sequence provided in Table 1, e.g., any one of SEQ ID NOs: 93, 102, or 130; or a sequence having at least 5, 10, or 20 substitutions to an LC CDR2 sequence provided in Table 1, e.g., any one of SEQ ID NOs: 93, 102, or 130; and / or (c) an LC CDR3 sequence provided in Table 1, e.g., any one of SEQ ID NOs: 94, 103, 110, 118, 126, 131, 138, 204, 208, or 217; an LC CDR4 sequence provided in Table 1, e.g., any one of SEQ ID NOs: 94, 103, 110, 118, 126, 131, 138, 204, 208, or 217; a CDR3 sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity to any one of SEQ ID NOs: 94, 103, 110, 118, 126, 131, 138, 204, 208 or 217; or a LC CDR3 sequence provided in Table 1, for example, a sequence having at least 5, 10, or 20 substitutions to any one of SEQ ID NOs: 94, 103, 110, 118, 126, 131, 138, 204, 208 or 217.

[0011] In some embodiments, the GDF15 antibody agent is selected from the group consisting of: (a) a HC CDR1 sequence provided in Table 2, e.g., SEQ ID NO:1, SEQ ID NO:10, SEQ ID NO:14, SEQ ID NO:18, SEQ ID NO:22, SEQ ID NO:31, SEQ ID NO:40, SEQ ID NO:49, SEQ ID NO:56, SEQ ID NO:63, SEQ ID NO:68, SEQ ID NO:73, SEQ ID NO:78, SEQ ID NO:82, or SEQ ID NO:88; a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity to a HC CDR1 sequence provided in Table 2, e.g., SEQ ID NO:1, SEQ ID NO:10, SEQ ID NO:14, SEQ ID NO:18, SEQ ID NO:22, SEQ ID NO:31, SEQ ID NO:40, SEQ ID NO:49, SEQ ID NO:56, SEQ ID NO:63, SEQ ID NO:68, SEQ ID NO:73, SEQ ID NO:78, SEQ ID NO:82, or SEQ ID NO:88; or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity to a HC CDR1 sequence provided in Table 2, e.g., SEQ ID NO:1, SEQ ID NO:10, SEQ ID NO:14, SEQ ID NO:18, SEQ ID NO:22, SEQ ID NO:31, SEQ ID NO:40, SEQ ID NO: (b) a CDR1 sequence, e.g., a sequence having at least 5, 10, or 20 substitutions compared to SEQ ID NO:1, SEQ ID NO:10, SEQ ID NO:14, SEQ ID NO:18, SEQ ID NO:22, SEQ ID NO:31, SEQ ID NO:40, SEQ ID NO:49, SEQ ID NO:56, SEQ ID NO:63, SEQ ID NO:68, SEQ ID NO:73, SEQ ID NO:78, SEQ ID NO:82, or SEQ ID NO:88; (c) a HC CDR2 sequence, e.g., SEQ ID NO:2, SEQ ID NO:11, SEQ ID NO:15, SEQ ID NO:19, SEQ ID NO:23, SEQ ID NO:32, SEQ ID NO:50, SEQ ID NO:57, SEQ ID NO:60, SEQ ID NO:64, SEQ ID NO:69, SEQ ID NO:74, SEQ ID NO:79, SEQ ID NO:83, or SEQ ID NO:200; a HC provided in Table 2 a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity to a CDR2 sequence, e.g., SEQ ID NO:2, SEQ ID NO:11, SEQ ID NO:15, SEQ ID NO:19, SEQ ID NO:23, SEQ ID NO:32, SEQ ID NO:50, SEQ ID NO:57, SEQ ID NO:60, SEQ ID NO:64, SEQ ID NO:69, SEQ ID NO:74, SEQ ID NO:79, SEQ ID NO:83 or SEQ ID NO:200;or a sequence having at least 5, 10, or 20 substitutions compared to a HC CDR2 sequence provided in Table 2, e.g., SEQ ID NO:2, SEQ ID NO:11, SEQ ID NO:15, SEQ ID NO:19, SEQ ID NO:23, SEQ ID NO:32, SEQ ID NO:50, SEQ ID NO:57, SEQ ID NO:60, SEQ ID NO:64, SEQ ID NO:69, SEQ ID NO:74, SEQ ID NO:79, SEQ ID NO:83, or SEQ ID NO:200, and / or (c) a HC CDR3 sequence provided in Table 2, e.g., SEQ ID NO:3, SEQ ID NO:191, SEQ ID NO:192, SEQ ID NO:193, SEQ ID NO:24, SEQ ID NO:33, SEQ ID NO:42, SEQ ID NO:51, SEQ ID NO:65, SEQ ID NO:70, SEQ ID NO:75, SEQ ID NO:84, SEQ ID NO:89; a HC CDR3 sequence provided in Table 2, e.g., SEQ ID NO:3, SEQ ID NO:192, SEQ ID NO:193, SEQ ID NO:24, SEQ ID NO:33, SEQ ID NO:42, SEQ ID NO:51, SEQ ID NO:65, SEQ ID NO:70, SEQ ID NO:75, SEQ ID NO:84, SEQ ID NO:89; a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity to a CDR3 sequence, e.g., SEQ ID NO:3, SEQ ID NO:191, SEQ ID NO:192, SEQ ID NO:193, SEQ ID NO:24, SEQ ID NO:33, SEQ ID NO:42, SEQ ID NO:51, SEQ ID NO:65, SEQ ID NO:70, SEQ ID NO:75, SEQ ID NO:84, SEQ ID NO:89; or a sequence having at least 5, 10, or 20 substitutions compared to a HC CDR3 sequence provided in Table 2, e.g., SEQ ID NO:3, SEQ ID NO:191, SEQ ID NO:192, SEQ ID NO:193, SEQ ID NO:24, SEQ ID NO:33, SEQ ID NO:42, SEQ ID NO:51, SEQ ID NO:65, SEQ ID NO:70, SEQ ID NO:75, SEQ ID NO:84, SEQ ID NO:89;

[0012] In some embodiments, the GDF15 antibody agent is a GDF15 antibody comprising (a) (i) a LC CDR1 provided in Table 1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto, (ii) a LC CDR2 provided in Table 1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto, and / or (iii) a LC CDR3 provided in Table 1. CDR3 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to the LC CDR3 provided in Table 1;and (b) a light chain comprising: (i) an HC CDR1 provided in Table 2, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; (ii) an HC CDR2 provided in Table 2, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; and / or (iii) an HC CDR1 provided in Table 2. a heavy chain comprising a HC CDR3 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to a HC CDR3 provided in Table 2;

[0013] In some embodiments, a GDF15 antibody agent comprising a light chain comprising one, two, or three LC CDRs further comprises at least one framework region (FR) provided in Table 1, or a sequence having at least 92% identity thereto. In some embodiments, a GDF15 antibody agent comprises one, two, three, or four FR regions provided in Table 1, or a sequence having at least 92% identity thereto.

[0014] In some embodiments, a GDF15 antibody agent comprising a light chain comprises (i) a sequence of SEQ ID NO: 99, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 99; (ii) a sequence of SEQ ID NO: 107, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto; , 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 107; (iii) a sequence of SEQ ID NO: 115, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 115; (iv) a sequence of SEQ ID NO: 123, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto. 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 123; (v) a sequence of SEQ ID NO: 127 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 127; (vi) the sequence of SEQ ID NO: 135, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 135; (vii) the sequence of SEQ ID NO: 139, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto;or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 139; (viii) the sequence of SEQ ID NO: 205 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 205; (ix) the sequence of SEQ ID NO: 209 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto. (x) a sequence of SEQ ID NO: 214 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 214; or (xi) a sequence of SEQ ID NO: 218 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 218.

[0015] In some embodiments, a GDF15 antibody agent comprising a light chain further comprises a constant region, eg, as described herein.

[0016] In some embodiments, a GDF15 antibody agent comprising a heavy chain comprising one, two, or three HC CDRs further comprises at least one framework region (FR) provided in Table 2, or a sequence having at least 92% identity thereto. In some embodiments, a GDF15 antibody agent comprises one, two, three, or four FR regions provided in Table 2, or a sequence having at least 92% identity thereto.

[0017] In some embodiments, the GDF15 antibody agent comprising a heavy chain comprises (i) a sequence of SEQ ID NO: 8, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; (ii) a sequence of SEQ ID NO: 12, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto; or a sequence having 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 12; (iii) a sequence of SEQ ID NO: 16, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 16; (iv) a sequence of SEQ ID NO: 20, or at least 85%, 86%, 87%, 88%, 89% thereto; a sequence having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 20; (v) a sequence of SEQ ID NO: 29, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 29; (vi) a sequence of SEQ ID NO: 38, or or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 38; (vii) a sequence of SEQ ID NO: 47 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 47;(viii) a sequence of SEQ ID NO: 54 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 54; (ix) a sequence of SEQ ID NO: 58 or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 58. or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 58; (x) the sequence of SEQ ID NO: 61, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 61; (xi) the sequence of SEQ ID NO: 66, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, (xii) a sequence of SEQ ID NO: 71 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto or a sequence having at least 5, 10, or 20 substitutions thereto; (xiii) a sequence of SEQ ID NO: 76 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto or a sequence having at least 5, 10, or 20 substitutions thereto; or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 76; (xiv) a sequence of SEQ ID NO: 80 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 80;(xv) a sequence of SEQ ID NO: 86 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 86; (xvi) a sequence of SEQ ID NO: 90 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 90, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto, or (xvii) a sequence of SEQ ID NO: 201, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto.

[0018] In some embodiments, a GDF15 antibody agent comprising a heavy chain further comprises a constant region, e.g., as described herein. In some embodiments, the constant region comprises an Fc region, e.g., the Fc domain of an IgG, e.g., a human IgG.

[0019] In some embodiments, the IgG constant region comprises one or more modifications, such as a LAGA mutation, a FEGG mutation, an AAGG mutation, an AAGA mutation, a LALA mutation, or a combination thereof. In some embodiments, the IgG constant region comprises an AAGA mutation. In some embodiments, the AAGA mutation is also referred to as Leu234Ala / Leu235Ala / Glu237Ala (LALAGA).

[0020] In some embodiments, the IgG constant region comprises a modification that reduces, e.g., ablates, binding to the neonatal Fc receptor (FcRn). In some embodiments, the modification to the Fc region that reduces, e.g., ablates, binding to FcRn can be or comprise a LAGA mutation, a FEGG mutation, an AAGG mutation, an AAGA mutation, a LALA mutation, or a combination thereof. In some embodiments, the modification to the Fc region that reduces, e.g., ablates, binding to FcRn is or comprises a I253A mutation, a H310A mutation, a H435R mutation, a H435A mutation, or a combination thereof.

[0021] In some embodiments, the GDF15 antibody agent comprises a VL provided in Table 1 or a sequence having at least 85% identity thereto, and a VH provided in Table 2 or a sequence having at least 85% identity thereto.

[0022] In some embodiments, the GDF15 antibody agent comprises (i) a light chain (LC) comprising: (a) one, two, or three LC CDRs provided in Table 1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto; (b) at least one FR provided in Table 1, or a sequence having at least 92% identity thereto; (c) a constant region (CL); and (ii) a light chain (LC) comprising: (a) one, two, or three LC CDRs provided in Table 2, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto; (b) at least one CDR, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto; (b) at least one FR provided in Table 1, or a sequence having at least 92% identity thereto; and (c) a heavy chain (HC) comprising at least one constant region.

[0023] In some embodiments, provided GDF15 antibody agents have a binding affinity (K D) which, for example, in Fab format, binds to human GDF15.

[0024] In some embodiments, the provided GDF15 antibody agents are characterized in that, when tested in an assay that assesses GDF15 activity and / or levels, the antibody agent reduces GDF15 activity and / or levels relative to a comparator agent, which in some embodiments is or includes a sample that has not been contacted with a GDF15 antibody agent disclosed herein.

[0025] In some embodiments, the GDF15 antibody agent reduces the level of free and / or active GDF15.

[0026] In some embodiments, the GDF15 antibody agent reduces, e.g., inhibits, GDF15 activity. In some embodiments, inhibiting GDF15 activity includes inhibiting the binding of GDF15 to GFRAL. In some embodiments, inhibiting the binding of GDF15 to GFRAL reduces, e.g., inhibits, GFRAL activity and / or GFRAL-mediated signaling pathways.

[0027] In some embodiments, the GDF15 antibody agent reduces the activity and / or levels of GDF15 (e.g., free and / or active GDF15) by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99% or about 100%.

[0028] In some embodiments, the GDF15 antibody agent may be produced at a concentration of about 1000-20,000 mg / L, about 2000-20,000 mg / L, about 5000-20,000 mg / L, about 6000-20,000 mg / L, about 7000-20,000 mg / L, about 8000-20,000 mg / L, about 9000-20,000 mg / L, 10,000-20,000 mg / L, or about 15,000-20,000 mg / L.

[0029] Also provided herein are isolated nucleic acids encoding the GDF15 antibody agents described herein.

[0030] The disclosure further provides vectors, including nucleic acids, encoding GDF15 antibody agents, cells (eg, host cells) containing such vectors, and methods for their production.

[0031] Also provided herein are compositions comprising the GDF15 antibody drug polypeptides disclosed herein, or pharmaceutical compositions comprising the GDF15 antibody drug polypeptides disclosed herein.

[0032] Additionally, the present disclosure provides methods of using compositions comprising the provided GDF15 antibody agents or pharmaceutical compositions comprising the provided GDF15 antibody agents.

[0033] In some embodiments, the methods disclosed herein include administering a GDF15 composition or a GDF15 pharmaceutical composition to a cell, tissue, or subject. In some embodiments, the administration occurs in vitro. In some embodiments, the administration occurs in vivo. In some embodiments, the administration occurs ex vivo.

[0034] In some embodiments, the methods disclosed herein are therapeutic methods. In some embodiments, the subject has a condition or disorder associated with increased GDF15. In some embodiments, increased GDF15 comprises, for example, a level of about 1 ng / ml or greater, as assessed in a sample from the subject, such as a blood, plasma, serum, or urine sample. In some embodiments, administration of a GDF15 antibody agent reduces GDF15 levels, e.g., free and / or active GDF15 levels.

[0035] In some embodiments, the condition or disorder (e.g., a disorder or condition associated with increased GDF15) is selected from nausea, vomiting, cancer, anorexia, immunosuppression, fibrosis, aging, senescence, mitochondrial dysfunction, chronic kidney disease, chronic heart failure, growth impairment, cytokine storm, cytokine release syndrome, COPD, cyclic vomiting syndrome (CVS), cannabinoid hyperemesis syndrome (CHS), or migraine-associated nausea / vomiting (MAN / V) (e.g., such a disorder or condition in a subject demonstrated to have increased GDF15).

[0036] In some embodiments, the methods disclosed herein improve symptoms of a disorder in a subject, e.g., a disorder associated with increased GDF15. In some embodiments, the symptom is nausea, weight loss, vomiting, loss of appetite, fatigue, muscle loss, immunosuppression, fibrosis, mitochondrial dysfunction, senescence, and / or aging, or a combination thereof.

[0037] Also provided herein are methods for inhibiting GDF15 in a cell, tissue, or subject. In some embodiments, the method comprises administering a GDF15 composition or a GDF15 pharmaceutical composition to the cell, tissue, or subject. In some embodiments, inhibiting GDF15 comprises reducing the activity, level, and / or stability of GDF15.

[0038] In some embodiments, reducing the level of GDF15 (e.g., free and / or active GDF15) comprises reducing it to less than 1 ng / mL. In some embodiments, the level of free and / or active GDF15 is reduced.

[0039] In some embodiments, inhibition of GDF15 is assessed in comparison to a comparator, which in some embodiments includes otherwise similar cells, tissues, or subjects that have not been administered the GDF15 pharmaceutical composition or a GDF15 inhibitor, a different GDF15 antibody agent.

[0040] In some embodiments, GDF15 is inhibited, e.g., GDF15 levels (e.g., free and / or active GDF15) are reduced by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 99%.

[0041] In some embodiments, activity of GDF15 is associated with: (a) decreased food intake, (b) decreased appetite, (c) decreased body weight, (d) increased weight loss, (e) decreased fat mass, (f) decreased lean mass, (g) increased fat mass loss, (h) prevention of weight gain, (i) increased loss of lean muscle mass, (j) increased fatigue, (k) decreased inflammation induction, (l) decreased immune cell infiltration in tumors, (m) increased metastasis, (n) decreased efficacy of immunotherapy (e.g., immune checkpoint inhibitor therapy), (o) increased cellular senescence, (p) binding to GFRAL, (q) increased downstream signaling mediated by RET, (r) increased phosphorylation of ERK, (s) increased ribosomal expression of GDF15. In some embodiments, the therapeutic effects of GDF15 include one or more, all, or any combination of the following: (i) increased phosphorylation of rheumatoid arthritis protein S6, (ii) increased RET-mediated activation of the MAPK signaling pathway, (iii) increased RET activation of the AKT signaling pathway, (iv) increased activation of the PLC-D1 signaling pathway, (v) increased activation of the PLC-D1 signaling pathway, (w) increased nausea, vomiting, and / or emesis, (x) decreased T cell adhesion to endothelial cells (e.g., inhibition of LFA1-ICAM interaction), or (y) increased stimulation of the hypothalamic-pituitary-adrenal axis as assessed by increased growth hormone (GH), adrenocorticotropic hormone (ACTH), corticosterone / cortisol, or a combination thereof. In some embodiments, administration of the GDF15 antibody agent inhibits one or more, all, or any combination of the GDF15 activities provided in (a) through (y).

[0042] In some embodiments, administration of a GDF15 antibody agent results in: (a) increased food intake, (b) increased appetite, (c) increased body weight, (d) decreased weight loss, (e) increased fat mass, (f) increased lean mass, (g) decreased fat mass loss, (h) increased weight gain, (i) decreased lean muscle mass loss, (j) decreased fatigue, (k) increased inflammation induction, (l) increased immune cell infiltration in tumors, (m) decreased metastasis, (n) increased efficacy of immunotherapy (e.g., immune checkpoint inhibitor therapy), (o) decreased cellular senescence, (p) inhibition of binding of GDF15 to its receptor, e.g., GFRAL, (q) decreased downstream signaling mediated by RET, (r) decreased ER activity, (p) increased inflammatory response, (p) decreased ER activity, (r) decreased ER activity, (p) increased ... (v) decrease in activation of the PLC-D1 signaling pathway; (w) decrease in nausea, vomiting, and / or emesis; (x) increase in T cell adhesion to endothelial cells (e.g., inhibition of LFA1-ICAM interaction); or (y) decrease in stimulation of the hypothalamic-pituitary-adrenal axis as assessed by decreases in growth hormone (GH), adrenocorticotropic hormone (ACTH), and corticosterone / cortisol.

[0043] Also provided herein are methods for reducing nausea, preventing weight loss, reducing vomiting, and reducing anorexia. In some embodiments of any of the methods disclosed herein, the method further comprises administering a GDF15 composition or a GDF15 pharmaceutical composition to a cell, tissue, or subject.

[0044] In some embodiments, administration of a GDF15 composition or GDF15 pharmaceutical composition reduces the level and / or activity of GDF15 relative to a comparator drug, in some embodiments, reducing the level of free and / or active GDF15.

[0045] In some embodiments of any of the methods disclosed herein, the subject has previously been diagnosed with, or has, cancer or a hyperproliferative disorder, hi some embodiments, the cancer is associated with increased levels and / or activity of GDF15.

[0046] In some embodiments, the subject has previously undergone cancer therapy. In some embodiments, the symptoms disclosed herein are induced by the cancer therapy. In some embodiments, the cancer therapy increases the level and / or activity of GDF15. In some embodiments, the cancer therapy does not increase the level and / or activity of GDF15.

[0047] In some embodiments, the cancer therapy comprises chemotherapy, for example, as described herein.

[0048] In some embodiments, the cancer is selected from gastric cancer, sarcoma, lymphoma, leukemia, head and neck cancer, thymic cancer, epithelial cancer, salivary cancer, liver cancer, stomach cancer, thyroid cancer, lung cancer, ovarian cancer, breast cancer, prostate cancer, esophageal cancer, pancreatic cancer, glioma, leukemia, lymphoma, multiple myeloma, renal cell carcinoma, bladder cancer, cervical cancer, choriocarcinoma, colon cancer, oral cancer, skin cancer, melanoma, endometrial cancer, myofibrosis, bone cancer, or brain cancer.

[0049] In some embodiments, the cancer is breast cancer, eg, early stage breast cancer.

[0050] In some embodiments of any of the methods disclosed herein, the subject is a mammal. In some embodiments, the subject is a human, e.g., an adult or a child. In some embodiments, the subject is a dog. In some embodiments, the subject is a cat. [Brief explanation of the drawings]

[0051] [Figure 1]Figure 1 shows the binding affinity of two exemplary GDF15 antibody agents (clone A and clone C) to biotinylated GDF15 as measured by surface plasmon resonance assay. (A) Graph showing data for biotinylated human GDF15Fc bound to a chip with 9 nM, 3 nM, 1 nM, 0.33 nM, or 0.11 nM Fab of clone A in solution. The data shows a Kd of 41.7 pM. (B) Graph showing data for biotinylated human GDF15Fc bound to a chip with 9 nM, 3 nM, 1 nM, 0.33 nM, or 0.11 nM Fab of clone C in solution. The data shows a Kd of 17 pM.

[0052] [Figure 2] Figure 1 shows the binding affinity of clone A to GDF15. A shows biolayer interferometry data for clone A IgG bound to a sensor chip with 100 nM human GDF-15 Fc [Avid] in solution as the analyte. A good theoretical fit to the data (thin line) indicating 1:1 binding is shown, yielding a KD of 263 pM. B shows biolayer interferometry data for human GDF15 Fc bound to a sensor chip with 100 nM Fab [monovalent] of clone A in solution. A good theoretical fit to the data (thin line) indicating 1:1 binding is shown, yielding a KD of 1005 pM. C shows biolayer interferometry data with cynomolgus monkey GDF15 Fc bound to a sensor chip with 100 nM monovalent Fab of clone A in solution as the analyte. A good theoretical fit to the data (thin line) indicating 1:1 binding is shown, yielding a KD of 536 pM. D shows biolayer interferometry data with mouse GDF15Fc bound to a sensor chip and 100 nM monovalent Fab of clone A in solution. The data show no binding of clone A to mouse GDF15Fc.

[0053] [Figure 3]Figure 1 shows the binding affinity of clone C to GDF15. A shows biolayer interferometry data for clone C IgG bound to a sensor chip with 100 nM human GDF15Fc [Avid] in solution as the analyte. A good theoretical fit to the data (thin line) indicating 1:1 binding is shown, yielding a KD of 254 pM. B shows biolayer interferometry data for human GDF15Fc bound to a sensor chip with 100 nM Fab [monovalent] of clone C in solution. A good theoretical fit to the data (thin line) indicating 1:1 binding is shown, yielding a KD of 731 pM. C shows biolayer interferometry data with cynomolgus monkey GDF15Fc bound to a sensor chip with 100 nM monovalent Fab of clone C in solution as the analyte. A good theoretical fit to the data (thin line) indicating 1:1 binding is shown, yielding a KD of 360 pM. D shows biolayer interferometry data with mouse GDF15Fc bound to a sensor chip and 100 nM monovalent Fab of clone C in solution, with a KD of 156 nM.

[0054] [Figure 4] Pharmacokinetic profiles of an exemplary GDF15 antibody agent are shown. (A) Mean serum concentration-time profile of an exemplary GDF15 antibody agent administered intravenously to male C57BL / 6 mice (N=3 / time point) at a dose of 1 mg / Kg. (B) Mean serum concentration-time profile of an exemplary GDF15 antibody agent administered subcutaneously to male C57BL / 6 mice (N=3 / time point) at a dose of 10 mg / Kg. Blood samples were collected from the animals at 0, 1, 2, 6, 8, 24, 48, 144, 132, 312, 480, and 648 hours after administration, and anti-GDF15 antibody levels were measured by affinity capture liquid chromatography-mass spectrometry (LC-MS).

[0055] [Figure 5A]Pharmacokinetic profiles of exemplary GDF15 antibody agents in primates are shown. These graphs provide the mean concentration-time profiles of exemplary GDF15 antibody agents administered intravenously (A-B) or subcutaneously (C) at a dose of 5 mg / kg in male immature cynomolgus monkeys (N=3 / time point). Samples were collected on days 0, 2, and 8 hours (days 1, 2, 3, 7, 10, 14, 21, 28, and 35 after administration, and anti-GDF15 antibody levels were measured by ELISA. A shows data with intravenous administration of clone C, B shows data with intravenous administration of clone B, and C shows data with subcutaneous administration of clone C. [Figure 5B] Pharmacokinetic profiles of exemplary GDF15 antibody agents in primates are shown. These graphs provide the mean concentration-time profiles of exemplary GDF15 antibody agents administered intravenously (A-B) or subcutaneously (C) at a dose of 5 mg / kg in male immature cynomolgus monkeys (N=3 / time point). Samples were collected on days 0, 2, and 8 hours (days 1, 2, 3, 7, 10, 14, 21, 28, and 35 after administration, and anti-GDF15 antibody levels were measured by ELISA. A shows data with intravenous administration of clone C, B shows data with intravenous administration of clone B, and C shows data with subcutaneous administration of clone C. [Figure 5C] Pharmacokinetic profiles of exemplary GDF15 antibody agents in primates are shown. These graphs provide the mean concentration-time profiles of exemplary GDF15 antibody agents administered intravenously (A-B) or subcutaneously (C) at a dose of 5 mg / kg in male immature cynomolgus monkeys (N=3 / time point). Samples were collected on days 0, 2, and 8 hours (days 1, 2, 3, 7, 10, 14, 21, 28, and 35 after administration, and anti-GDF15 antibody levels were measured by ELISA. A shows data with intravenous administration of clone C, B shows data with intravenous administration of clone B, and C shows data with subcutaneous administration of clone C.

[0056] [Figure 6A]Illustrates the reversal of weight loss by GDF15 antibody agents. Illustrates the reversal of weight loss by exemplary GDF15 antibody agents. Mice were administered an AAV vector expressing GDF15 to induce weight loss. 21 days after AAV GDF15 administration, when animals showed a weight loss of >10%, the animals were divided into groups and treated as shown in the graph. Mice treated with a single 20 mg / kg SC dose of exemplary GDF15 antibody agents showed a significant reversal of weight loss, as observed with an increase in body weight compared to controls. [Figure 6B] Figure 1 shows the reversal of weight loss by a GDF15 antibody agent. An exemplary GDF15 antibody agent (clone C) reversed GDF-15-induced weight loss in mice after multiple administrations. Healthy mice overexpressing human GDF-15 experienced a 10% weight loss. In mice administered clone C at a dose of 10 mg / kg, SC reversed sustained GDF-15-induced weight loss (n=5 / group). Arrows indicate mAb injection.

[0057] [Figure 7] 1 is a graph showing increased plasma GDF15 levels in animals treated with the non-platinum chemotherapy adriamycin.

[0058] [Figure 8A] 1 shows the inhibition of the GDF15-GFRAL axis by anti-GDF15 antibodies. 1 is a GDF15 concentration response graph showing the increase in luciferase assay. [Figure 8B] Figure 1 shows inhibition of the GDF15-GFRAL axis by anti-GDF15 antibodies. Graph showing anti-GDF15 antibody IC50 normalized data from luciferase assays. Percent response was determined in 2 nM GDF15 (approximately EC80 value) stimulated cells. [Figure 8C] 1 shows the inhibition of the GDF15-GFRAL axis by anti-GDF15 antibodies. 2 shows a GDF15 concentration-response graph showing increased pERK activity. [Figure 8D]Figure 1 shows inhibition of the GDF15-GFRAL axis by anti-GDF15 antibodies. Figure 2 shows graphs depicting anti-GDF15 antibody IC50 normalized data from a phosphorylated ERK (pERK) assay. Percent response was determined in 850 pM GDF (approximate EC80 value) stimulated cells.

[0059] [Figure 9] Figure 1 shows a protein homology analysis of GDF15 and related TGF-beta superfamily members. Regions of homology between the proteins are indicated by blue bars labeled "potential epitopes." Cysteines in GDF15 are labeled with their position and the position of their paired cysteines. Color is added to help visualize disulfide bond pairing.

[0060] [Figure 10] The location of the predicted binding epitope of an anti-GDF15 antibody with weak affinity for activin A, activin B, and GDF-10, and its location relative to the GFRAL-binding domain, are shown. The epitope does not appear to be close to a region that directly interacts with the GFRAL-binding pocket.

[0061] [Figure 11] Figure 1 shows the prevention of food intake reduction by an exemplary GDF15 antibody agent. To evaluate the effectiveness of GDF15 antibody agent clone C in preventing human GDF-15-induced food intake reduction in mice, an acute food intake test was performed by administering recombinant human GDF-15 (hGDF-15, 4 nmol / Kg) to healthy mice. hGDF-15 suppressed food intake by 22% over 8 hours. GDF15 antibody agent clone C (10 mg / Kg, SC) alone had minimal effect on food intake but prevented the hGDF-15-induced reduction (n=8, P<0.01).

[0062] [Figure 12]Figure 1 shows the reversal of tumor-induced weight loss in mice using an exemplary GDF15 antibody agent. Female SCID mice subcutaneously implanted with human HT-1080 tumor cells developed involuntary weight loss (A, black squares). Administration of GDF15 antibody agent clone B (A) or GDF15 antibody agent clone C (B) (10 mg / kg SC, n = 8-12, purple triangles) completely reversed tumor-induced weight loss. Administration of GDF15 antibody agent clone B (C) or GDF15 antibody agent clone C (D) had minimal effect on tumor volume. Arrows indicate mAb injection. NTB = non-tumor-bearing; TB = tumor-bearing.

[0063] [Figure 13] This figure shows the suppression of pica activity in rats in response to chemotherapy by administration of a GDF15 antibody. Rats were fed a normal diet (Altromin 1324) and tap water. During a 2-week acclimation period, rats were exposed to both diets and kaolin (Kaolin Research diet, US), with the feeding containers for both diets switched every 2 days. Body weight and food intake (diet and kaolin were recorded separately) were recorded daily from day -7. On day -3, animals were randomized based on body weight into four groups (n = 12-14 per group): 1) vehicle (IP) + IgG1 (20 mg / kg), 2) cisplatin (6 mg / kg, IP) + IgG1 (20 mg / kg, SC), 3) cisplatin (6 mg / kg, IP) + Clone C (20 mg / kg, SC), and 4) cisplatin (6 mg / kg, IP) + Clone I (20 mg / kg, SC). On day -1, 24 hours before cisplatin administration, animals were administered a single dose of antibody. On day 1, 24 hours after the first dose, animals were administered a single dose of vehicle or cisplatin, and kaolin intake was recorded. Data are presented as mean ± standard error of the mean. (A) Suppression of pica activity by administration of GDF15 antibody clone C; (B) Suppression of pica activity by administration of GDF15 antibody clone I.

[0064] [Figure 14]Fc region variants containing the AAGA mutation and FcRn binding are shown. A: Binding of GDF15 antibody clone B to FcRn at pH 6.0 (top) and no binding at pH 7.4 (bottom). B: Binding of GDF15 antibody clone C to FcRn at pH 6.0 (top) and no binding at pH 7.4 (bottom). DETAILED DESCRIPTION OF THE INVENTION

[0065] definition In this application, unless otherwise clear from the context, (i) the term "a" may be interpreted to mean "at least one," (ii) the term "or" may be interpreted to mean "and / or," (iii) the terms "comprising" and "including" may be interpreted to encompass itemized elements or steps, whether presented by themselves or with one or more additional elements or steps, (iv) the terms "about" and "approximately" may be interpreted to allow for standard variations that would be understood by one of ordinary skill in the art, and (v) when ranges are specified, both endpoints are included.

[0066] GDF15: As used herein, the term "GDF15" refers to growth differentiation factor 15, a member of the TGF-beta superfamily. The amino acid sequence of full-length GDF15 and / or the nucleic acid encoding it can be found in public databases such as GenBank, UniProt, and Swiss-Prot. For example, the amino acid sequence of human GDF15 (SEQ ID NO:183, residues 1-29 represent the signal peptide, residues 30-194 represent the propeptide, residues 195-308 represent the mature polypeptide, position 70 is identified as a glycosylation site, intrachain disulfide bonds are reported between residues 203 / 210, 211 / 274, 240 / 305, 244 / 307, and residue 273 is listed as the site of an interchain disulfide bond) can be found under UniProt / Swiss-Prot accession number Q99988, and the nucleic acid sequence encoding human GDF15 (SEQ ID NO:190) can be found under accession number NM_004864.3. GDF15 is also known, for example, as macrophage inhibitory cytokine 1 (MIC-1), prostate-derived factor (PDF), placental bone morphogenetic protein (PLAB), NSAID-activated gene 1 (NAG-1), and placental transforming growth factor beta (PTGFB). Those skilled in the art will understand that the sequences set forth in SEQ ID NOs: 183 and 190 are exemplary, and that certain variations (e.g., including conservative substitutions in SEQ ID NO: 183, codon-optimized variants of SEQ ID NO: 190, etc.) are also understood to encode human GDF15. Furthermore, those skilled in the art will understand that homologs and orthologs of human GDF15 are known and / or are known by exercise or by routine techniques, for example, based on the degree of sequence identity, the presence of one or more characteristic sequence elements, and / or one or more shared activities.

[0067] GDF15 Polypeptide: The phrase "GDF15 polypeptide" is used herein to refer to a polypeptide that shares significant sequence identity and / or at least one characteristic sequence element with a suitable reference polypeptide, such as, for example, (a) human GDF15, e.g., as set forth in SEQ ID NO: 183; (b) cynomolgus monkey GDF15, e.g., as set forth in SEQ ID NO: 184; (c) canine GDF15, e.g., as set forth in SEQ ID NO: 185; and / or (d) feline GDF15, e.g., as set forth in SEQ ID NO: 186. In some embodiments, a GDF15 polypeptide is or comprises a fragment of a parent GDF15 polypeptide (e.g., of SEQ ID NO: 183, or a homolog, ortholog, or variant [e.g., functional variant] thereof). In some embodiments, a GDF15 polypeptide shares at least one characteristic sequence element with a reference GDF15 polypeptide (e.g., of SEQ ID NO: 183, or a homolog, ortholog, or variant [e.g., functional variant] thereof). Alternatively or additionally, in some embodiments, the GDF15 polypeptide shares significant amino acid sequence identity with a related reference polypeptide (e.g., of SEQ ID NO: 183, or a homolog, ortholog, or variant thereof [e.g., functional variant]). For example, in some embodiments, the GDF15 polypeptide shares at least 50% amino acid sequence identity with the reference GDF15. In some embodiments, the GDF15 polypeptide is characterized by the ability to activate a receptor that binds to GDF15, such as the GFRAL receptor, and in some such embodiments, such ability is comparable to that of a suitable reference GDF15 (e.g., of SEQ ID NO: 183, or a homolog, ortholog, or variant thereof [e.g., functional variant]). For example, in some embodiments, the GDF15 polypeptide activates the GFRAL receptor with a binding affinity reasonably comparable to that of a suitable reference GDF15 (e.g., of SEQ ID NO: 183, or a homolog, ortholog, or variant thereof [e.g., functional variant]).In some embodiments, the GDF15 polypeptide is characterized by competing with a suitable reference GDF15 (e.g., of SEQ ID NO: 183, or a homolog, ortholog, or variant thereof [e.g., a functional variant]) for binding and / or activation of the GFRAL receptor. In some such embodiments, such competition is observed over a range of concentrations (e.g., the range may span 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or more). In some embodiments, the GDF15 polypeptide is or comprises a polypeptide having at least 50% identity to SEQ ID NO: 183.

[0068] About: The term "about," when used herein with respect to a value, refers to a value that is similar in context to the referenced value. Generally, a person of ordinary skill in the art familiar with the context will understand the reasonable degree of variation encompassed by "about" in that context. For example, in some embodiments, the term "about" can encompass a range of values ​​that are within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less of the reference value.

[0069] Administration: As used herein, the term "administration" typically refers to administering a composition to a subject or system, e.g., to achieve delivery of an agent that is, is contained in, or is otherwise delivered by the composition. Those skilled in the art will recognize various routes that may be utilized for administration to a subject, e.g., an animal or a human, under appropriate circumstances. In some embodiments, the animal is a companion animal, e.g., a domestic animal such as a dog or cat, and in some embodiments, the animal is an animal used for agriculture (e.g., farming [e.g., cattle, sheep, or horses]) or recreation. For example, in some embodiments, administration can be systemic or local. Those skilled in the art will recognize appropriate routes of administration for use with particular therapies described herein, including, for example, bronchial (e.g., by bronchial infusion), buccal, transdermal (which may be or include, e.g., one or more of topical, intradermal, interdermal, transdermal, etc., into the dermis), enteral, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, intraspecific organ (e.g., intrahepatic), mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., by intratracheal infusion), intravaginal, intravitreal, etc. In some embodiments, administration may be by injection (e.g., intramuscular, intravenous, or subcutaneous injection). In some embodiments, injection may include bolus injection, infusion, perfusion, or infusion. In some embodiments, administration may involve only a single dose. In some embodiments, administration may include the application of a number of doses. In some embodiments, administration can involve administration that is intermittent (e.g., multiple doses separated in time) and / or periodic (e.g., individual doses separated by a common period of time) administration. In some embodiments, administration can involve continuous administration (e.g., perfusion) for at least a selected period of time.

[0070] Adult: As used herein, the term "adult" refers to a human over the age of 18. In some embodiments, a human adult has a weight within the range of about 90 pounds to about 250 pounds.

[0071] Affinity: As known in the art, "affinity" is a measure of the tightness with which two or more binding partners associate with one another. Those skilled in the art will be knowledgeable of various assays that can be used to assess affinity and will also be aware of appropriate controls for such assays. In some embodiments, affinity is assessed in a quantitative assay. In some embodiments, affinity (e.g., of one binding partner at a time) is assessed across multiple concentrations. In some embodiments, affinity is assessed in the presence of one or more potential competitors (e.g., that may be present in a relevant physiological situation). In some embodiments, affinity is compared to a reference (e.g., a known affinity above a certain threshold [see "positive control"] or with a known affinity below a certain threshold [see "negative control"]). In some embodiments, affinity may be assessed relative to a concurrent reference, and in some embodiments, affinity may be assessed relative to a background reference. Typically, when affinity is assessed relative to a reference, it is assessed under comparable conditions.

[0072] "Affinity matured" (or "affinity matured antibody"): As used herein, refers to an antibody with one or more modifications in one or more CDRs that result in an improvement in the affinity of the antibody for antigen compared to a parent antibody that does not have those modification(s). In some embodiments, an affinity matured antibody has nanomolar or even picomolar affinity for the target antigen. Affinity matured antibodies can be produced by any of a variety of procedures known in the art. Marks et al., BioTechnology 10:779-783 (1992) describe affinity matured antibodies. H and V LAffinity maturation by domain shuffling has been described. Random mutagenesis of CDR and / or framework residues is described by Barbas et al., Proc. Nat. Acad. Sci. USA 91:3809-3813 (1994), Schier et al., Gene 169:147-155 (1995), Yelton et al., J. Immunol. 155:1994-2004 (1995), Jackson et al., J. Immunol. 154(7):3310-9 (1995), and Hawkins et al., J. Mol. Biol. 226:889-896 (1992).

[0073] Agent: As used herein, the term "agent" may refer to a physical entity or phenomenon. In some embodiments, an agent may be characterized by a particular feature and / or effect. In some embodiments, an agent may be a compound, molecule, or entity of any chemical class, including, for example, a small molecule, polypeptide, nucleic acid, sugar, lipid, metal, or combination or complex thereof. In some embodiments, the term "agent" may refer to a compound, molecule, or entity that comprises a macromolecule. In some embodiments, the term may refer to a compound or entity that comprises one or more macromolecular moieties. In some embodiments, the term "agent" may refer to a compound, molecule, or entity that is substantially free of a particular macromolecule or macromolecular moiety. In some embodiments, the term may refer to a compound, molecule, or entity that lacks or is substantially free of any macromolecule or macromolecular moiety.

[0074] Agonist: Those skilled in the art will understand that the term "agonist" can be used to refer to an agent, condition, or event whose presence, level, degree, type, or form correlates with an increase in the level or activity of another agent (i.e., a stimulated agent or a target agent). Generally, an agonist can be or include an agent of any chemical class, including, for example, small molecules, polypeptides, nucleic acids, carbohydrates, lipids, metals, and / or any other entity that exhibits related activation activity. In some embodiments, an agonist can be direct (in which case the agonist directly affects its target). In some embodiments, an agonist can be indirect (in which case the agonist affects something other than binding to the target, e.g., by interacting with a regulator of the target such that the level or activity of the target is altered). Amino acid: As used herein in its broadest sense, refers to any compound and / or substance that can be incorporated into a polypeptide chain, for example, through one or more peptide bond formats. In some embodiments, an amino acid has the general structure HN-C(H)(R)-COOH. In some embodiments, an amino acid is a naturally occurring amino acid. In some embodiments, an amino acid is a non-naturally occurring amino acid. In some embodiments, an amino acid is a D-amino acid. In some embodiments, an amino acid is an L-amino acid. "Standard amino acid" refers to any of the 20 standard L-amino acids commonly found in naturally occurring peptides. "Non-standard amino acid" refers to any amino acid other than the standard amino acids, whether it is synthetically prepared or obtained from a natural source. In some embodiments, an amino acid, including the carboxy- and / or amino-terminal amino acids in a polypeptide, may contain structural modifications compared to the general structures above. For example, in some embodiments, an amino acid may be modified relative to the general structure by methylation, amidation, acetylation, pegylation, glycosylation, phosphorylation, and / or substitution (e.g., of an amino group, a carboxylic acid group, one or more protons, and / or a hydroxyl group). In some embodiments, such modifications may, for example, alter the circulating half-life of a polypeptide comprising the modified amino acid compared to one comprising the otherwise identical amino acid. In some embodiments, such modifications do not significantly alter the relevant activity of a polypeptide comprising the modified amino acid compared to one comprising the otherwise identical amino acid. As will be clear from the context, in some embodiments, the term "amino acid" may be used to refer to a free amino acid. In some embodiments, the term may be used to refer to an amino acid residue of a polypeptide.

[0075] Animal: As used herein, refers to a member of the animal kingdom. In some embodiments, "animal" refers to a human, and unless otherwise specified, in many embodiments, a human can be of either sex and / or at any stage of development. In some embodiments, "animal" refers to a non-human animal, and unless otherwise specified, in many embodiments, a non-human animal can be of either sex and / or at any stage of development. In certain embodiments, the non-human animal is a mammal (e.g., a rodent, mouse, rat, rabbit, monkey, dog, cat, sheep, cow, primate, and / or pig). In some embodiments, the animal can be, for example, a mammal, bird, reptile, amphibian, fish, insect, worm, etc. In some embodiments, the animal can be a transgenic animal, a genetically modified animal, and / or a clone.

[0076] Antagonist: As used herein, those skilled in the art will understand that the term "antagonist" can be used to refer to an agent, condition, or event whose presence, level, degree, type, or form correlates with a decrease in the level or activity of another agent (i.e., an inhibitor or target agent). Generally, an antagonist can be or include any chemical class of agent, including, for example, small molecules, polypeptides, nucleic acids, carbohydrates, lipids, metals, and / or any other entity that exhibits related inhibitory activity. In some embodiments, an antagonist can be direct (in which case it directly affects its target). In some embodiments, an antagonist can be indirect (in which case it affects something other than binding to the target, e.g., by interacting with a regulator of the target such that the level or activity of the target is altered).

[0077] Antibody: As used herein, the term "antibody" refers to a polypeptide containing sufficient standard immunoglobulin sequence elements to confer specific binding to a particular target antigen. As is known in the art, intact antibodies, as produced in nature, are approximately 150 kD tetrameric agents composed of two identical heavy chain polypeptides (about 50 kD each) and two identical light chain polypeptides (about 25 kD each) that associate with each other into what is commonly referred to as a "Y-shaped" structure. Each heavy chain consists of at least four domains (each about 110 amino acids long)—an amino-terminal variable (VH) domain (located at the tip of the Y structure), followed by three constant domains, CH1, CH2, and carboxy-terminal CH3 (located at the base of the stem of the Y). A short region known as the "switch" connects the heavy chain variable and constant regions. A "hinge" connects the CH2 and CH3 domains to the rest of the antibody. Two disulfide bonds in this hinge region connect the two heavy chain polypeptides to each other in an intact antibody. Each light chain consists of two domains: an amino-terminal variable (VL) domain followed by a carboxy-terminal constant (CL) domain separated from each other by another "switch." An intact antibody tetramer is composed of two heavy-light chain dimers, in which the heavy and light chains are linked to each other by one disulfide bond and two other disulfide bonds connect the heavy chain hinge regions to form a tetramer. Naturally produced antibodies are typically glycosylated in the CH2 domain. Each domain of a natural antibody has a structure characterized by an "immunoglobulin fold," formed by two beta sheets (e.g., three-, four-, or five-stranded sheets) packed together into an antiparallel beta barrel. Each variable domain contains three hypervariable loops known as "complement determining regions" (CDR1, CDR2, and CDR3) and four somewhat invariant "framework" regions (FR1, FR2, FR3, and FR4).When a natural antibody folds, the FR regions form beta sheets, providing a structural framework for the domain, and the CDR loop regions of both the heavy and light chains join in three-dimensional space to create a single hypervariable antigen-binding site located at the tip of a Y-structure. The Fc region of a naturally occurring antibody binds to elements of the complement system and also to receptors on effector cells, including, for example, effector cells that mediate cytotoxicity. As is known in the art, the affinity and / or other binding properties of the Fc region for an Fc receptor can be modulated through glycosylation or other modifications. In some embodiments, antibodies produced and / or utilized in accordance with the present disclosure comprise a glycosylated Fc domain, including Fc domains with modified or engineered glycosylation. In some embodiments, antibodies produced and / or utilized in accordance with the present disclosure comprise one or more modifications in the Fc domain, e.g., effector-null mutations, e.g., LALA, LAGA, FEGG, AAGG, or AAGA mutations. For the purposes of this disclosure, in certain embodiments, any polypeptide or polypeptide complex that contains a sufficient immunoglobulin domain sequence as found in a natural antibody may be referred to and / or used as an "antibody," regardless of whether such polypeptide is produced naturally (e.g., generated by an organism in response to an antigen) or by recombinant engineering, chemical synthesis, or other artificial systems or methodologies. In some embodiments, an antibody is polyclonal; in some embodiments, an antibody is monoclonal. In some embodiments, an antibody has constant region sequences characteristic of canine, feline, murine, rabbit, primate, or human antibodies. In some embodiments, antibody sequence elements are human, humanized, primatized, chimeric, etc., as known in the art. Furthermore, as used herein, the term "antibody" can, in appropriate embodiments (unless otherwise specified or apparent from the context), refer to any of the constructs or formats known or developed in the art for utilizing the structural and functional characteristics of antibodies in alternative presentations.For example, in some embodiments, antibodies utilized in accordance with the present invention are in a format selected from, but not limited to, intact IgA, IgG, IgE, or IgM antibodies; bispecific or multispecific antibodies (e.g., Zybodies®, etc.); antibody fragments such as Fab fragments, Fab' fragments, F(ab')2 fragments, Fd' fragments, Fd fragments, and isolated CDRs or sets thereof; single-chain Fvs; polypeptide-Fc fusions; single domain antibodies, alternative scaffolds, or antibody mimetics (e.g., anti-cullins, FN3 monobodies, DARPins, affinity antibodies, affilins, affilimers, affitins, alphabodies, avimers, fynomers, Im7, VLRs, VNARs, trimabs, CrossMabs, Tridents); nanobodies, binanobodies, F(ab')2, Fab', di-sdFvs, single domain antibodies, trifunctional antibodies, diabodies, and minibodies, etc. In some embodiments, the relevant format may be or include Adnectins®, Affibodies®, Affilins®, Anticalins®, Avimers®, BiTEs®, cameloid antibodies, Centyrins®, ankyrin repeat proteins or DARPINs®, dual affinity retargeting (DART) agents, Fynomers®, shark single domain antibodies such as IgNARs, immune monoclonal T cell receptors against cancer (ImmTACs), KALBITOR®, MicroProteins, Nanobodies® minibodies, masked antibodies (e.g., Probodies®), Small Modular ImmunoPharmaceuticals ("SMIPs™"), single chain or tandem dibodies (TandAbs®), TCR-like antibodies, Trans-bodies®, TrimerX®, VHHs. In some embodiments, the antibody may lack covalent modifications (eg, glycan attachment) that it would have if produced in nature.In some embodiments, the antibody can include a covalent modification (e.g., the attachment of a glycan, a payload (e.g., a detectable moiety, a therapeutic moiety, a catalytic moiety, etc.), or other pendant group (e.g., polyethylene glycol, etc.).

[0078] Antibody agent: As used herein, the term "antibody agent" refers to an agent that specifically binds to a particular antigen. In some embodiments, the term encompasses any polypeptide or polypeptide complex that contains sufficient immunoglobulin structural elements to confer specific binding. Exemplary antibody agents include, but are not limited to, monoclonal or polyclonal antibodies. In some embodiments, an antibody agent may contain one or more constant region sequences characteristic of canine, feline, murine, rabbit, primate, or human antibodies. In some embodiments, an antibody agent may contain one or more sequence elements that are human, humanized, primatized, chimeric, etc., as known in the art. In some embodiments, an antibody agent may contain one or more complementarity-determining regions that are human and / or one or more constant region sequences characteristic of human antibodies. In many embodiments, the term "antibody agent" is used to refer to one or more constructs or formats known or developed in the art for utilizing the structural and functional characteristics of antibodies in alternative presentations.For example, in some embodiments, antibody agents utilized in accordance with the present disclosure include, but are not limited to, intact IgA, IgG, IgE, or IgM antibodies; bispecific or multispecific antibodies (e.g., Zybodies®, etc.); antibody fragments such as Fab fragments, Fab' fragments, F(ab')2 fragments, Fd' fragments, Fd fragments, and isolated CDRs or sets thereof; single chain Fv; polypeptides comprising an antigen-binding specificity fused to an Fc; single domain antibodies (e.g., shark single domain antibodies such as IgNAR or fragments thereof); cameloid antibodies; masked antibodies (e.g., Probodies®); small modular immunopharmaceuticals ("SMIPs™"); single The format is selected from: chain or tandem diabody (TandAb®); VHH; Anticalins®; Nanobodies® minibodies; BiTEs®; ankyrin repeat proteins or DARPINs®; Avimers®; DART; TCR-like antibodies; Adnectins®; Affilins®; Trans-bodies®; Affibodies®; TrimerX®; MicroProteins; Fynomers®; Centyrins®; and KALBITOR®. In some embodiments, the antibody may lack covalent modifications (e.g., glycan attachment) that it would have if produced in nature. In some embodiments, antibodies can include covalent modifications (e.g., the attachment of a glycan, a payload (e.g., a detectable moiety, a therapeutic moiety, a catalytic moiety, etc.), or other pendant groups (e.g., polyethylene glycol, etc.). In many embodiments, an antibody agent is or includes a polypeptide whose amino acid sequence includes one or more structural elements recognized by those of skill in the art as complementarity-determining regions (CDRs). In some embodiments, an antibody agent is or includes a polypeptide whose amino acid sequence includes at least one CDR (e.g., at least one heavy chain CDR and / or at least one light chain CDR) that is substantially identical to that found in a reference antibody.In some embodiments, the included CDRs are substantially identical to the reference CDRs in that they are sequence identical or contain 1 to 5 amino acid substitutions compared to the reference CDRs. In some embodiments, the included CDRs are substantially identical to the reference CDRs in that they exhibit at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the reference CDRs. In some embodiments, the included CDRs are substantially identical to the reference CDRs in that they exhibit at least 96%, 96%, 97%, 98%, 99%, or 100% sequence identity with the reference CDRs. In some embodiments, the included CDRs are substantially identical to the reference CDRs in that at least one amino acid within the included CDRs has been deleted, added, or substituted relative to the reference CDR, but the included CDRs otherwise have an amino acid sequence that is identical to the amino acid sequence of the reference CDR. In some embodiments, the included CDRs are substantially identical to the reference CDRs in that 1 to 5 amino acids within the included CDRs have been deleted, added, or substituted relative to the reference CDR, but the included CDRs otherwise have an amino acid sequence that is identical to the reference CDR. In some embodiments, the included CDRs are substantially identical to the reference CDRs in that at least one amino acid within the included CDRs has been substituted relative to the reference CDR, but the included CDRs otherwise have an amino acid sequence that is identical to the amino acid sequence of the reference CDR. In some embodiments, the included CDRs are substantially identical to the reference CDRs in that 1 to 5 amino acids within the included CDRs have been deleted, added, or substituted relative to the reference CDR, but the included CDRs otherwise have an amino acid sequence that is identical to the reference CDR. In some embodiments, an antibody agent is or comprises a polypeptide whose amino acid sequence comprises structural elements recognized by those skilled in the art as an immunoglobulin variable domain.In some embodiments, an antibody agent is a polypeptide protein having a binding domain that is homologous to an immunoglobulin binding domain or that is largely homologous to an immunoglobulin binding domain.

[0079] Antibody-dependent cellular cytotoxicity: As used herein, the term "antibody-dependent cellular cytotoxicity" or "ADCC" refers to the phenomenon in which target cells bound by an antibody are killed by immune effector cells. Without wishing to be bound by any particular theory, it is observed that ADCC is typically understood to involve the ability of effector cells bearing Fc receptors (FcRs) to recognize and subsequently kill antibody-coated target cells (e.g., cells expressing a specific antigen on their surface to which the antibody is bound). Effector cells that mediate ADCC can include immune cells, including, but not limited to, one or more of natural killer (NK) cells, macrophages, neutrophils, and eosinophils.

[0080] Antibody fragment: As used herein, "antibody fragment" refers to a portion of an antibody or antibody agent as described herein, and typically refers to an antigen-binding portion or portion comprising a variable region thereof. Antibody fragments may be produced by any means. For example, in some embodiments, antibody fragments may be produced enzymatically or chemically by fragmentation of an intact antibody or antibody agent. Alternatively, in some embodiments, antibody fragments may be produced recombinantly (i.e., by expression of an engineered nucleic acid sequence). In some embodiments, antibody fragments may be wholly or partially synthetically produced. In some embodiments, antibody fragments (particularly antigen-binding antibody fragments) are at least about 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or more amino acids in length, and in some embodiments, are at least about 200 amino acids in length.

[0081] Antibody Polypeptide: As used herein, the term "antibody polypeptide" refers to a polypeptide(s) that comprises the characteristic sequence element(s) of an antibody (e.g., one or more CDRs, or a set of CDRs, such as each of CDR1, 2, and 3 found in a reference antibody chain, and / or one or more FR regions and / or a set of FR regions, e.g., the complete variable region of a heavy or light chain of a reference antibody). In many embodiments, an antibody polypeptide comprises sufficient such sequence element(s) that it binds to an epitope (e.g., an epitope bound by a reference antibody that comprises the characteristic sequence elements). In some embodiments, an antibody polypeptide is a full-length antibody, or a heavy or light chain thereof. In some embodiments, an antibody polypeptide is or comprises the complete heavy and / or light chain variable region of a reference antibody. In some such embodiments, an antibody polypeptide comprises sufficient specific antibody sequence element(s) to confer specific binding to the relevant epitope, i.e., such that the antibody polypeptide comprises at least one binding site. In some embodiments, an "antibody polypeptide" may comprise a binding domain that is homologous or largely homologous (e.g., exhibits significant sequence homology and / or, in some embodiments, significant sequence identity) to an immunoglobulin binding domain. In some embodiments, an antibody polypeptide exhibits at least 99% identity to an immunoglobulin binding domain. In some embodiments, an "antibody polypeptide" has an immunoglobulin binding domain, e.g., a binding domain that exhibits at least 70%, 80%, 85%, 90%, or 95% identity to a reference immunoglobulin binding domain. In some embodiments, an "antibody polypeptide" may have an amino acid sequence identical to that of an antibody, or a chain or variable region (or combination of variable region(s)) thereof, found in a natural source. In some embodiments, an antibody polypeptide may be prepared, for example, by isolation from a natural source or antibody library, recombinant production in or with a host system, chemical synthesis, etc., or a combination thereof. In some embodiments, an antibody polypeptide is an antibody agent described herein.

[0082] Antigen: As used herein, the term "antigen" refers to an agent that elicits an immune response and / or (ii) an agent that binds to a T cell receptor (e.g., when presented by an MHC molecule) or an antibody. In some embodiments, an antigen elicits a humoral response (e.g., including the production of antigen-specific antibodies). In some embodiments, an antigen elicits a cellular response (e.g., engagement of T cells whose receptors specifically interact with the antigen). In some embodiments, an antigen binds to an antibody and may or may not induce a specific physiological response in an organism. Generally, an antigen can be or include any chemical entity, such as, for example, a small molecule, a nucleic acid, a polypeptide, a carbohydrate, a lipid, a polymer (in some embodiments, other than a biopolymer [e.g., other than a nucleic acid or amino acid polymer]), etc. In some embodiments, an antigen is or includes a polypeptide. In some embodiments, an antigen is or includes a glycan. Those skilled in the art will understand that, generally, antigens may be provided in isolated or pure form, or alternatively, may be provided in crude form (e.g., together with other materials, such as cell extracts or other relatively crude preparations of antigen-containing sources). In some embodiments, antigens utilized in accordance with the present invention are provided in crude form. In some embodiments, the antigen is a recombinant antigen.

[0083] Approximately: As used herein, the term "approximately" or "about," when applied to one or more values ​​of interest, refers to a value similar to a stated reference value. In certain embodiments, the term "approximately" or "about" refers to a range of values ​​that is within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% in either direction (above or below) of the stated reference value, unless otherwise stated or a different meaning is apparent from the context (except where such number would exceed 100% of the possible values).

[0084] Binding: Those skilled in the art will understand that the term "binding," as used herein, typically refers to a non-covalent association between or among two or more entities. "Direct" binding involves physical contact between the entities or moieties, while indirect binding involves a physical interaction due to physical contact through one or more intermediate entities. Binding between two or more entities can typically be assessed in any of a variety of contexts, including when the interacting entities or moieties are studied in isolation or in the context of a more complex system (e.g., in covalent or other association with a carrier entity, and / or in a biological system or cell).

[0085] Cancer: The terms "cancer," "malignancy," "neoplasm," "tumor," and "carcinoma" are used herein to refer to cells that exhibit relatively abnormal, uncontrolled, and / or autonomous growth, resulting in an aberrant growth phenotype characterized by a significant loss of control of cell proliferation. In some embodiments, tumors may be or include pre-cancerous (e.g., benign), malignant, pre-metastatic, metastatic, and / or non-metastatic cells. The present disclosure specifically identifies particular cancers to which its teachings may be particularly relevant. In some embodiments, the relevant cancers may be characterized as solid tumors. In some embodiments, the relevant cancers may be characterized as hematological tumors. In general, examples of different types of cancer known in the art include, for example, hematopoietic cancers including leukemia, lymphoma (Hodgkin's and non-Hodgkin's), myeloma and myeloproliferative disorders; genitourinary cancers such as sarcoma, melanoma, adenoma, carcinoma of solid tissue, squamous cell carcinoma of the mouth, throat, larynx, lung, liver cancer, prostate cancer, cervical cancer, bladder cancer, uterine cancer, ovarian cancer, endometrial cancer, as well as benign lesions such as renal cell carcinoma, bone cancer, pancreatic cancer, skin cancer, cutaneous or intraocular melanoma, endocrine system cancer, thyroid cancer, parathyroid cancer, head and neck cancer, breast cancer, gastrointestinal cancer and nervous system cancer tumors, papilloma, etc.

[0086] Carrier: As used herein, refers to a diluent, adjuvant, excipient, or vehicle with which a composition is administered. In some exemplary embodiments, a carrier can include sterile liquids such as, for example, water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as, for example, peanut oil, soybean oil, mineral oil, sesame oil, etc. In some embodiments, a carrier is or includes one or more solid ingredients.

[0087] CDR: As used herein, refers to a complementarity-determining region within an antibody variable region. There are three CDRs in each of the heavy and light chain variable regions, designated CDR1, CDR2, and CDR3 for each variable region. A "set of CDRs" or "CDR set" refers to a group of three or six CDRs present in either a single variable region capable of binding to an antigen or the CDRs of cognate heavy and light chain variable regions capable of binding to an antigen. Specific systems have been established in the art for defining CDR boundaries (e.g., Kabat, Chothia, etc.), and those skilled in the art will appreciate the differences between these systems and will be able to understand CDR boundaries to the extent necessary to understand and practice the claimed invention.

[0088] CDR-grafted antibody: As used herein, a CDR-grafted antibody comprises heavy and light chain variable region sequences from one species but H and / or V L The sequences of one or more of the CDR regions of the mouse V are CDR sequences of another species, for example, a mouse V in which one or more of the mouse CDRs (e.g., CDR3) are replaced with human CDR sequences. H and V L Similarly, a "CDR-grafted antibody" also refers to an antibody in which one or more of the human CDRs (e.g., CDR3) have been replaced with mouse CDR sequences. H and V L It may refer to an antibody having a region.

[0089] Child: As used herein, the term "child" refers to a human between the ages of 1 day and 18 years. In some embodiments, a child can be an infant (e.g., about 12 months, 11 months, 10 months, 9 months, 8 months, 7 months, 6 months, 5 months, 4 months, 3 months, 2 months, or less than 1 month old), and in some embodiments, a child can be older than an infant. In some embodiments, a child can be a toddler (e.g., about 1 to about 3 years old), and in some embodiments, a child can be younger than an toddler or older than an infant. In some embodiments, a child can be a teenager (e.g., about 12 years to about 18 years old), and in some embodiments, a child can be younger than a teenager (and / or younger than an toddler or older than an infant). Weight varies greatly depending on age and the particular child, with a typical range being 4 pounds to 150 pounds.

[0090] Combination therapy: As used herein, the term "combination therapy" refers to a situation in which a subject is exposed to two or more therapeutic regimens (e.g., two or more therapeutic agents) simultaneously. In some embodiments, the two or more regimens may be administered simultaneously. In some embodiments, the regimens may be administered sequentially (e.g., all "doses" of a first regimen are administered before any dose of a second regimen). In some embodiments, the agents are administered in overlapping dosing regimens. In some embodiments, "administration" of a combination therapy may include administering one or more agent(s) or modality(s) in combination to a subject receiving other agent(s) or modality(s). For clarity, combination therapy does not require that the individual agents be administered together in a single composition (or even necessarily simultaneously), although in some embodiments, two or more agents or their active portions may be administered together in a combined composition or even a combined compound (e.g., as part of a single chemical complex or covalent conjugate).

[0091] Equivalent: As used herein, the term "equivalent" refers to two or more agents, entities, circumstances, sets of conditions, etc. that may not be identical to one another, but that are sufficiently similar to permit a comparison between them where one of skill in the art would understand that conclusions can be reasonably drawn based on the observed differences or similarities. In some embodiments, a comparable set of conditions, circumstances, individuals, or populations is characterized by multiple substantially identical characteristics and one or a few different characteristics. Those of skill in the art will understand what degree of identity is required for two or more such agents, entities, circumstances, sets of conditions, etc. to be considered comparable in any given situation, depending on the context. For example, those of skill in the art will understand that sets of circumstances, individuals, or populations are comparable to one another when they are characterized by a sufficient number and type of substantially identical characteristics to warrant a reasonable conclusion that differences in results obtained or phenomena observed under or with different sets of circumstances, individuals, or populations are caused by or indicate variations in those characteristics.

[0092] Composition: Those skilled in the art will understand that the term "composition" can be used to mean a physically discrete entity that includes one or more specified components. Generally, unless otherwise specified, a composition can be in any form, e.g., gas, gel, liquid, solid, etc.

[0093] Comprising: A composition or method described herein as "comprising" one or more named elements or steps is open-ended, meaning that the named elements or steps are essential, but that other elements or steps may be added within the scope of the composition or method. To avoid redundancy, any composition or method described as "comprising" (or "comprises") one or more named elements or steps also represents a corresponding, more limited composition or method "consisting essentially of" (or "consists essentially of") the same named elements or steps, which should also be understood to mean that the composition or method includes the named essential elements or steps, and may include additional elements or steps that do not materially affect the basic and novel property(ies) of the composition or method. It should also be understood that any composition or method described herein as "comprising" or "consisting essentially of" one or more named elements or steps also represents a corresponding, more limited, closed-ended composition or method "consisting of" (or "consists of") the named elements or steps, excluding any other elements or steps not named. In any composition or method disclosed herein, known or disclosed equivalents of any named essential element or step may be substituted for that element or step.

[0094] Domain: As used herein, the term "domain" refers to a section or portion of an entity. In some embodiments, a "domain" relates to a particular structural and / or functional characteristic of an entity such that when the domain is physically separated from the remainder of its parent entity, it substantially or completely retains the particular structural and / or functional characteristic. Alternatively or additionally, a domain may be or comprise a portion of an entity that, when separated from its (parent) entity and associated with a different (recipient) entity, substantially retains and / or confers to the recipient entity one or more structural and / or functional characteristics that characterize the parent entity. In some embodiments, a domain is a section or portion of a molecule (e.g., a small molecule, carbohydrate, lipid, nucleic acid, or polypeptide). In some embodiments, a domain is a section of a polypeptide, and in some such embodiments, a domain is characterized by particular structural elements (e.g., particular amino acid sequences or sequence motifs, α-helical properties, β-sheet properties, coiled-coil properties, random coil properties, etc.) and / or particular functional properties (e.g., binding activity, enzymatic activity, folding activity, signaling activity, etc.).

[0095] Effector function: As used herein, refers to a biochemical event that results from the interaction of an antibody Fc region with an Fc receptor or ligand. Effector functions include, but are not limited to, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and complement-mediated cytotoxicity (CMC). In some embodiments, effector functions operate after antigen binding, independently of antigen binding, or both.

[0096] Effector cell: As used herein, refers to a cell of the immune system that expresses one or more Fc receptors and mediates one or more effector functions. In some embodiments, effector cells may include, but are not limited to, one or more of monocytes, macrophages, neutrophils, dendritic cells, eosinophils, mast cells, platelets, large granular lymphocytes, Langerhans cells, natural killer (NK) cells, T lymphocytes, B lymphocytes, and may be derived from any organism, including, but not limited to, human, mouse, rat, rabbit, and monkey.

[0097] Epitope: As used herein, includes any moiety that is specifically recognized by an immunoglobulin (e.g., antibody or receptor) binding component. In some embodiments, an epitope is composed of multiple chemical atoms or groups on an antigen. In some embodiments, such chemical atoms or groups are surface-exposed when the antigen is in a relevant three-dimensional conformation. In some embodiments, such chemical atoms or groups are physically close to each other in space when the antigen is in such a conformation. In some embodiments, at least some such chemical atoms or groups are physically separated from each other when the antigen is in an alternative conformation (e.g., linearized).

[0098] Excipient: As used herein, refers to a non-therapeutic agent that may be included in a pharmaceutical composition, for example, to provide or contribute to a desired consistency or stabilizing effect. Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, and the like.

[0099] Framework "or" framework region: As used herein, refers to the sequence of a variable region minus the CDRs. Because CDR sequences can be determined by different systems, framework sequences are likewise subject to correspondingly different interpretations. The six CDRs divide the framework regions on the heavy and light chains into four subregions (FR1, FR2, FR3, and FR4) on each chain, with CDR1 located between FR1 and FR2, CDR2 between FR2 and FR3, and CDR3 between FR3 and FR4. Without identifying specific subregions as FR1, FR2, FR3, and FR4, the framework region, as otherwise referred to, represents the combined FRs within the variable region of a single, naturally occurring immunoglobulin chain. As used herein, FR represents one of the four subregions; for example, FR1 represents the first framework region closest to the amino terminus of the variable region and is 5' with respect to CDR1, and FR represents two or more of the subregions that make up the framework region.

[0100] Functional: As used herein, a "functional" biomolecule is a biomolecule in a form in which it exhibits a property and / or activity by which it is characterized.

[0101] Fragment: A "fragment" of a substance or entity as described herein comprises a distinct portion of the whole, but has a structure that lacks one or more portions found in the whole. In some embodiments, the fragment consists of such a distinct portion. In some embodiments, the fragment consists of or comprises a characteristic structural element or portion found in the whole. In some embodiments, a fragment of a polymer comprises or consists of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500 or more monomer units (e.g., residues) present in the entire polymer. In some embodiments, a polymeric fragment comprises or consists of at least about 5%, 10%, 15%, 20%, 25%, 30%, 25%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more of the monomeric units (e.g., residues) found in the whole polymer. The whole substance or entity may, in some embodiments, be referred to as the "parent" of the fragment.

[0102] High affinity binding: As used herein, the term "high affinity binding" refers to the high tightness with which a particular ligand binds to its partner. Affinity can be measured by any available method, including those known in the art. In some embodiments, in a binding assay, K dis about 500 pM or less (e.g., less than about 400 pM, about 300 pM, about 200 pM, about 100 pM, about 90 pM, about 80 pM, about 70 pM, about 60 pM, about 50 pM, about 40 pM, about 30 pM, about 20 pM, about 10 pM, about 5 pM, about 4 pM, about 3 pM, about 2 pM, etc.). In some embodiments, the affinity is stronger for the polypeptide of interest than for a selected reference polypeptide (e.g., K d In some embodiments, the K of a selected reference polypeptide is low, and the binding is considered to be of high affinity. d K of the polypeptide of interest relative to d Binding is considered to be of high affinity when the ratio of K to a polypeptide of interest is 1:1 or less (e.g., 0.9:1, 0.8:1, 0.7:1, 0.6:1, 0.5:1, 0.4:1, 0.3:1, 0.2:1, 0.1:1, 0.05:1, 0.01:1 or less). d is the K for the selected reference polypeptide d Binding is considered to be high affinity when the affinity is about 100% or less (e.g., about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10%, about 5%, about 4%, about 3%, about 2%, about 1% or less).

[0103] Homology: As used herein, the term "homology" refers to the overall relatedness between polymer molecules, e.g., polypeptide molecules. In some embodiments, polymeric molecules, such as antibodies, are considered to be "homologous" to one another if their sequences are at least 80%, 85%, 90%, 95%, or 99% identical. In some embodiments, polymeric molecules are considered to be "homologous" to one another if their sequences are at least 80%, 85%, 90%, 95%, or 99% similar.

[0104] Human: In some embodiments, the human is an embryo, fetus, infant, child, teenager, adult, or elderly.

[0105] Humanized: As known in the art, the term "humanized" refers to the modification of a V antibody derived from a reference antibody raised in a non-human species (e.g., mouse). H and V L The term "humanized" is generally used to refer to antibodies (or antibody components) that contain variable domain sequences but also contain modifications of these sequences compared to a reference antibody intended to make them more "human-like," i.e., more similar to human germline variable sequences. In some embodiments, a "humanized" antibody (or antibody component) is one that immunospecifically binds to an antigen of interest and has framework (FR) regions having amino acid sequences substantially those of a human antibody and complementarity-determining regions (CDRs) having amino acid sequences substantially those of a non-human antibody. A humanized antibody comprises substantially all of at least one, and typically two, variable domains (Fab, Fab', F(ab')2, FabC, Fv), in which all or substantially all of the CDR regions correspond to the CDR regions of a non-human immunoglobulin (i.e., donor immunoglobulin) and all or substantially all of the framework regions are those of a human immunoglobulin consensus sequence. In some embodiments, a humanized antibody also comprises at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin constant region. In some embodiments, a humanized antibody comprises at least the variable domains of both a light chain and a heavy chain. H 1. Hinge, C H 2. C H 3, and optionally, C of the heavy chain constant region H In some embodiments, the humanized antibody may comprise a humanized V L In some embodiments, the humanized antibody contains only a humanized V region. H In some particular embodiments, the humanized antibody contains only a humanized V region. H and V L Includes the area.

[0106] Identity: As used herein, the term "identity" refers to the overall relatedness between polymeric molecules, e.g., between nucleic acid molecules (e.g., DNA molecules and / or RNA molecules) and / or between polypeptide molecules. In some embodiments, polymeric molecules are considered to be "substantially identical" to one another if their sequences are at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical. For example, calculation of the percent identity of two nucleic acid or polypeptide sequences can be performed by aligning the two sequences for optimal comparison purposes (e.g., gaps can be introduced into one or both of the first and second sequences for optimal alignment, and non-identical sequences can be disregarded for comparison purposes). In certain embodiments, the length of the aligned sequences for comparison purposes is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or substantially 100% of the length of the reference sequence. The nucleotides at corresponding positions are then compared. If a position in the first sequence is occupied by the same residue (e.g., nucleotide or amino acid) as the corresponding position in the second sequence, the molecules are identical at that position. The percent identity between two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps and the length of each gap that needs to be introduced for optimal alignment of the two sequences. Comparison of sequences and determination of percent identity between two sequences can be achieved using a mathematical algorithm. For example, the algorithm of Meyers and Miller (CABIOS, 1989, 4:11-17) incorporated into the ALIGN program (version 2.0) can be used to determine the percent identity between two nucleotide sequences. In some exemplary embodiments, comparisons of nucleic acid sequences using the ALIGN program use a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4.The percent identity between two nucleotide sequences can alternatively be determined using the GAP program in the GCG software package using the NWSgapdna.CMP matrix.

[0107] "Improve," "Increase," "Inhibit," or "Decrease": As used herein, the terms "improve," "increase," "inhibit," "decrease," or their grammatical equivalents refer to a value relative to a baseline or other reference measurement. In some embodiments, a suitable reference measurement may be or include a measurement in a particular system (e.g., in a single individual) under otherwise comparable conditions in the absence (e.g., before and / or after) of a particular agent or treatment, or in the presence of a suitable comparable reference agent. In some embodiments, a suitable reference measurement may be or include a measurement in a comparable system known or expected to respond in a particular manner in the presence of the relevant agent or treatment.

[0108] K D: As used herein, refers to the dissociation constant of a binding agent (e.g., an antibody or binding moiety thereof) from a complex with its partner (e.g., the epitope to which the antibody or binding moiety thereof binds).

[0109] Low affinity binding: As used herein, the term "low affinity binding" refers to the low tightness with which a particular ligand binds to its partner. As described herein, affinity can be measured by any available method, including methods known in the art. In some embodiments, K d is about 501 pM or greater (e.g., greater than about 501 pM, 600 pM, 700 pM, 800 pM, 900 pM, 1 nM, 1.1 nM, 1.2 nM, 1.3 nM, 1.4 nM, 1.5 nM, etc.). In some embodiments, the affinity is the same or lower (e.g., K) for the polypeptide of interest than for a selected reference polypeptide. dIn some embodiments, the binding is considered to be of low affinity if the K of the selected reference polypeptide is approximately the same as or higher. d K of the polypeptide of interest relative to d is 1:1 or greater (e.g., 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2:1, 3:1, 4:1, 5:1, 10:1, or greater). In some embodiments, the K of the polypeptide of interest is d is the K of the selected reference polypeptide d Binding is considered to be of low affinity if the affinity is 100% or more (e.g., 100%, 105%, 110%, 115%, 120%, 125%, 130%, 135%, 140%, 145%, 150%, 155%, 160%, 165%, 170%, 175%, 180%, 185%, 190%, 195%, 200%, 300%, 400%, 500%, 1000% or more) of the binding.

[0110] Peptide: As used herein, the term "peptide" refers to a polypeptide that is typically relatively short, e.g., having a length of less than about 100 amino acids, less than about 50 amino acids, less than about 40 amino acids, less than about 30 amino acids, less than about 25 amino acids, less than about 20 amino acids, less than about 15 amino acids, or less than 10 amino acids.

[0111] Pharmaceutical composition: As used herein, the term "pharmaceutical composition" refers to a composition in which an active agent is formulated with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in a unit dose suitable for administration in a treatment regimen that exhibits a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, the pharmaceutical composition may be specially formulated for administration in a particular form (e.g., a solid or liquid form) and / or may be specifically adapted for, for example, oral administration (e.g., specially formulated for buccal, sublingual, or systemic absorption, e.g., as a drench [aqueous or non-aqueous solution or suspension], tablet, capsule, bolus, powder, granules, paste, etc.); parenteral administration (e.g., subcutaneous, intramuscular, intravenous, or epidural injection, e.g., as a sterile solution or suspension, or sustained-release formulation); topical application (e.g., as a cream, ointment, patch, or spray applied, e.g., to the skin, lungs, or buccal cavity); vaginal or rectal administration (e.g., as a pessary, suppository, cream, or foam); intraocular administration; nasal or pulmonary administration, etc.

[0112] Polypeptide: As used herein, refers to a polymeric chain of amino acids. In some embodiments, a polypeptide has a naturally occurring amino acid sequence. In some embodiments, a polypeptide has a non-naturally occurring amino acid sequence. In some embodiments, a polypeptide has an engineered amino acid sequence, in that it is artificially designed and / or created. In some embodiments, a polypeptide can comprise or consist of natural amino acids, unnatural amino acids, or both. In some embodiments, a polypeptide can comprise or consist of only natural amino acids or only unnatural amino acids. In some embodiments, a polypeptide can comprise D-amino acids, L-amino acids, or both. In some embodiments, a polypeptide can comprise only D-amino acids. In some embodiments, a polypeptide can comprise only L-amino acids. In some embodiments, a polypeptide can comprise one or more pendant groups or other modifications, e.g., modification of or attachment to one or more amino acid side chains, at the N-terminus of the polypeptide, the C-terminus of the polypeptide, or any combination thereof. In some embodiments, such pendant groups or modifications can be selected from the group consisting of acetylation, amidation, lipidation, methylation, pegylation, etc., e.g., combinations thereof. In some embodiments, a polypeptide may be cyclic and / or include a cyclic portion. In some embodiments, a polypeptide is not cyclic and / or does not include a cyclic portion. In some embodiments, a polypeptide is linear. In some embodiments, a polypeptide may be or include a stapled polypeptide. In some embodiments, the term "polypeptide" may be appended to the name of a reference polypeptide, activity, or structure, and in such cases, it is used herein to refer to polypeptides that share a related activity or structure and can therefore be considered members of the same class or family of polypeptides. For each such class, the specification provides, and / or one of skill in the art will be aware of, exemplary polypeptides within the class whose amino acid sequence and / or function are known.In some embodiments, such exemplary polypeptides are reference polypeptides of a class or family of polypeptides. In some embodiments, members of a polypeptide class or family exhibit significant sequence homology or identity with the reference polypeptide of the class (and in some embodiments, with all polypeptides in the class), share common sequence motifs (e.g., characteristic sequence elements), and / or share a common activity (in some embodiments, at a similar level or within a specified range). For example, in some embodiments, member polypeptides exhibit an overall degree of sequence homology or identity with the reference polypeptide that is at least about 30-40%, and often greater than about 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more, and / or contain at least one region (e.g., a conserved region that, in some embodiments, is or may include a characteristic sequence element) that exhibits very high sequence identity, often greater than 90%, or even 95%, 96%, 97%, 98%, or 99%. Such conserved regions typically encompass at least 3-4, and often up to 20 or more, amino acids; in some embodiments, the conserved region encompasses at least one stretch of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more contiguous amino acids. In some embodiments, related polypeptides may comprise or consist of fragments of a parent polypeptide. In some embodiments, useful polypeptides may comprise or consist of multiple fragments, each of which is found in the same parent polypeptide in a different spatial arrangement relative to each other than that found in the polypeptide of interest (e.g., a fragment directly linked to the parent may be spatially separated in the polypeptide of interest, or vice versa, and / or the fragments may be present in a different order in the polypeptide of interest than in the parent), and thus the polypeptide of interest is a derivative of that parent polypeptide.

[0113] Reference: As used herein, describes a standard or control against which a comparison is made. For example, in some embodiments, an agent, animal, individual, population, sample, sequence, or value of interest is compared to a reference or control agent, animal, individual, population, sample, sequence, or value. In some embodiments, the reference or control is tested and / or determined substantially contemporaneously with the test or determination of interest. In some embodiments, the reference or control is a historical reference or control, optionally embodied in a tangible medium. Typically, as will be understood by one of skill in the art, a reference or control is determined or analyzed under conditions or circumstances comparable to those being evaluated. One of skill in the art will understand when there is sufficient similarity to justify reliance on and / or comparison to a particular reference or control considered.

[0114] Specific binding: As used herein, the term "specific binding" refers to the ability to distinguish between possible binding partners in the environment in which the binding occurs. A binding agent that interacts with one specific target in the presence of other potential targets is said to "specifically bind" to that interacting target. In some embodiments, specific binding is assessed by detecting or measuring the degree of association between the binding agent and its partner; in some embodiments, specific binding is assessed by detecting or measuring the degree of dissociation of the binding agent-partner complex; in some embodiments, specific binding is assessed by detecting or measuring the ability of a binding agent to compete with an alternative interaction of its partner with another entity. In some embodiments, specific binding is assessed by performing such detection or measurement over a range of concentrations.

[0115] Specific: The term "specific," as used herein with respect to an active agent, is understood by those skilled in the art to mean that the agent discriminates between potential target entities or aspects. For example, in some embodiments, an agent is said to bind "specifically" to a target if it preferentially binds to that target in the presence of one or more competing alternative targets. In many embodiments, the specific interaction depends on the presence of particular structural features of the target entity (e.g., epitopes, clefts, binding sites). It should be understood that specificity need not be absolute. In some embodiments, specificity can be assessed relative to the specificity of a binding agent for one or more other potential target entities (e.g., competitors). In some embodiments, specificity is assessed relative to that of a reference specific binding agent. In some embodiments, specificity is assessed relative to that of a reference nonspecific binding agent. In some embodiments, an agent or entity does not directly bind to competing alternative targets under conditions in which it binds to its target entity. In some embodiments, a binding agent binds to its target entity with a higher on-rate, a lower off-rate, increased affinity, decreased dissociation, and / or increased stability when compared to competing surrogate target(s).

[0116] Specificity: As known in the art, "specificity" is the degree to which a particular ligand is able to distinguish its binding partner from other potential binding partners.

[0117] Substantially: As used herein, the term "substantially" refers to the qualitative state of exhibiting the entire or nearly entire extent or degree of a desired characteristic or property. Those skilled in the art of biology will understand that biological and chemical phenomena rarely, if ever, proceed to completion and / or perfection or achieve or avoid absolute results. Thus, the term "substantially" is used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.

[0118] Substantial identity: As used herein, refers to a comparison between amino acid or nucleic acid sequences. As will be understood by those skilled in the art, two sequences are generally considered to be "substantially identical" if they contain identical residues at corresponding positions. As is well known in the art, amino acid or nucleic acid sequences can be compared using any of a variety of algorithms, including those available in commercially available computer programs, such as BLASTN for nucleotide sequences, BLASTP for amino acid sequences, gapped BLAST, and PSI-BLAST. Exemplary such programs are described in Altschul et al., Basic local alignment search tool, J. Mol. Biol., 215(3):403-410, 1990, Altschul et al., Methods in Enzymology, Altschul et al., Nucleic Acids Res. 25:3389-3402, 1997, Baxevanis et al., Bioinformatics: A Practical Guide to the Analysis of Genes and Proteins, Wiley, 1998, and Misener, et al. (eds.), Bioinformatics Methods and Protocols (Methods in Molecular Biology, Vol. 132), Humana Press, 1999. In addition to identifying identical sequences, the above programs typically provide an indication of the degree of identity. In some embodiments, two sequences are considered to be substantially identical if at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more of their corresponding residues are identical over the relevant stretch of residues, which in some embodiments is the complete sequence.In some embodiments, the relevant extension is at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, or more residues. In the context of CDRs, references to "substantial identity" typically refer to CDRs that have no more than a small number (e.g., 3, 2, or 1) of amino acid sequence changes compared to the amino acid sequence of the reference CDR. In some embodiments, a CDR that is substantially identical to a reference CDR differs from the reference CDR by one or more amino acid changes at the ends of the reference CDR. In some such embodiments, the relevant CDR is identical to the reference CDR except at one or both ends. As is known in the art, CDR elements typically have lengths ranging from a few amino acids (e.g., 3, 4, 5, 6, or 7) to about 20 or 30 amino acids (see, e.g., Collis et al. J. Mol. Biol. 325:337, 2003, incorporated herein by reference). Thus, in some embodiments, a CDR may be considered substantially identical to a reference CDR when it shares at least about 80% (or less for shorter CDRs), at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100% identity with the reference CDR.

[0119] Substantial sequence homology: The phrase "substantial homology" is used herein to refer to a comparison between amino acid or nucleic acid sequences. As will be understood by those skilled in the art, two sequences are generally considered to be "substantially homologous" if they contain identical residues at corresponding positions. Homologous residues may be identical residues. Alternatively, homologous residues may be non-identical residues, with appropriately similar structural and / or functional properties. For example, as is well known to those skilled in the art, certain amino acids are typically classified as "hydrophobic" or "hydrophilic" amino acids and / or as having "polar" or "non-polar" side chains. Substitution of one amino acid for another amino acid of the same type can often be considered a "homologous" substitution. Typical amino acid classifications are summarized below. [Table 14] [Table 15] As is well known in the art, amino acid or nucleic acid sequences can be compared using any of a variety of algorithms, including those available in commercially available computer programs, such as BLASTN for nucleotide sequences, BLASTP for amino acid sequences, Gapped BLAST, and PSI-BLAST. Exemplary such programs are described in Altschul, et al., Basic local alignment search tool, J. Mol. Biol., 215(3):403-410, 1990; Altschul, et al., Methods in Enzymology; Altschul, et al., "Gapped BLAST and PSI-BLAST: a new generation of protein database search programs," Nucleic Acids Res. 25:3389-3402, 1997; Baxevanis, et al., Bioinformatics: A Practical Guide to the Analysis of Genes and Proteins, Wiley, 1998; and Misener, et al., (eds.), Bioinformatics Methods and Protocols (Methods in Molecular Biology, Vol. 132), Humana Press, 1999. In addition to identifying homologous sequences, the above programs typically provide an indication of the degree of homology. In some embodiments, two sequences are considered to be substantially homologous if at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or more of their corresponding residues are homologous over the relevant stretch of residues. In some embodiments, the relevant stretch is the complete sequence.In some embodiments the relevant extension is at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, at least 100, at least 125, at least 150, at least 175, at least 200, at least 225, at least 250, at least 275, at least 300, at least 325, at least 350, at least 375, at least 400, at least 425, at least 450, at least 475, at least 500 or more residues.

[0120] Treat: As used herein, the terms "treat," "treatment," or "treating" are used to refer to one or more of the partial or complete alleviation, amelioration, palliation, inhibition, prevention, delay in onset, reduction in severity, and / or reduction in frequency (e.g., incidence) of one or more symptoms or characteristics of a disease, disorder, and / or condition. In some embodiments, treatment may be prophylactic, e.g., administered to a subject who does not exhibit signs of a disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject who exhibits only early signs of a disease, disorder, and / or condition, e.g., to reduce the risk of developing pathology associated with the disease, disorder, and / or condition, and / or to delay the onset of one or more characteristics of the disease, disorder, and / or condition, and / or to reduce the rate of onset or worsening of one or more characteristics of the disease, disorder, and / or condition.

[0121] Treatment: As used herein, the term "treatment" (also "treat" or "treating") refers to the administration of a therapy that partially or completely alleviates, ameliorates, palliates, inhibits, delays the onset of, reduces the severity of, and / or reduces the incidence of one or more symptoms, characteristics, and / or causes of a particular disease, disorder, and / or condition. In some embodiments, such treatment may be of subjects who do not exhibit symptoms of the associated disease, disorder, and / or condition and / or who exhibit only early signs of the disease, disorder, and / or pathology. Alternatively or additionally, such treatment may be of subjects who exhibit one or more symptoms of the associated disease, disorder, and / or condition. In some embodiments, treatment may be of subjects who have been diagnosed with the associated disease, disorder, and / or pathology. In some embodiments, treatment may be of subjects known to have one or more susceptibility factors, e.g., susceptibility factors that statistically correlate with an increased risk of developing the associated disease, disorder, and / or condition. Thus, in some embodiments, treatment may be prophylactic. In some embodiments, treatment may be therapeutic.

[0122] Variant: As used herein, the term "variant" refers to a molecule or entity (e.g., a nucleic acid, protein, or small molecule, e.g., a molecule or entity that exhibits significant structural identity with a reference molecule or entity, but that is structurally different from the reference molecule or entity, e.g., in the presence or absence, or level, of one or more chemical moieties compared to the reference molecule or entity. In some embodiments, a variant also differs functionally from its reference molecule or entity. In many embodiments, whether a particular molecule or entity is properly considered a "variant" of a reference is based on the degree of structural identity with the reference molecule. As will be understood by those skilled in the art, biological or chemical reference molecules are typically characterized by certain characteristic structural elements. A variant, by definition, is a distinct molecule or entity that shares one or more such characteristic structural elements but differs from the reference molecule or entity in at least one aspect. To give some examples, a polypeptide may have characteristic sequence elements composed of multiple amino acids that have designated positions relative to each other in linear or three-dimensional space and / or that contribute to a particular structural motif and / or biological function, and a nucleic acid may have characteristic sequence elements composed of multiple nucleotide residues that have designated positions relative to each other in linear or three-dimensional space. In some embodiments, a variant polypeptide or nucleic acid may differ from a reference polypeptide or nucleic acid as a result of one or more differences in amino acid or nucleotide sequence and / or one or more differences in chemical moieties (e.g., carbohydrates, lipids, phosphate groups) that are covalent components of the polypeptide or nucleic acid (e.g., to which the polypeptide or nucleic acid backbone is attached). In some embodiments, a variant polypeptide or nucleic acid exhibits an overall sequence identity with a reference polypeptide or nucleic acid that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, or 99%. In some embodiments, a variant polypeptide or nucleic acid does not share at least one characteristic sequence element with a reference polypeptide or nucleic acid.In some embodiments, a reference polypeptide or nucleic acid has one or more biological activities. In some embodiments, a variant polypeptide or nucleic acid shares one or more of the biological activities of the reference polypeptide or nucleic acid. In some embodiments, a variant polypeptide or nucleic acid lacks one or more of the biological activities of the reference polypeptide or nucleic acid. In some embodiments, a variant polypeptide or nucleic acid exhibits a reduced level of one or more biological activities compared to a reference polypeptide or nucleic acid. In some embodiments, a polypeptide or nucleic acid of interest is considered a "variant" of a reference polypeptide or nucleic acid if the amino acid or nucleotide sequence of the reference polypeptide or nucleic acid is identical to the reference amino acid or nucleotide sequence but has a small number of sequence changes at specific positions. Typically, less than about 20%, about 15%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, or about 2% of the residues in the variant are substituted, inserted, or deleted compared to the reference. In some embodiments, a variant polypeptide or nucleic acid contains about 10, about 9, about 8, about 7, about 6, about 5, about 4, about 3, about 2, or about 1 substituted residues compared to the reference. Often, a variant polypeptide or nucleic acid contains very few (e.g., less than about 5, about 4, about 3, about 2, or about 1) functional residues (i.e., residues responsible for a particular biological activity) substituted, inserted, or deleted compared to the reference. In some embodiments, a variant polypeptide or nucleic acid contains no more than about 5, about 4, about 3, about 2, or about 1 additions or deletions compared to the reference, and in some embodiments, no additions or deletions compared to the reference. In some embodiments, the variant polypeptide or nucleic acid comprises less than about 25, about 20, about 19, about 18, about 17, about 16, about 15, about 14, about 13, about 10, about 9, about 8, about 7, about 6, and less than about 5, about 4, about 3, or about 2 additions or deletions compared to the reference. In some embodiments, the reference polypeptide or nucleic acid is one that occurs in nature.In some embodiments, the reference polypeptide or nucleic acid is a human polypeptide or nucleic acid. (Mode for Carrying Out the Invention)

[0123] The present disclosure provides, inter alia, novel GDF15 antibody agents that have improved binding rate, binding affinity, pharmacokinetics, and / or function, e.g., compared to a suitable reference anti-GDF15 antibody (e.g., an anti-GDF15 antibody known in the art, such as an anti-GDF15 antibody described in WO2014049087, WO21544855, WO2017055613, US2020 / 0055930A1, or U.S. Patent No. 9,175,076). In some embodiments, the GDF15 antibody agents disclosed herein bind to GDF15 with high specificity. In some embodiments, the provided GDF15 antibody agents may exhibit preferential binding to GDF15 relative to one or more TGF-beta family members other than GDF15. In some such embodiments, preferential binding may be assessed, for example, by simultaneously contacting the GDF15 antibody agent with GDF15 and one or more other TGF-beta family members. Alternatively or additionally, in some embodiments, preferential binding may be assessed in comparison to a suitable reference GDF15 antibody agent (e.g., as described in one or more of WO2014049087, WO21544855, WO2017055613, US2020 / 0055930A1, or U.S. Patent No. 9,175,076), and may reflect, for example, a higher level of binding to GDF15 relative to one or more other TGF-beta family members than observed with the reference antibody. In some embodiments, the GDF15 antibody agent does not bind to one or more TGF-beta family members other than GDF15. In some embodiments, the GDF15 antibody agents disclosed herein bind to GDF15 and also to one or more other TGF-beta family members. For example, in some embodiments, provided GDF15 antibody agents bind to GDF15 and one or more of activin A, activin B, and GDF10.

[0124] In some embodiments, the GDF15 antibody agents disclosed herein inhibit the activity of GDF15 and / or reduce the level of GDF15 (e.g., free and / or active GDF15) when administered to a cell, tissue, or subject. In some embodiments, the GDF15 antibody agents disclosed herein can be used to treat a condition or disease associated with increased GDF15. In some embodiments, the GDF15 antibody agents disclosed herein can be used to treat symptoms of a condition or disease associated with increased GDF15 (e.g., nausea, weight loss, and / or loss of appetite). Compositions comprising the GDF15 antibody agents disclosed herein, as well as methods for making and using the same, are also provided herein.

[0125] GDF15 Growth differentiation factor 15 (GDF15 or GDF-15) is a secreted protein whose monomer is 12 kDa and forms a 25 kDa disulfide-linked homodimer. GDF15 is a member of the transforming growth factor beta (TGF-beta) superfamily. GDF15 is also known as macrophage inhibitory cytokine 1 (MIC-1), prostate-derived factor (PDF), placental bone morphogenetic protein (PLAB), NSAID-activated gene 1 (NAG-1), and placental transforming growth factor beta (PTGFB). Typically, GDF15 expression in tissues or plasma is low, but GDF15 expression can be upregulated in response to stimuli such as inflammation, malignant tumors, and / or exposure to treatment.

[0126] The human GDF15 polypeptide sequence, having UniProt accession number Q99988, is provided herein as SEQ ID NO: 183: MPGQELRTVNGSQMLLVLLVLSWLPHGGALSLAEASRASFPGPSELHSEDSRFRELRKRYEDLLTRLRANQSWEDSNTDLVPAPAVRILTPEVRLGSGGHLHLRISRAALPEGLPEASRLHRALFRLSPTASRSWDVTRPLRRQLSLARPQAPA LHLRLSPPSQSDQLLAESSSARPQLELHLRPQAARGRRRARARNGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI

[0127] The amino acid sequence of human GDF15 (SEQ ID NO: 183) includes a signal peptide (residues 1-29), a propeptide (residues 30-194), and a mature polypeptide (residues 195-308).

[0128] Human GDF15 signal peptide (SEQ ID NO: 187) MPGQELRTVN GSQMLLVLLV LSWLPHGGA

[0129] Human GDF15 propeptide (SEQ ID NO: 188) LSLAEASRASF PGPSELHSED SRFRELRKRY EDLLTRLRAN QSWEDSNTDL VPAPAVRILT PEVRLGSGGH LHLRISRAAL PEGLPEASRL HRALFRLSPT ASRSWDVTRP LRRQLSLARP QAPALHLRLS PPPSQSDQLL AESSSARPQL ELHLRPQAAR GRRR

[0130] Human GDF15 mature polypeptide (SEQ ID NO: 189) ARARNG DHCPLGPGRC CRLHTVRASL EDLGWADWVL SPREVQVTMC IGACPSQFRA ANMHAQIKTS LHRLKPDTVP APCCVPASYN PMVLIQKTDT GVSLQTYDDL LAKDCHCI

[0131] GDF15 is also expressed by other mammals besides humans, and exemplary sequences are provided below:

[0132] Cynomolgus monkey GDF15 (SEQ ID NO: 184) with UniProt accession number G7PWZ3 MPGQELKTLNGSQMLLVLLVLLWPPHGGAVSLAEASRASFPGPSDLHSEDSRFRELRKRYEDLLTRLRANQSWEDSNTDLIQAPEVRILTPEVRLGSGGHLHLRISRAVLPEGLPEACRIHRALFRLSPTASRSRDVTRPLRRQLRLARPQAPA LHLRLSPPSQSDQLLVKSSSSRPQLALHLRPRASRGRRRARARNGDRCPLGPGRCCRLHTVHASLEDLGWADWVLSPREVQVTMCIGACPSQFREANMHAQIKMNLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCV

[0133] Canis familiaris (dog) GDF15 (SEQ ID NO: 185) with UniProt accession number F1PDK9 MPGQGPAPAHCSPMLVILVMLSWLPSGGALSLAQEHLPAFPGPSDPHSSTDVSRIQELRKRYEHLQTKLRLNQGWADSNPDLVPATRVRILTPKLRLGPRGHLHLRIARADLTAGLPAASRLHRALLRLSPTEPSSWDVTRPLQRQLSRVGSR TPTLRLRLLPRWDRSRALPSARPQLELHWRPRAARGRRNAHAHARDGCPLGEGRCCRLQSLRASLQDLGWANWVVAPRELDVRMCVGACPSQFRSANTHAQMQARLHGLNPDAAPAPCCVPASYEPVVLMHQDSDGRVSLTPFDDLVAKDCHCV

[0134] Felis catus (cat) GDF15 (SEQ ID NO: 186) with UniProt accession number M3WC01 SVQNSASTGMPGPGPTPPMLLMLLMLLMLCWLPSGGALSLAQEHLPAFPPGPSEARSGTDVSRFEEFRKLYEHLQTRLRLNQSWEDSNPDRVISEAQVRILTPKLRLGLGHHLRIARADLTKGLPASFRLHRALLRLSPTELSSWDVTRPLR RQLSLGGSGRDRSPAALPSSARPQLELHWRPRAARGRRNAHARSKDDCPLGAGRCCRLQSLRASLEDLGWASWVVAPRELDVRMCIGACPSQFRSANTHAQMQARLHGLNPDATPAPCCVPARYEPVVLMHQDSDGRVSLTPFDDLVAKDCHCL

[0135] GDF15 can bind to and activate glial cell line-derived neurotrophic factor receptor alpha-like (GFRAL). GFRAL is primarily expressed in the hindbrain and is an orphan member of the GFR-alpha family (see, e.g., Hsu et al., 2017, Nature 550:255-259; Yang et al., 2017, Nature Med. 23(10):1158; and Emmerson et al., 2017, Nature Med. 23(10):1215). Studies of GDF15 binding to GFRAL have demonstrated that this binding activates the GFRAL-mediated signaling pathway, thereby activating the receptor tyrosine kinase, RET, which functions as a co-receptor for GFRAL. RET then mediates downstream phosphorylation of, among others, ERK (pERK), ribosomal protein S6 (pS6), AKT, MAPK, and phospholipase C gamma 1 (PLC-gamma 1). Activation of GFRAL by GDF15 has also been shown to occur in brainstem regions (e.g., the posterior brainstem and brainstem nuclei) that play a role in regulating appetite and emesis. These brainstem regions have a leaky blood-brain barrier (BBB) ​​and are therefore accessible, among other things, to antibodies that can bind to GDF15 and / or GFRAL and modulate this interaction.

[0136] Without wishing to be bound by any particular theory, in some embodiments, the GDF15 antibody agents disclosed herein bind to GDF15 and inhibit the binding of endogenous GDF15 to the GFRAL interaction, thereby preventing activation of GFRAL and / or one or more downstream signaling pathways. In some embodiments, modulation of the GDF15-GFRAL pathway by the GDF15 antibody agents disclosed herein allows for the treatment of conditions, diseases, or disorders associated with (e.g., mediated by) GDF15.

[0137] Furthermore, without wishing to be bound by any particular theory, in some embodiments, the GDF15 antibody agent disclosed herein binds to GDF15 and inhibits the binding of endogenous GDF15 to a receptor, for example, a receptor that binds to GDF15, for example, GFRAL. In some embodiments, the GDF15 receptor is present on cells outside the brain. In some embodiments, the GDF15 receptor is present on cells in the brainstem. In some embodiments, the GDF15 receptor is accessible to, for example, an antibody agent as disclosed herein.

[0138] Recent reports demonstrate that increased levels of GDF15 can induce nausea and vomiting, weight loss, and anorexia. For example, hyperemesis gravidarum is associated with elevated GDF15 levels during pregnancy (Fejzo et al., 2018). A recent report by Breen et al., 2020, disclosed elevated GDF15 in cancer patients treated with platinum-based chemotherapy and found that increased GDF15 is associated with weight loss, nausea, and anorexia in animal models. Increased plasma GDF15 has also been shown to be associated with weight loss in cancer patients with cachexia (see, e.g., US2020 / 0055930A1, WO2005 / 099746, WO2009 / 021293, WO2014 / 100689, and WO2016 / 049470, the contents of each of which are incorporated herein by reference in their entireties).

[0139] Although GDF15 antibodies have been previously developed, none of the antibodies known in the art have been demonstrated to date as a viable therapeutic option for preventing and treating conditions, diseases, or disorders associated with (e.g., mediated by) elevated levels of GDF15, or symptoms thereof. In some embodiments, the elevated level of GDF15 is greater than or equal to about 1 ng / ml, for example, as assessed in a sample from a subject, such as a blood, plasma, serum, or urine sample. The present disclosure provides novel GDF15 antibody agents that can be used to fulfill this unmet need.

[0140] GDF15 antibody Disclosed herein are GDF15 antibody agents that bind, e.g., specifically bind, to GDF15, e.g., with high affinity. The anti-GDF15 antibodies disclosed herein can be effective in plasma and / or multiple tissue compartments, and GDF15 can act on its target cells, e.g., cells that express a receptor that binds to GDF15.

[0141] In some embodiments, the GDF15 target cells are or include cells that express a GDF15 receptor, e.g., GFRAL. In some embodiments, the GDF15 antibody agent can modulate the GDF15-GFRAL pathway to inhibit one or more activities of GDF15 or reduce the level of GDF15, e.g., reduce the level of free and / or active GDF15. In some embodiments, the GDF15 antibody agent disclosed herein binds to GDF15 and inhibits the activity and / or reduces the level of GDF15, e.g., reduce the level of free and / or active GDF15. In some embodiments, the GDF15 antibody agent disclosed herein binds to GDF15 and prevents binding of GDF15 to a receptor, e.g., GFRAL. In some embodiments, binding of the GDF15 antibody agent to GDF15 prevents activation of a GDF15 receptor, e.g., GFRAL.

[0142] In some embodiments, the GDF15 target cells are or include cells that express the GDF15 receptor. In some embodiments, the GDF15 target cells are in the brainstem, and in some embodiments, the GDF15 target cells are outside the brain, e.g., in the circulation or in tissues other than the brain. In some embodiments, the GDF15 antibody agents disclosed herein bind to GDF15 and inhibit the activity and / or reduce the level of GDF15, e.g., reduce the level of free and / or active GDF15. In some embodiments, the GDF15 antibody agents disclosed herein bind to GDF15 and prevent GDF15 from binding to the GDF15 receptor.

[0143] In some embodiments, the GDF15 antibody agents disclosed herein bind to any or all forms of GDF15, e.g., intracellular GDF15, soluble GDF15, ECM-bound GDF15, mature GDF15, proprotein GDF15 (e.g., preprocessed), and / or active GDF15.

[0144] In some embodiments, the GDF15-binding agent specifically binds to GDF15 and reduces levels of GDF15 (e.g., free and / or active GDF15). In some embodiments, it reduces levels of circulating GDF15. In some embodiments, it reduces levels of free and / or active GDF15. In some embodiments, it reduces levels of free and active GDF15.

[0145] In some embodiments, the level of GDF15 (e.g., free and / or active GDF15) is reduced relative to a comparator agent, which in some embodiments includes cells, tissues, or subjects not contacted with a GDF15 antibody agent disclosed herein.

[0146] In some embodiments, the level of GDF15 (e.g., free and / or active GDF15) is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100%. In some embodiments, the level of GDF15 (e.g., free and / or active GDF15) is reduced by about 5% to about 100%, about 10% to about 100%, about 15% to about 100%, about 20% to about 100%, about 25% to about 100%, about 30% to about 100%, about 35% to about 100%, about 40% to about 100%, about 45% to about 100%, about 50% to about 100%, about 55% to about 100%, about 60% to about 100%, about 65% to about 100%, about 70% to about 100%, about 75% to about 100%, about 80% to about 100%, about 90% to about 100%, or about 95% to about 100%.

[0147] In some embodiments, the level of GDF15 (e.g., free and / or active GDF15) is reduced by about 5% to about 100%, about 5% to about 95%, about 5% to about 90%, about 5% to about 85%, about 5% to about 80%, about 5% to about 75%, about 5% to about 70%, about 5% to about 65%, about 5% to about 60%, about 5% to about 55%, about 5% to about 50%, about 5% to about 45%, about 5% to about 40%, about 5% to about 35%, about 5% to about 30%, about 5% to about 25%, about 5% to about 20%, about 5% to about 15%, or about 5% to about 10%.

[0148] In some embodiments, GDF15 activity is associated with: (a) decreased food intake, (b) decreased appetite, (c) decreased body weight, (d) increased weight loss, (e) decreased fat mass, (f) decreased lean mass, (g) increased fat mass loss, (h) prevention of weight gain, (i) increased loss of lean muscle mass, (j) increased fatigue, (k) decreased inflammation induction, (l) decreased immune cell infiltration in tumors, (m) increased metastasis, (n) decreased efficacy of immunotherapy (e.g., immune checkpoint inhibitor therapy), (o) increased cellular senescence, (p) binding to receptors, e.g., GFRAL, (q) increased downstream signaling mediated by RET, (r) increased phosphorylation of ERK, (s) increased phospholipids, (t ... (u) increased RET activation of the AKT signaling pathway; (v) increased activation of the PLC-D1 signaling pathway; (w) increased nausea, vomiting, and / or emesis; (x) decreased T cell adhesion to endothelial cells (e.g., inhibition of LFA1-ICAM interaction); or (y) increased stimulation of the hypothalamic-pituitary-adrenal axis, as assessed, for example, by increased growth hormone (GH), adrenocorticotropic hormone (ACTH), corticosterone / cortisol, or a combination thereof.

[0149] Disclosed herein are GDF15-binding agents that can modulate the activity of GDF15. In some embodiments, the GDF15-binding agent specifically binds to GDF15, and the antibody agent modulates one or more, or all, or any combination of, detectable GDF15 activities, such that the antibody agent (a) increases food intake, (b) increases appetite, (c) increases body weight, (d) increases weight loss, (e) increases fat mass, (f) increases lean mass, (g) decreases fat mass loss, (h) promotes weight gain, (i) decreases lean muscle mass loss, (j) decreases fatigue, (k) increases inflammation induction, (l) increases immune cell infiltration in tumors, (m) decreases metastasis, (n) increases the efficacy of immunotherapy (e.g., immune checkpoint inhibitor therapy), (o) decreases cellular senescence, (p) inhibits receptors, such as , inhibiting GDF15 binding to GFRAL, (q) decreasing downstream signaling mediated by RET, (r) decreasing phosphorylation of ERK, (s) decreasing phosphorylation of ribosomal protein S6, (t) decreasing RET-mediated activation of the MAPK signaling pathway, (u) decreasing RET activation of the AKT signaling pathway, (v) decreasing activation of the PLC-D1 signaling pathway, (w) decreasing nausea, vomiting, and / or emesis, (x) increasing T cell adhesion to endothelial cells (e.g., inhibiting LFA1-ICAM interaction), or (y) decreasing stimulation of the hypothalamic-pituitary-adrenal axis as assessed by increases in growth hormone (GH), adrenocorticotropic hormone (ACTH), and corticosterone / cortisol.

[0150] Those skilled in the art will understand that in some embodiments, GDF15 activity can be assessed using one or more artisan-recognized assays, for example, as described herein. For example, as disclosed in Example 4 herein, an assay using cells co-expressing GFRAL and RET can be used to assess GDF15 activity. Several assays can be used to measure activation of the MAPK pathway after stimulation with GDF15, for example, a luciferase-based gene reporter system, or a phosphoprotein assay (e.g., assessing phospho-ERK1 / 2).

[0151] In some embodiments, the GDF15 antibody agents disclosed herein specifically bind to human GDF15. In some embodiments, the GDF15 antibody agents disclosed herein specifically bind to cynomolgus monkey GDF15. In some embodiments, the GDF15 antibody agents disclosed herein specifically bind to mouse GDF15.

[0152] In some embodiments, provided GDF15 antibody agents may exhibit preferential binding to GDF15 relative to one or more TGF-beta family members other than GDF15. In some such embodiments, preferential binding may be assessed, for example, by simultaneously contacting the GDF15 antibody agent with GDF15 and one or more other TGF-beta family members. Alternatively, or additionally, in some embodiments, preferential binding may be assessed in comparison to an appropriate reference GDF15 antibody agent (e.g., as described in one or more of WO2014049087, WO21544855, WO2017055613, US2020 / 0055930A1, or U.S. Patent No. 9,175,076), and may reflect, for example, a higher level of binding to GDF15 relative to one or more other TGF-beta family members than observed with the reference antibody.

[0153] In some embodiments, the GDF15 antibody agents disclosed herein preferentially bind to GDF15. In some embodiments, the GDF15 antibody agents disclosed herein do not bind to one or more members of the TGF beta superfamily other than GDF15. In some embodiments, the GDF15 antibody agents disclosed herein do not bind to GDNF, GDF8, GDF10, GDF11, BMP9, BMP10, activin A, activin B, or a combination thereof.

[0154] In some embodiments, a GDF15 antibody agent disclosed herein preferentially binds to GDF15. In some embodiments, a GDF15 antibody agent disclosed herein binds to one or more members of the TGF-beta superfamily in addition to GDF15. In some embodiments, a GDF15 antibody agent disclosed herein binds to GDF15 and one or more of the following: activin A, activin B, or GDF10. In some embodiments, a GDF15 antibody agent disclosed herein binds to GDF15 and activin A. In some embodiments, a GDF15 antibody agent disclosed herein binds to GDF15 and activin B. In some embodiments, a GDF15 antibody agent disclosed herein binds to GDF15 and GDF10. In some embodiments, a GDF15 antibody agent disclosed herein binds to GDF15, activin A, and activin B. In some embodiments, a GDF15 antibody agent disclosed herein binds to GDF15, activin A, activin B, and GDF10.

[0155] In some embodiments, a GDF15-binding agent that binds to GDF15 and activin A does not modulate activin A activity and / or levels, for example, when characterized in an assay that assesses activin A activity and / or levels.

[0156] In some embodiments, a GDF15-binding agent that binds to GDF15 and activin B does not modulate activin B activity and / or levels, for example, when characterized in an assay that assesses activin B activity and / or levels.

[0157] Those skilled in the art will understand that in some embodiments, the activity of activin A, activin B, or GDF11 can be assessed using one or more artisan-recognized assays, for example, as described herein. For example, as disclosed in Example 2 herein, an assay using cells expressing an activin 2B receptor / SMAD reporter can be used to assess the activity of activin A, activin B, or GDF11. Several assays can be used to measure activation of the activin 2B receptor and induction of SMAD signaling following stimulation with activin A, activin B, or GDF11, for example, a luciferase-based reporter system.

[0158] Without wishing to be bound by theory, the provided GDF15 antibody agents can bind to GDF15 and one or more members of the TGF beta superfamily, but the regulatory effect of the provided GDF15 antibody agents on GDF15 may be independent of binding to one or more TGF beta superfamily members.

[0159] In some embodiments, the GDF15 antibody agents disclosed herein bind to a conformation-dependent epitope on GDF15. In some embodiments, the GDF15 antibody agents disclosed herein bind to a nonlinear epitope on GDF15. In some embodiments, the GDF15 epitope bound by the GDF15 antibody agents disclosed herein comprises a portion of the exposed beta chain.

[0160] In some embodiments, the GDF15 epitope bound by the provided GDF15 antibody agents does not include the portion of GDF15 that binds to GFRAL. In some embodiments, the provided GDF15 antibody agents bind to a GDF15 epitope outside the GFRAL binding interface, e.g., a binding pocket. Without wishing to be bound by theory, in some embodiments, the GDF15 antibody agents disclosed herein use steric hindrance to prevent GDF15 from binding to or interacting with GFRAL.

[0161] Those skilled in the art reading this disclosure will understand that, in some embodiments, antibody agents provided by the present disclosure include (i) intact IgA, IgG, IgD, IgE, or IgM antibodies, (ii) antibody fragments (e.g., antibody variable regions containing both heavy and light chain sequences, e.g., Fab), (iii) single domain antibodies (e.g., light chain antibodies or heavy chain antibodies), (iv) single chain antibodies (e.g., single chain Fv, camelid antibodies, etc.), (v) antibody-drug conjugates, (vi) bispecific or other multispecific antibodies, (vii) polypeptides comprising an antigen-binding specificity fused to an Fc region, etc.

[0162] Those of skill in the art reading this disclosure will further appreciate if the contributions provided are not limited to intact antibodies or fragments thereof (eg, including both heavy and light chain sequences).

[0163] For example, one of skill in the art will understand that individual light chains and / or individual heavy chains, or their variable region sequences (e.g., as exemplified herein, e.g., as presented in Table 1), described herein may be useful in combination with other light chains and / or heavy chains. In some embodiments, a single light chain (or its variable region sequence) described herein may be utilized with two (or more) different heavy chains (e.g., which may be or include heavy chains exemplified herein), or their variable region sequences, in a "common light chain" bispecific format. In some embodiments, exemplary light and heavy chains (e.g., their variable region sequences) may be "mixed and matched" with each other in antibody agents provided by the present disclosure (e.g., antibody agents that specifically bind to GDF15 and / or have one or more other structural and / or functional properties described herein).

[0164] Furthermore, one of skill in the art will appreciate that the present disclosure provides useful heavy and light chain antibody sequences, specifically including useful variable region sequences, including, for example, useful CDR and / or framework (FR) sequences.

[0165] In some embodiments, the present disclosure provides polypeptides (e.g., which may be or be included in an antibody agent that specifically binds to GDF15) that comprise one or more CDR and / or FR sequences set forth in Table 1 or 2. In some embodiments, the present disclosure provides polypeptides that comprise two or more CDR elements from Table 1 or 2, and in particular, the present disclosure provides polypeptides that comprise three or six CDR elements from Table 1 or 2.

[0166] In some embodiments, the disclosure provides a polypeptide (e.g., which may be or be included in an antibody agent that specifically binds to GDF15) that includes one LC CDR1, one LC CDR2, and one LC CDR3 from Table 1. In some such embodiments, two or three CDRs are from the same LC from Table 1.

[0167] In some embodiments, the present disclosure provides a polypeptide (e.g., which may be or be included in an antibody agent that specifically binds to GDF15) that includes one HC CDR1, one HC CDR2, and one HC CDR3 from Table 2. In some such embodiments, two or three CDRs are from the same HC in Table 2.

[0168] In some embodiments, the present disclosure provides a polypeptide (e.g., which may be or be included in an antibody agent that specifically binds to GDF15) that includes one each of an LC CDR1, an LC CDR2, an LC CDR3, an HC CDR1, an HC CDR2, and an HC CDR3 from Table 1 or 2. In some such embodiments, two or more CDRs, and in some embodiments, all of the LC CDRs, all of the HC CDRs, or both, are derived from the same antibody of Table 1 or 2.

[0169] Those of skill in the art will further understand that, in some embodiments, useful polypeptides described herein comprising one or more CDRs from Table 1 or 2 may comprise a heavy or light chain CDR set (i.e., each of CDR1, CDR2, and CDR3) comprising one or two CDRs from a first antibody chain (i.e., LC or HC) in Table 1 or 2 and at least one from a second antibody chain (e.g., of the same type) in Table 1 or 2. Alternatively, or additionally, those of skill in the art will understand that, in some embodiments, useful polypeptides described herein comprising one or more CDRs from Table 1 or 2 may comprise a heavy or light chain CDR set (i.e., each of CDR1, CDR2, and CDR3) comprising at least one CDR from a first antibody chain (i.e., LC or HC) in Table 1 or 2 and at least one other CDR that differs from its corresponding CDR in the relevant chain in Table 1 or 2. In some such embodiments, the different CDR(s) will differ from the corresponding CDR(s) at no more than 3, no more than 2, or no more than 1 position; alternatively or additionally, in some such embodiments, the different CDR(s) will differ from the corresponding CDR(s) only at the terminal residue(s).

[0170] In some embodiments, a GDF15 antibody agent disclosed herein that binds to GDF15 comprises LC CDR1, LC CDR2, and LC CDR3 as provided in Table 1. In some embodiments, the presence of LC CDR1, LC CDR2, and LC CDR3 is sufficient to confer binding and / or otherwise useful (i.e., specific binding to GDF15) in an antibody agent disclosed herein. In some embodiments, an antibody agent comprising LC CDR1, LC CDR2, and LC CDR3 can be in any format disclosed herein. For example, in some embodiments, an antibody agent comprising LC CDR1, LC CDR2, and LC CDR3 can be a single-chain antibody and can bind to GDF15.

[0171] In some embodiments, the GDF15 antibody agents disclosed herein that bind to GDF15 comprise HC CDR1, HC CDR2, and HC CDR3 and are sufficient to confer binding and / or otherwise useful to GDF15 in the antibody agents disclosed herein. In some embodiments, the antibody agents comprising HC CDR1, HC CDR2, and HC CDR3 can be in any format disclosed herein. For example, in some embodiments, the antibody agents comprising HC CDR1, HC CDR2, and HC CDR3 can be single-chain antibodies and can bind to GDF15.

[0172] In some embodiments, a GDF15 antibody agent disclosed herein that binds to GDF15 comprises any set of three LC CDRs (e.g., LC CDR1, LC CDR2, and LC CDR3) provided in Table 1 and any set of three HC CDRs (e.g., HC CDR1, HC CDR2, and HC CDR3) provided in Table 2. In some embodiments, the presence of any set of three LC CDRs and any set of three HC CDRs is sufficient to confer binding to GDF15 of any antibody agent disclosed herein. In some embodiments, such a GDF15 antibody agent can be a fragment (e.g., an scFv, Fab, or other fragment) fused to Fc, or an intact antibody, or a polypeptide that comprises antigen-binding specificity.

[0173] In some embodiments, disclosed herein are GDF15 antibody agents that compete for binding to human GDF15 with a different GDF15 antibody agent (e.g., when tested in a standard competition assay) with a different GDF15 antibody agent, e.g., a GDF15 antibody agent disclosed in US 2020 / 0055930A1, U.S. Patent No. 10,174,119, or U.S. Patent No. 9,175,076. In some embodiments, a GDF15 antibody agent disclosed herein competes for binding to human GDF15 with a different GDF15 antibody agent when evaluated at two or more concentrations (e.g., over a concentration range of at least 2-fold, 4-fold, 6-fold, 8-fold, 10-fold, or more).

[0174] In some embodiments, disclosed herein are GDF15 antibody agents that do not compete for binding to human GDF15 with different GDF15 antibody agents, e.g., GDF15 antibody agents disclosed in US2020 / 0055930A1, U.S. Patent No. 10,174,119, and U.S. Patent No. 9,175,076 (e.g., when tested in a standard competition assay).

[0175] In some embodiments, disclosed herein are GDF15 antibody agents that bind to sterically overlapping (e.g., partially or completely overlapping) epitopes as the GDF15 antibody agents disclosed in US2020 / 0055930A1, U.S. Patent No. 10,174,119, U.S. Patent No. 9,175,076, or U.S. Patent No. 10,604,565.

[0176] Light chain (e.g., light chain variable region) polypeptide (LC polypeptide) The present disclosure provides polypeptides comprising light chain (LC) sequences (e.g., light chain variable region sequence(s)) that may be useful, for example, in the antibody agents described herein that target GDF15. In some such embodiments, such provided polypeptides are useful and / or included in such antibody agents described herein. In some embodiments, the LC polypeptide comprises at least one LC CDR provided in Table 1 or a sequence having at least 85% identity thereto. In some embodiments, the LC polypeptide comprises one, two, or three LC CDRs (e.g., LC CDR1, LC CDR2, and / or LC CDR3). In some embodiments, the LC polypeptide comprises an LC CDR1. In some embodiments, the LC polypeptide comprises an LC CDR2. In some embodiments, the LC polypeptide comprises an LC CDR3. In some embodiments, the LC polypeptide comprises an LC CDR1, an LC CDR2, and an LC CDR3.

[0177] In some embodiments, for example, in a GDF15 antibody agent, an LC polypeptide having LC CDR1, LC CDR2, and LC CDR3 can bind (eg, specifically bind) to GDF15.

[0178] In some embodiments, the LC polypeptide further comprises one or more framework regions and / or constant regions.

[0179] In some embodiments, the LC polypeptide comprises a light chain constant region and / or a heavy chain constant region, hi some embodiments, the LC polypeptide comprises a light chain constant region or a portion thereof (e.g., a lambda light chain constant region or a variant or portion thereof, or a kappa light chain constant region or a variant or portion thereof).

[0180] In some embodiments, the light chain kappa constant region comprises the sequence of SEQ ID NO: 175, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 175.

[0181] RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 175)

[0182] In some embodiments, the LC polypeptide comprises the sequence of SEQ ID NO: 175, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 175.

[0183] In some embodiments, the LC polypeptide disclosed herein further comprises a half-life extender. In some embodiments, the half-life extender is or comprises albumin, such as human serum albumin. In some embodiments, the half-life extender comprises a modification that increases binding to neonatal Fc receptor (FcRn).

[0184] In some embodiments, the LC polypeptide comprises (i) an LC CDR1 sequence provided in Table 1, e.g., any one of SEQ ID NOs: 92, 101, 117, 125, 129, 137, 212; (ii) a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity to an LC CDR1 sequence provided in Table 1, e.g., any one of SEQ ID NOs: 92, 101, 117, 125, 129, 137, 212; or (iii) a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) to an LC CDR1 sequence provided in Table 1, e.g., any one of SEQ ID NOs: 92, 101, 117, 125, 129, 137, 212.

[0185] In some embodiments, the LC polypeptide comprises (i) an LC CDR2 sequence provided in Table 1, e.g., any one of SEQ ID NOs: 93, 102, or 130; (ii) a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity to an LC CDR2 sequence provided in Table 1, e.g., any one of SEQ ID NOs: 93, 102, or 130; or (iii) a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) to an LC CDR2 sequence provided in Table 1, e.g., any one of SEQ ID NOs: 93, 102, or 130.

[0186] In some embodiments, the LC polypeptide is (i) a LC CDR3 sequence provided in Table 1, e.g., any one of SEQ ID NOs: 94, 103, 110, 118, 126, 131, 138, 204, 208, or 217; (ii) a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity to a LC CDR3 sequence provided in Table 1, e.g., any one of SEQ ID NOs: 94, 103, 110, 118, 126, 131, 138, 204, 208, or 217; or (iii) a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity to a LC CDR3 sequence provided in Table 1, e.g., any one of SEQ ID NOs: 94, 103, 110, 118, 126, 131, 138, 204, 208, or 217. CDR3 sequences, such as sequences having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) relative to any one of SEQ ID NOs: 94, 103, 110, 118, 126, 131, 138, 204, 208, or 217.

[0187] In some embodiments, the LC polypeptide comprises (i) the LC CDR1, LC CDR2, and LC CDR3 sequences provided in Table 1, (ii) a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity to the LC CDR1, LC CDR2, and LC CDR3 sequences provided in Table 1, or (iii) a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) relative to the LC CDR1, LC CDR2, and LC CDR3 sequences provided in Table 1.

[0188] In some embodiments, the LC polypeptide comprises (i) the LC CDR1 of SEQ ID NO: 92, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity thereto, or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 92; (ii) the LC CDR1 of SEQ ID NO: 93; and / or (iii) the LC CDR3 of SEQ ID NO: 94 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity thereto, or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 94.

[0189] In some embodiments, the LC polypeptide comprises (i) the LC CDR1 of SEQ ID NO: 101, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity thereto, or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 101; (ii) the LC CDR1 of SEQ ID NO: 102; and / or (iii) the LC CDR2 of SEQ ID NO: 103 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity thereto, or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 103.

[0190] In some embodiments, the LC polypeptide comprises (i) the LC CDR1 of SEQ ID NO: 92, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity thereto, or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 92; (ii) the LC CDR1 of SEQ ID NO: 93; and / or (iii) the LC CDR3 of SEQ ID NO: 110, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity thereto, or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 110.

[0191] In some embodiments, the LC polypeptide comprises (i) the LC CDR1 of SEQ ID NO: 117, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity thereto, or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 117; (ii) the LC CDR1 of SEQ ID NO: 93; and / or (iii) the LC CDR3 of SEQ ID NO: 118 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity thereto, or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 118.

[0192] In some embodiments, the LC polypeptide comprises (i) the LC CDR1 of SEQ ID NO: 125, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity thereto, or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 125; (ii) the LC CDR1 of SEQ ID NO: 102; and / or (iii) the LC CDR3 of SEQ ID NO: 126 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity thereto, or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 102; and / or (iv) the LC CDR3 of SEQ ID NO: 126 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity thereto, or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 126.

[0193] In some embodiments, the LC polypeptide comprises (i) the LC CDR1 of SEQ ID NO: 129, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity thereto, or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 129; (ii) the LC CDR1 of SEQ ID NO: 130; and / or (iii) the LC CDR2 of SEQ ID NO: 131 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity thereto, or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 131.

[0194] In some embodiments, the LC polypeptide comprises (i) the LC CDR1 of SEQ ID NO: 137, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity thereto, or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 137; (ii) the LC CDR1 of SEQ ID NO: 102; and / or (iii) the LC CDR2 of SEQ ID NO: 138 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity thereto, or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 102; and / or (iv) the LC CDR3 of SEQ ID NO: 138 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity thereto, or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 138.

[0195] In some embodiments, the LC polypeptide comprises (i) an LC CDR1 of SEQ ID NO: 92, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 92; (ii) an LC CDR2 of SEQ ID NO: 93, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 93; and / or (iii) an LC CDR3 of SEQ ID NO: 204. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 204.

[0196] In some embodiments, the LC polypeptide comprises (i) an LC CDR1 of SEQ ID NO: 92, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 92; (ii) an LC CDR2 of SEQ ID NO: 93, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 93; and / or (iii) an LC CDR3 of SEQ ID NO: 208. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 208.

[0197] In some embodiments, the LC polypeptide comprises (i) the LC CDR1 of SEQ ID NO: 212, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 212; (ii) the LC CDR2 of SEQ ID NO: 102, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 102; and / or (iii) the LC CDR3 of SEQ ID NO: 103. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 103.

[0198] In some embodiments, the LC polypeptide comprises (i) the LC CDR1 of SEQ ID NO: 101, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 101; (ii) the LC CDR2 of SEQ ID NO: 102, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 102; and / or (iii) the LC CDR3 of SEQ ID NO: 217. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 217.

[0199] In some embodiments, the LC polypeptide further comprises one or more framework regions (FRs), e.g., as described herein. In some embodiments, the LC polypeptide comprises one, two, three, or four FRs, e.g., as described herein. In some embodiments, the FRs comprise LC FRs derived from a human mature antibody, a human germline sequence, a non-human framework (e.g., a rodent framework); or a non-human framework that has been modified, e.g., immunodepleted or partially humanized, e.g., to remove antigenic or cytotoxic determinants, or a sequence having at least 85% sequence identity to the LC FR sequences described herein, or a sequence having at least 5, 10, or 20 changes to the LC FR sequences described herein.

[0200] In some embodiments, the LC polypeptide comprises (i) a FR sequence provided in Table 1, (ii) a sequence having at least 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a FR sequence provided in Table 1, or (iii) a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) compared to a FR sequence provided in Table 1.

[0201] In some embodiments, the LC polypeptide comprises an LC FR1 provided in Table 1; a sequence having at least 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to an LC FR1 sequence provided in Table 1; or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) compared to an LC FR1 sequence provided in Table 1.

[0202] In some embodiments, the LC polypeptide comprises an LC FR2 provided in Table 1; a sequence having at least 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to an LC FR2 sequence provided in Table 1; or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) compared to an LC FR2 sequence provided in Table 1.

[0203] In some embodiments, the LC polypeptide comprises an LC FR3 provided in Table 1; a sequence having at least 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to an LC FR3 sequence provided in Table 1; or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) compared to an LC FR3 sequence provided in Table 1.

[0204] In some embodiments, the LC polypeptide comprises an LC FR4 provided in Table 1; a sequence having at least 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to an LC FR4 sequence provided in Table 1; or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) compared to an LC FR4 sequence provided in Table 1.

[0205] In some embodiments, the LC polypeptide comprises LC CDR1, LC CDR2, and LC CDR3 provided in Table 1, or a sequence having at least 85% identity thereto, and LC FR1, LC FR2, LC FR3, and LC FR4 provided in Table 1, or a sequence having at least 92% identity thereto.

[0206] In some embodiments, the LC polypeptide comprises the sequence of SEQ ID NO: 99, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity thereto, or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) relative to sequence 99.

[0207] In some embodiments, the LC polypeptide comprises the sequence of SEQ ID NO: 107, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity thereto, or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) relative to sequence 107.

[0208] In some embodiments, the LC polypeptide comprises the sequence of SEQ ID NO: 115, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity thereto, or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) relative to sequence 115.

[0209] In some embodiments, the LC polypeptide comprises the sequence of SEQ ID NO: 123, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity thereto, or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) relative to sequence 123.

[0210] In some embodiments, the LC polypeptide comprises the sequence of SEQ ID NO: 127, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity thereto, or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) relative to sequence 127.

[0211] In some embodiments, the LC polypeptide comprises the sequence of SEQ ID NO: 135, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity thereto, or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) relative to sequence 135.

[0212] In some embodiments, the LC polypeptide comprises the sequence of SEQ ID NO: 139, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity thereto, or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) relative to sequence 139.

[0213] In some embodiments, the LC polypeptide comprises the sequence of SEQ ID NO:205, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:205.

[0214] In some embodiments, the LC polypeptide comprises the sequence of SEQ ID NO:209, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:209.

[0215] In some embodiments, the LC polypeptide comprises the sequence of SEQ ID NO:214, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:214.

[0216] In some embodiments, the LC polypeptide comprises the sequence of SEQ ID NO:218, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:218.

[0217] In some embodiments, the LC polypeptide comprises an LC sequence provided in Table 1, e.g., any one of SEQ ID NOs: 159, 163, 164, 166, 169, 171, 173, or 206, 210, 215, or 219; or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity thereto; or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) relative to any one of SEQ ID NOs: 159, 163, 164, 166, 169, 171, 173, or 206, 210, 215, or 219.

[0218] Exemplary useful LC polypeptides that can be included in the GDF15 antibody agents disclosed herein are disclosed in Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18] [Table 1-19]

[0219] Heavy chain (e.g., heavy chain variable region) polypeptide (HC polypeptide) The present disclosure provides polypeptides comprising heavy chain (HC) sequences (e.g., heavy chain variable region sequence(s)) that may be useful, for example, in the antibody agents described herein that target GDF15. In some such embodiments, such provided polypeptides are useful and / or included in such antibody agents described herein. In some embodiments, the HC polypeptide comprises at least one HC CDR of a GDF15 antibody agent provided in Table 2 or a sequence having at least 85% identity thereto. In some embodiments, the HC polypeptide comprises one, two, or three HC CDRs (e.g., HC CDR1, HC CDR2, and / or HC CDR3). In some embodiments, the HC polypeptide comprises HC CDR1. In some embodiments, the HC polypeptide comprises HC CDR2. In some embodiments, the HC polypeptide comprises HC CDR3. In some embodiments, the HC polypeptide comprises HC CDR1, HC CDR2, and HC CDR3.

[0220] In some embodiments, a HC polypeptide comprising HC CDR1, HC CDR2, and HC CDR3 can bind (eg, specifically bind) to GDF15.

[0221] In some embodiments, the HC polypeptide further comprises one or more framework regions, and / or a heavy chain constant region, or portion or variant thereof (e.g., CH1, CH2, and / or CH3 regions). In some embodiments, the HC polypeptide comprises a CH1, CH2, or CH3, or a combination thereof. In some embodiments, the HC polypeptide comprises a CH2 and a CH3, e.g., an Fc domain.

[0222] In some embodiments, the Fc domain comprises a mammalian Fc domain. In some embodiments, the Fc domain comprises a dog, cat, mouse, rat, rabbit, primate, or human Fc domain. In some embodiments, the Fc domain comprises a human Fc domain. In some embodiments, the Fc domain comprises a dog Fc domain. In some embodiments, the Fc domain comprises a feline Fc domain. In some embodiments, the Fc domain is selected from Fc domains of immunoglobulin isotypes. In some embodiments, the immunoglobulin isotypes include IgA, IgD, IgG, IgM, or IgE. In some embodiments, the Fc domain comprises the Fc domain of an IgG, e.g., a human IgG. In some embodiments, the IgG is or comprises an IgG1, IgG2, IgG3, or IgG4.

[0223] In some embodiments, the Fc region is a wild-type Fc region, e.g., a wild-type human Fc region. In some embodiments, the Fc region comprises a variant, e.g., an Fc region, comprising an addition, substitution, or deletion of at least one amino acid residue within the Fc region, which, e.g., results in reduced or ablated affinity for at least one Fc receptor.

[0224] The Fc region of an antibody interacts with a number of receptors or ligands, including Fc receptors (e.g., FcyRI, FcyRIIA, FcyRIIIA), complement protein Clq, and other molecules such as proteins A and G. These interactions are essential for a variety of effector functions and downstream signaling events, including antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC).

[0225] In some embodiments, the HC polypeptide comprising the variant Fc region has one or more of the following properties: (1) reduced effector function (e.g., reduced ADCC, ADCP, and / or CDC), (2) reduced binding to one or more Fc receptors, and / or (3) reduced binding to Clq complement. In some embodiments, the reduction in any one or all of properties (1)-(3) is compared to an otherwise similar antibody having a wild-type Fc region. In some embodiments, the GDF15 antibody agent comprising the variant Fc region has reduced affinity for human Fc receptors, e.g., FcγRI, FcγRII, and / or FcγRIII. Exemplary Fc region variants are disclosed in Saunders KO, (2019) Frontiers in Immunology; vol. 10, Article 296, the entire contents of which are incorporated herein by reference. For example, the Fc region variant is or includes the modifications provided in Table 3 of Saunders KO (2019). In some embodiments, the Fc region variant comprises a Leu234Ala / Leu235Ala (LALA) mutation, a Leu235Glu (LE) mutation, a Ser228Pro / Leu235Glu (SPLE) mutation, a Leu234Ala / Leu235Ala / Pro239Gly (LALA-PG) mutation, a Pro331Ser / Leu234Glu / Leu235Phe (TM) mutation, an Asp265Ala (DA) mutation, a Leu235Ala / Gly237Ala (LAGA) mutation, or a combination thereof.

[0226] In some embodiments, the HC polypeptides disclosed herein comprise a Leu234Ala / Leu235Ala (LALA) mutation.

[0227] In some embodiments, the HC polypeptides disclosed herein comprise Leu235Ala / Gly237Ala (LAGA) mutations.

[0228] In some embodiments, the Fc region variant comprises mutations to a wild-type Fc region, e.g., an IgG1 FcR wild-type region. In some embodiments, the hinge and CH2 sequence of the IgG1 FcR wild-type region comprises the following sequence: CPPCPAPELLGGPSVFLFPPK (SEQ ID NO: 176).

[0229] In some embodiments, the Fc region variant is, for example, SEQ ID NO: 177: [ka] In some embodiments, the HC polypeptide comprises an Fc region with a LAGA mutation, for example, as provided in SEQ ID NO: 177.

[0230] In some embodiments, the Fc region variant is, for example, SEQ ID NO: 178: [ka] In some embodiments, the HC polypeptide comprises an Fc region with a FEGG mutation, for example, as provided in SEQ ID NO: 178.

[0231] In some embodiments, the Fc region variant is, for example, SEQ ID NO: 179: [ka] In some embodiments, the HC polypeptide comprises an Fc region with an AAGG mutation, for example, as provided in SEQ ID NO: 179.

[0232] In some embodiments, the Fc region variant is, for example, SEQ ID NO: 180: [ka] In some embodiments, the HC polypeptide comprises an Fc region with an AAGA mutation, for example, as provided in SEQ ID NO: 180.

[0233] In some embodiments, Fc region variants comprising Fc mutations (e.g., as described herein) have reduced (e.g., no) binding to the neonatal Fc receptor (FcRn), e.g., when compared to an otherwise similar Fc region without the relevant Fc mutations. In some embodiments, GDF15 antibody agents comprising an Fc region with Fc mutations (e.g., as described herein) have reduced (e.g., no) binding to FcRn and reduced placental transfer, compared to an otherwise similar GDF15 antibody agent having an Fc region without the relevant Fc mutations.

[0234]

[0235] In some embodiments, Fc region variants comprising a LAGA mutation, a FEGG mutation, an AAGG mutation, an AAGA mutation, a LALA mutation, or a combination thereof, exhibit reduced binding (e.g., no binding) to the neonatal Fc receptor (FcRn), e.g., compared to an otherwise similar Fc region without the relevant mutation (e.g., a LAGA mutation, a FEGG mutation, an AAGG mutation, an AAGA mutation, a LALA mutation, or a combination thereof). In some embodiments, a GDF15 antibody agent comprising an Fc region with a LAGA mutation, a FEGG mutation, an AAGG mutation, an AAGA mutation, a LALA mutation, or a combination thereof exhibits reduced binding (e.g., no binding) to FcRn and reduced placental transfer, compared to an otherwise similar GDF15 antibody agent having an Fc region without the relevant mutation (e.g., a LAGA mutation, a FEGG mutation, an AAGG mutation, an AAGA mutation, a LALA mutation, or a combination thereof). In some embodiments, Fc region variants comprising an I253A mutation, an H310A mutation, an H435R mutation, an H435A mutation, or a combination thereof, exhibit reduced (e.g., no) binding to the neonatal Fc receptor (FcRn), e.g., compared to an otherwise similar Fc region without the relevant mutation (e.g., the relevant I253A mutation, an H310A mutation, an H435R mutation, an H435A mutation, or a combination thereof). In some embodiments, GDF15 antibody agents comprising an Fc region with an I253A mutation, an H310A mutation, an H435R mutation, an H435A mutation, or a combination thereof exhibit reduced (e.g., no) binding to FcRn and reduced placental transfer, compared to an otherwise similar GDF15 antibody agent having an Fc region without the relevant mutation (e.g., the relevant I253A mutation, an H310A mutation, an H435R mutation, an H435A mutation, or a combination thereof).

[0236] In some embodiments, the HC polypeptide disclosed herein further comprises a half-life extender.In some embodiments, the half-life extender is or comprises albumin, such as human serum albumin.In some embodiments, the half-life extender comprises a modification that increases binding to neonatal Fc receptor (FcRn).

[0237] In some embodiments, the HC polypeptide comprises a CH3 domain or a variant thereof. In some embodiments, the CH3 variant is characterized in that, when introduced into the HC polypeptide, the half-life of the HC polypeptide is extended without reducing one or more other desirable characteristics, such as neutralizing potency, effector function, and / or generability. In some embodiments, the HC polypeptide having a CH3 variant has an extended half-life compared to other similar HC polypeptides without the associated CH3 variant.

[0238] In some embodiments, a CH3 variant has at least one amino acid residue addition, substitution, or deletion compared to a reference CH3 domain, eg, a wild-type CH3 domain.

[0239] In some embodiments, a CH3 variant has an amino acid residue at position 428 that differs from a reference CH3 domain, e.g., a wild-type CH3 domain. In some embodiments, a CH3 variant has an amino acid residue at position 434 that differs from a reference CH3 domain, e.g., a wild-type CH3 domain. In some embodiments, a CH3 variant has amino acid residues at positions 428 and 434 that differ from a reference CH3 domain, e.g., a wild-type CH3 domain.

[0240] In some embodiments, the CH3 variant has a leucine at position 428.

[0241] In some embodiments, the CH3 variant has an alanine at position 434.

[0242] In some embodiments, the CH3 variant has a leucine at position 428 and an alanine at position 434.

[0243] In some embodiments, an HC polypeptide comprising a CH3 variant is characterized in that, when administered to a subject, increased antibody-dependent cellular cytotoxicity (ADCC) and / or antibody-dependent cellular phagocytosis (ADCP) is observed compared to that observed when an HC polypeptide without the associated CH3 variant is administered to a comparable subject. In some embodiments, the increased ADCC is characterized by one or more of increased surface expression of CD107α on natural killer (NK) cells, increased interferon-γ (IFNγ) production by NK cells, or increased tumor necrosis factor-α (TNFα) production by NK cells. In some embodiments, the increased ADCP is characterized by one or more of co-localization of target cells and macrophages using microscopy or flow cytometry, and inclusion of a pH-sensitive dye to distinguish between cell-associated and internalized target cells.

[0244] In some embodiments, a HC polypeptide comprising a CH3 variant has improved generativity compared to a HC polypeptide that does not contain the related CH3 variant. In some embodiments, improving the generativity of a HC polypeptide comprising a CH3 variant comprises increasing expression, increasing solubility, increasing covalent bond integrity, increasing conformational stability, increasing colloidal stability, decreasing polyspecificity, and / or decreasing immunogenicity of a HC polypeptide comprising a CH3 variant compared to a HC polypeptide that does not contain the related CH3 variant.

[0245] In some embodiments, disclosed herein are preparations of antibody agents comprising a human constant region comprising a variant CH3 domain, wherein the antibody agent is characterized by a neutralizing potency and / or effector function of the antibody agent that is comparable to that of an antibody agent comprising a parent CH3 domain, and / or wherein the antibody agent is characterized by an increased developability of the antibody agent compared to that of an antibody agent comprising a reference (e.g., parent) CH3 domain, wherein the variant CH3 domain differs from the parent CH3 domain at positions 428 and 434, wherein the variant CH3 domain comprises a leucine at position 428 and an alanine at position 434. In some embodiments, the developability of the antibody agent comprises high-level expression, high solubility, covalent integrity, conformational stability, colloidal stability, reduced polyspecificity, and / or reduced immunogenicity.

[0246] According to IMGT, the CH3 domain is amino acid positions (or simply referred to herein as "positions") 341-446 (EU numbering). The term "CH3 domain" is used broadly herein to refer to a heavy chain region comprising at least seven consecutive amino acid positions from heavy chain positions 341-446 (EU numbering). A CH3 domain reference sequence corresponding to amino acid positions 341-446 according to EU numbering is provided herein as SEQ ID NO: 221, which is an exemplary amino acid sequence of a wild-type (WT) CH3 domain.

[0247] Exemplary CH3 domain reference sequences:

[0248] GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 221).

[0249] In some embodiments, the HC polypeptide is (i) a HC CDR1 sequence provided in Table 2, e.g., SEQ ID NO:1, SEQ ID NO:10, SEQ ID NO:14, SEQ ID NO:18, SEQ ID NO:22, SEQ ID NO:31, SEQ ID NO:40, SEQ ID NO:49, SEQ ID NO:56, SEQ ID NO:63, SEQ ID NO:68, SEQ ID NO:73, SEQ ID NO:78, SEQ ID NO:82, or SEQ ID NO:88; (ii) a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity to a HC CDR1 sequence provided in Table 2, e.g., SEQ ID NO:1, SEQ ID NO:10, SEQ ID NO:14, SEQ ID NO:18, SEQ ID NO:22, SEQ ID NO:31, SEQ ID NO:40, SEQ ID NO:49, SEQ ID NO:56, SEQ ID NO:63, SEQ ID NO:68, SEQ ID NO:73, SEQ ID NO:78, SEQ ID NO:82, or SEQ ID NO:88; or (iii) a HC CDR1 sequence provided in Table 2. CDR1 sequences include sequences having at least 5, 10, or 20 substitutions compared to, for example, SEQ ID NO:1, SEQ ID NO:10, SEQ ID NO:14, SEQ ID NO:18, SEQ ID NO:22, SEQ ID NO:31, SEQ ID NO:40, SEQ ID NO:49, SEQ ID NO:56, SEQ ID NO:63, SEQ ID NO:68, SEQ ID NO:73, SEQ ID NO:78, SEQ ID NO:82, or SEQ ID NO:88.

[0250] In some embodiments, the HC polypeptide is (i) a HC CDR2 sequence provided in Table 2, e.g., SEQ ID NO:2, SEQ ID NO:11, SEQ ID NO:15, SEQ ID NO:19, SEQ ID NO:23, SEQ ID NO:32, SEQ ID NO:50, SEQ ID NO:57, SEQ ID NO:60, SEQ ID NO:64, SEQ ID NO:69, SEQ ID NO:74, SEQ ID NO:79, SEQ ID NO:83, or SEQ ID NO:200; (ii) a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity to a HC CDR2 sequence provided in Table 2, e.g., SEQ ID NO:2, SEQ ID NO:11, SEQ ID NO:15, SEQ ID NO:19, SEQ ID NO:23, SEQ ID NO:32, SEQ ID NO:50, SEQ ID NO:57, SEQ ID NO:60, SEQ ID NO:64, SEQ ID NO:69, SEQ ID NO:74, SEQ ID NO:79, SEQ ID NO:83, or SEQ ID NO:200; or (iii) a HC CDR2 sequence provided in Table 2. CDR2 sequences include sequences having at least 5, 10, or 20 substitutions compared to, for example, SEQ ID NO:2, SEQ ID NO:11, SEQ ID NO:15, SEQ ID NO:19, SEQ ID NO:23, SEQ ID NO:32, SEQ ID NO:50, SEQ ID NO:57, SEQ ID NO:60, SEQ ID NO:64, SEQ ID NO:69, SEQ ID NO:74, SEQ ID NO:79, SEQ ID NO:83, or SEQ ID NO:200.

[0251] In some embodiments, the HC polypeptide is selected from the group consisting of (i) a HC CDR3 sequence provided in Table 2, e.g., SEQ ID NO:3, SEQ ID NO:191, SEQ ID NO:192, SEQ ID NO:193, SEQ ID NO:24, SEQ ID NO:33, SEQ ID NO:42, SEQ ID NO:51, SEQ ID NO:65, SEQ ID NO:70, SEQ ID NO:75, SEQ ID NO:84, SEQ ID NO:89, (ii) a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity to a HC CDR3 sequence provided in Table 2, e.g., SEQ ID NO:3, SEQ ID NO:191, SEQ ID NO:192, SEQ ID NO:193, SEQ ID NO:24, SEQ ID NO:33, SEQ ID NO:42, SEQ ID NO:51, SEQ ID NO:65, SEQ ID NO:70, SEQ ID NO:75, SEQ ID NO:84, SEQ ID NO:89, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity to a HC CDR3 sequence provided in Table 2, e.g., SEQ ID NO:3, SEQ ID NO:191, SEQ ID NO:192, SEQ ID NO:193, SEQ ID NO:24, SEQ ID NO:33, SEQ ID NO:42, SEQ ID NO:51, SEQ ID NO:65, SEQ ID NO:70, SEQ ID NO:75 CDR3 sequences, such as sequences having at least 5, 10, or 20 substitutions compared to SEQ ID NO:3, SEQ ID NO:191, SEQ ID NO:192, SEQ ID NO:193, SEQ ID NO:24, SEQ ID NO:33, SEQ ID NO:42, SEQ ID NO:51, SEQ ID NO:65, SEQ ID NO:70, SEQ ID NO:75, SEQ ID NO:84, SEQ ID NO:89.

[0252] In some embodiments, the HC polypeptide comprises (i) the HC CDR1, HC CDR2, and HC CDR3 sequences provided in Table 1, (ii) a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the HC CDR1, HC CDR2, and HC CDR3 sequences provided in Table 1, or (iii) a sequence having at least 5, 10, or 20 substitutions relative to the HC CDR1, HC CDR2, and HC CDR3 sequences provided in Table 1.

[0253] In some embodiments, the HC polypeptide comprises (i) the HC CDR1 of SEQ ID NO: 1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 1; (ii) the HC CDR2 of SEQ ID NO: 2, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 2; and / or (iii) the HC CDR2 of SEQ ID NO: 3. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:3.

[0254] In some embodiments, the HC polypeptide comprises (i) the HC CDR1 of SEQ ID NO: 10, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 10; (ii) the HC CDR2 of SEQ ID NO: 11, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 11; and / or (iii) the HC CDR2 of SEQ ID NO: 191. CDR3 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 191.

[0255] In some embodiments, the HC polypeptide comprises (i) the HC CDR1 of SEQ ID NO: 14, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 14; (ii) the HC CDR2 of SEQ ID NO: 15, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 15; and / or (iii) the HC CDR1 of SEQ ID NO: 192. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 192.

[0256] In some embodiments, the HC polypeptide comprises (i) the HC CDR1 of SEQ ID NO: 18, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 18; (ii) the HC CDR2 of SEQ ID NO: 19, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 19; and / or (iii) the HC CDR1 of SEQ ID NO: 193. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 193.

[0257] In some embodiments, the HC polypeptide comprises (i) the HC CDR1 of SEQ ID NO: 22, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 22; (ii) the HC CDR2 of SEQ ID NO: 23, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 23; and / or (iii) the HC CDR1 of SEQ ID NO: 24. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:24.

[0258] In some embodiments, the HC polypeptide comprises (i) the HC CDR1 of SEQ ID NO: 31, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 31; (ii) the HC CDR2 of SEQ ID NO: 32, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 32; and / or (iii) the HC CDR1 of SEQ ID NO: 33. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 33.

[0259] In some embodiments, the HC polypeptide comprises (i) the HC CDR1 of SEQ ID NO: 40, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 40; (ii) the HC CDR2 of SEQ ID NO: 32, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 32; and / or (iii) the HC CDR1 of SEQ ID NO: 42. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:42.

[0260] In some embodiments, the HC polypeptide comprises (i) the HC CDR1 of SEQ ID NO: 49, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 49; (ii) the HC CDR2 of SEQ ID NO: 50, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 50; and / or (iii) the HC CDR1 of SEQ ID NO: 51. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:51.

[0261] In some embodiments, the HC polypeptide comprises (i) the HC CDR1 of SEQ ID NO: 56, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 56; (ii) the HC CDR2 of SEQ ID NO: 57, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 57; and / or (iii) the HC CDR1 of SEQ ID NO: 24. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:24.

[0262] In some embodiments, the HC polypeptide comprises (i) the HC CDR1 of SEQ ID NO: 22, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 22; (ii) the HC CDR2 of SEQ ID NO: 60, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 60; and / or (iii) the HC CDR1 of SEQ ID NO: 24. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:24.

[0263] In some embodiments, the HC polypeptide comprises (i) the HC CDR1 of SEQ ID NO: 63, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 63; (ii) the HC CDR2 of SEQ ID NO: 64, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 64; and / or (iii) the HC CDR1 of SEQ ID NO: 65. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 65.

[0264] In some embodiments, the HC polypeptide comprises (i) the HC CDR1 of SEQ ID NO: 68, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 68; (ii) the HC CDR2 of SEQ ID NO: 69, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 69; and / or (iii) the HC CDR1 of SEQ ID NO: 70. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 70.

[0265] In some embodiments, the HC polypeptide comprises (i) the HC CDR1 of SEQ ID NO: 73, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 73; (ii) the HC CDR2 of SEQ ID NO: 74, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 74; and / or (iii) the HC CDR1 of SEQ ID NO: 75. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 75.

[0266] In some embodiments, the HC polypeptide comprises (i) the HC CDR1 of SEQ ID NO: 78, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 78; (ii) the HC CDR2 of SEQ ID NO: 79, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 79; and / or (iii) the HC CDR1 of SEQ ID NO: 75. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 75.

[0267] In some embodiments, the HC polypeptide comprises (i) the HC CDR1 of SEQ ID NO: 82, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 82; (ii) the HC CDR2 of SEQ ID NO: 83, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 83; and / or (iii) the HC CDR1 of SEQ ID NO: 84. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 84.

[0268] In some embodiments, the HC polypeptide comprises (i) the HC CDR1 of SEQ ID NO: 88, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 88; (ii) the HC CDR2 of SEQ ID NO: 57, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 57; and / or (iii) the HC CDR1 of SEQ ID NO: 89. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:89.

[0269] In some embodiments, the HC polypeptide comprises (i) the HC CDR1 of SEQ ID NO: 10, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 10; (ii) the HC CDR2 of SEQ ID NO: 200, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 200; and / or (iii) the HC CDR2 of SEQ ID NO: 191. CDR3 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 191.

[0270] In some embodiments, the HC polypeptide further comprises one or more framework regions (FRs), e.g., as described herein. In some embodiments, such HC polypeptides comprise one, two, three, or four FRs, e.g., as described herein. In some embodiments, the FRs comprise HC FRs derived from a human mature antibody, a human germline sequence, a non-human framework (e.g., a rodent framework); or a non-human framework that has been modified, e.g., immunodepleted or partially humanized, e.g., to remove antigenic or cytotoxic determinants, or a sequence having at least 85% sequence identity to the HC FR sequences described herein, or a sequence having at least 5, 10, or 20 changes relative to the HC FR sequences described herein.

[0271] In some embodiments, the HC polypeptide comprises (i) a FR sequence provided in Table 2, (ii) a sequence having at least 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a FR sequence provided in Table 2, or (iii) a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) compared to a FR sequence provided in Table 2.

[0272] In some embodiments, the HC polypeptide comprises an HC FR1 provided in Table 2, a sequence having at least 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the HC FR1 sequence provided in Table 2, or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) compared to the HC FR1 sequence provided in Table 2.

[0273] In some embodiments, the HC polypeptide comprises an HC FR2 provided in Table 2, a sequence having at least 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to an HC FR2 sequence provided in Table 2, or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) compared to an HC FR2 sequence provided in Table 2.

[0274] In some embodiments, the HC polypeptide comprises an HC FR3 provided in Table 2, a sequence having at least 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to an HC FR3 sequence provided in Table 2, or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) compared to an HC FR3 sequence provided in Table 2.

[0275] In some embodiments, the HC polypeptide comprises an HC FR4 provided in Table 2, a sequence having at least 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to an HC FR4 sequence provided in Table 2, or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) compared to an HC FR4 sequence provided in Table 2.

[0276] In some embodiments, the HC polypeptide comprises HC CDR1, HC CDR2, and HC CDR3 provided in Table 2, or a sequence having at least 85% identity thereto, and HC FR1, HC FR2, HC FR3, and HC FR4 provided in Table 2, or a sequence having at least 92% identity thereto.

[0277] In some embodiments, the HC polypeptide comprises the sequence of SEQ ID NO:8, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:8.

[0278] In some embodiments, the HC polypeptide comprises the sequence of SEQ ID NO:12, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:12.

[0279] In some embodiments, the HC polypeptide comprises the sequence of SEQ ID NO:16, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:16.

[0280] In some embodiments, the HC polypeptide comprises the sequence of SEQ ID NO:20, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:20.

[0281] In some embodiments, the HC polypeptide comprises the sequence of SEQ ID NO:29, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:29.

[0282] In some embodiments, the HC polypeptide comprises the sequence of SEQ ID NO:38, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:38.

[0283] In some embodiments, the HC polypeptide comprises the sequence of SEQ ID NO:47, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:47.

[0284] In some embodiments, the HC polypeptide comprises the sequence of SEQ ID NO:54, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:54.

[0285] In some embodiments, the HC polypeptide comprises the sequence of SEQ ID NO:58, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:58.

[0286] In some embodiments, the HC polypeptide comprises the sequence of SEQ ID NO:61, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:61.

[0287] In some embodiments, the HC polypeptide comprises the sequence of SEQ ID NO:66, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:66.

[0288] In some embodiments, the HC polypeptide comprises the sequence of SEQ ID NO:71, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:71.

[0289] In some embodiments, the HC polypeptide comprises the sequence of SEQ ID NO:76, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:76.

[0290] In some embodiments, the HC polypeptide comprises the sequence of SEQ ID NO:80, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:80.

[0291] In some embodiments, the HC polypeptide comprises the sequence of SEQ ID NO:86, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:86.

[0292] In some embodiments, the HC polypeptide comprises the sequence of SEQ ID NO:90, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:90.

[0293] In some embodiments, the HC polypeptide comprises the sequence of SEQ ID NO:201, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:201.

[0294] In some embodiments, the HC polypeptide has a sequence identical to or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 1109%, 1110, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, 125%, 126%, 127%, 128%, 129%, 130%, 131%, 132%, 133%, 134%, 135%, 136%, 137%, 138%, 139%, 140%, 141%, 142%, 143%, 144%, 145%, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, or 202 thereof. Sequences having 4%, 95%, 96%, 97%, 98%, or 99% identity, or at least 5, 10, or 20 substitutions to any one of the HC amino acid sequences provided in Table 2, e.g., SEQ ID NOs: 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, or 202.

[0295] In some embodiments, the HC polypeptides disclosed herein comprise a terminal lysine, for example, as provided in Table 2. In some embodiments, the HC polypeptides disclosed herein do not comprise a terminal lysine.

[0296] In some embodiments, the HC polypeptide comprises the amino acid sequence of SEQ ID NO: 143, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 143.

[0297] In some embodiments, the HC polypeptide comprises the amino acids of SEQ ID NO: 143 without the terminal lysine, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 143 without the terminal lysine.

[0298] In some embodiments, the HC polypeptide comprises the amino acid sequence of SEQ ID NO: 144, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 144.

[0299] In some embodiments, the HC polypeptide comprises the amino acids of SEQ ID NO: 144 without the terminal lysine, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 144 without the terminal lysine.

[0300] In some embodiments, the HC polypeptide comprises the amino acid sequence of SEQ ID NO: 145, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 145.

[0301] In some embodiments, the HC polypeptide comprises the amino acids of SEQ ID NO: 145 without the terminal lysine, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 145 without the terminal lysine.

[0302] In some embodiments, the HC polypeptide comprises the amino acid sequence of SEQ ID NO: 146, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 146.

[0303] In some embodiments, the HC polypeptide comprises the amino acids of SEQ ID NO: 146 without the terminal lysine, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 146 without the terminal lysine.

[0304] In some embodiments, the HC polypeptide comprises the amino acid sequence of SEQ ID NO: 147, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 147.

[0305] In some embodiments, the HC polypeptide comprises the amino acids of SEQ ID NO: 147 without the terminal lysine, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 147 without the terminal lysine.

[0306] In some embodiments, the HC polypeptide comprises the amino acid sequence of SEQ ID NO: 148, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 148.

[0307] In some embodiments, the HC polypeptide comprises the amino acids of SEQ ID NO: 148 without the terminal lysine, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 148 without the terminal lysine.

[0308] In some embodiments, the HC polypeptide comprises the amino acid sequence of SEQ ID NO: 149, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 149.

[0309] In some embodiments, the HC polypeptide comprises the amino acids of SEQ ID NO: 149 without the terminal lysine, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 149 without the terminal lysine.

[0310] In some embodiments, the HC polypeptide comprises the amino acid sequence of SEQ ID NO: 150, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 150.

[0311] In some embodiments, the HC polypeptide comprises the amino acids of SEQ ID NO: 150 without the terminal lysine, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 150 without the terminal lysine.

[0312] In some embodiments, the HC polypeptide comprises the amino acid sequence of SEQ ID NO: 151, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 151.

[0313] In some embodiments, the HC polypeptide comprises the amino acids of SEQ ID NO: 151 without the terminal lysine, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 151 without the terminal lysine.

[0314] In some embodiments, the HC polypeptide comprises the amino acid sequence of SEQ ID NO: 152, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 152.

[0315] In some embodiments, the HC polypeptide comprises the amino acids of SEQ ID NO: 152 without the terminal lysine, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 152 without the terminal lysine.

[0316] In some embodiments, the HC polypeptide comprises the amino acid sequence of SEQ ID NO: 153, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 153.

[0317] In some embodiments, the HC polypeptide comprises the amino acids of SEQ ID NO: 153 without the terminal lysine, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 153 without the terminal lysine.

[0318] In some embodiments, the HC polypeptide comprises the amino acid sequence of SEQ ID NO: 154, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 154.

[0319] In some embodiments, the HC polypeptide comprises the amino acids of SEQ ID NO: 154 without the terminal lysine, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 154 without the terminal lysine.

[0320] In some embodiments, the HC polypeptide comprises the amino acid sequence of SEQ ID NO: 155, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 155.

[0321] In some embodiments, the HC polypeptide comprises the amino acids of SEQ ID NO: 155 without the terminal lysine, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 155 without the terminal lysine.

[0322] In some embodiments, the HC polypeptide comprises the amino acid sequence of SEQ ID NO: 156, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 156.

[0323] In some embodiments, the HC polypeptide comprises the amino acids of SEQ ID NO: 156 without the terminal lysine, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 156 without the terminal lysine.

[0324] In some embodiments, the HC polypeptide comprises the amino acid sequence of SEQ ID NO: 157, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 157.

[0325] In some embodiments, the HC polypeptide comprises the amino acids of SEQ ID NO: 157 without the terminal lysine, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 157 without the terminal lysine.

[0326] In some embodiments, the HC polypeptide comprises the amino acid sequence of SEQ ID NO: 158, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 158.

[0327] In some embodiments, the HC polypeptide comprises the amino acids of SEQ ID NO: 158 without the terminal lysine, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 158 without the terminal lysine.

[0328] In some embodiments, the HC polypeptide comprises the amino acid sequence of SEQ ID NO:202, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:202.

[0329] In some embodiments, the HC polypeptide comprises the amino acids of SEQ ID NO: 202 without the terminal lysine, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 202 without the terminal lysine.

[0330] Exemplary useful HC polypeptides that can be included in the GDF15 antibody agents disclosed herein are disclosed in Table 2 below. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9]

Table 2-10

Table 2-11

Table 2-12

Table 2-13

Table 2-14

Table 2-15

Table 2-16

Table 2-17

Table 2-18

Table 2-19

Table 2-20

Table 2-21

Table 2-22

Table 2-23

Table 2-24

Table 2-25

[0331] GDF15 antibody preparation containing light chain polypeptide and heavy chain polypeptide In some embodiments, a GDF15 antibody agent disclosed herein, e.g., a GDF15 antibody agent polypeptide, comprises a light chain comprising a variable region comprising one, two, or three LC CDRs, and a heavy chain comprising a variable region comprising one, two, or three HC CDRs. In some embodiments, a GDF15 antibody agent comprises a light chain comprising an LC CDR1, an LC CDR2, and an LC CDR3, and a heavy chain comprising an HC CDR1, an HC CDR2, and an HC CDR3.

[0332] In some embodiments, a GDF15 antibody agent comprising LC CDR1, LC CDR2, and LC CDR3, and a heavy chain comprising HC CDR1, HC CDR2, and HC CDR3, can specifically bind to GDF15, e.g., human, cynomolgus monkey, or mouse GDF15.

[0333] In some embodiments, the GDF15 antibody agent comprises one, two, or three LC CDRs provided in Table 1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, and one, two, or three HC CDRs provided in Table 2, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto.

[0334] In some embodiments, the GDF15 antibody agent is selected from the group consisting of (a) (i) a LC CDR1 provided in Table 1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto, (ii) a LC CDR2 provided in Table 1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto, and / or (iii) a LC CDR3 provided in Table 1. a light chain comprising (i) an HC CDR1 provided in Table 2 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; and (b) (i) an HC CDR1 provided in Table 2 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; and / or (iii) a heavy chain comprising an HC CDR2 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to an HC CDR2 provided in Table 2; and / or (iv) an HC CDR3 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to an HC CDR3 provided in Table 2.

[0335] In some embodiments, the GDF15 antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 92, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 92; an LC CDR2 of SEQ ID NO: 93, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 93; and an LC CDR3 of SEQ ID NO: 94. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 94, and (ii) HC CDR1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 1; HC CDR2, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 1; CDR2 of SEQ ID NO: 2 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 2; and HC CDR3 of SEQ ID NO: 3 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 3.

[0336] In some embodiments, the GDF15 antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 92, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 92; an LC CDR2 of SEQ ID NO: 93, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 93; and an LC CDR3 of SEQ ID NO: 94. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 94, and (ii) the HC CDR1 of SEQ ID NO: 10, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 10; the HC CDR1 of SEQ ID NO: 11. CDR2 of SEQ ID NO: 11 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 11; and HC CDR3 of SEQ ID NO: 191 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 191.

[0337] In some embodiments, the GDF15 antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 92, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 92; an LC CDR2 of SEQ ID NO: 93, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 93; and an LC CDR3 of SEQ ID NO: 94. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 94, and (ii) HC CDR1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 14; ...2, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 14; CDR2 of SEQ ID NO: 15 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 15; and HC CDR3 of SEQ ID NO: 192 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 192.

[0338] In some embodiments, the GDF15 antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 92, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 92; an LC CDR2 of SEQ ID NO: 93, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 93; and an LC CDR3 of SEQ ID NO: 94. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 94, and (ii) the HC CDR1 of SEQ ID NO: 18, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 18; the HC CDR1 of SEQ ID NO: 19. CDR2 of SEQ ID NO: 19 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 19; and HC CDR3 of SEQ ID NO: 193 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 193.

[0339] In some embodiments, the GDF15 antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 101, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 101; an LC CDR2 of SEQ ID NO: 102, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 102; and an LC CDR3 of SEQ ID NO: 103. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 103, and (ii) HC CDR1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 22; HC CDR1 of SEQ ID NO: 23 CDR2 of SEQ ID NO:23 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:23; and HC CDR3 of SEQ ID NO:24 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:24.

[0340] In some embodiments, the GDF15 antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 92, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 92; an LC CDR2 of SEQ ID NO: 93, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 93; and an LC CDR3 of SEQ ID NO: 110. CDR3 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 110, and (ii) HC CDR1 of SEQ ID NO: 31 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 31; HC CDR1 of SEQ ID NO: 32 CDR2 of SEQ ID NO: 32 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 32; and HC CDR3 of SEQ ID NO: 33 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 33.

[0341] In some embodiments, the GDF15 antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 92, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 92; an LC CDR2 of SEQ ID NO: 93, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 93; and an LC CDR3 of SEQ ID NO: 110. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 110, and (ii) HC CDR1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 40; HC CDR1 of SEQ ID NO: 32 CDR2 of SEQ ID NO: 32 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 32; and HC CDR3 of SEQ ID NO: 42 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 42.

[0342] In some embodiments, the GDF15 antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 117, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 117; an LC CDR2 of SEQ ID NO: 93, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 93; and an LC CDR3 of SEQ ID NO: 118. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 118, and (ii) HC CDR1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 49; HC CDR1 of SEQ ID NO: 50 CDR2 of SEQ ID NO:50 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:50; and HC CDR3 of SEQ ID NO:51 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:51.

[0343] In some embodiments, the GDF15 antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 101, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 101; an LC CDR2 of SEQ ID NO: 102, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 102; and an LC CDR3 of SEQ ID NO: 103. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 103, and (ii) HC CDR1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 56; ...2, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 57; CDR2 of SEQ ID NO: 57 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 57; and HC CDR3 of SEQ ID NO: 24 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 24.

[0344] In some embodiments, the GDF15 antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 101, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 101; an LC CDR2 of SEQ ID NO: 102, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 102; and an LC CDR3 of SEQ ID NO: 103. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 103, and (ii) HC CDR1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 22; HC CDR1 of SEQ ID NO: 60 CDR2 of SEQ ID NO: 60 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 60; and HC CDR3 of SEQ ID NO: 24 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 24.

[0345] In some embodiments, the GDF15 antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 125, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 125; an LC CDR2 of SEQ ID NO: 102, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 102; and an LC CDR3 of SEQ ID NO: 126. CDR3 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 126, and (ii) HC CDR1 of SEQ ID NO: 63 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 63; HC CDR1 of SEQ ID NO: 64 CDR2 of SEQ ID NO: 64 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 64; and HC CDR3 of SEQ ID NO: 65 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 65.

[0346] In some embodiments, the GDF15 antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 125, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 125; an LC CDR2 of SEQ ID NO: 102, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 102; and an LC CDR3 of SEQ ID NO: 126. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 126, and (ii) HC CDR1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 68; ...2, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 69; CDR2 of SEQ ID NO: 69 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 69; and HC CDR3 of SEQ ID NO: 70 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 70.

[0347] In some embodiments, the GDF15 antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 129, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 129; an LC CDR2 of SEQ ID NO: 130, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 130; and an LC CDR3 of SEQ ID NO: 131. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 131, and (ii) HC CDR1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 73; HC CDR1 of SEQ ID NO: 74 CDR2 of SEQ ID NO: 74 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 74; and HC CDR3 of SEQ ID NO: 75 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 75.

[0348] In some embodiments, the GDF15 antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 129, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 129; an LC CDR2 of SEQ ID NO: 130, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 130; and an LC CDR3 of SEQ ID NO: 131. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 131, and (ii) HC CDR1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 78; HC CDR1 of SEQ ID NO: 79 CDR2 of SEQ ID NO: 75 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 79; and HC CDR3 of SEQ ID NO: 75 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 75.

[0349] In some embodiments, the GDF15 antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 137, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 137; an LC CDR2 of SEQ ID NO: 102, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 102; and an LC CDR3 of SEQ ID NO: 138. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 138, and (ii) HC CDR1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 82; HC CDR1 of SEQ ID NO: 83 CDR2 of SEQ ID NO: 84 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 83; and HC CDR3 of SEQ ID NO: 84 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 84.

[0350] In some embodiments, the GDF15 antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 137, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 137; an LC CDR2 of SEQ ID NO: 102, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 102; and an LC CDR3 of SEQ ID NO: 138. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 138, and (ii) the HC CDR1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 88; the HC CDR1 of SEQ ID NO: 57 CDR2 of SEQ ID NO: 57 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 57; and HC CDR3 of SEQ ID NO: 89 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 89.

[0351] In some embodiments, the GDF15 antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 92, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 92; an LC CDR2 of SEQ ID NO: 93, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 93; and an LC CDR3 of SEQ ID NO: 204. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 204, and (ii) HC CDR1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 10; HC CDR1 of SEQ ID NO: 11 CDR2 of SEQ ID NO: 11 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 11; and HC CDR3 of SEQ ID NO: 191 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 191.

[0352] In some embodiments, the GDF15 antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 92, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 92; an LC CDR2 of SEQ ID NO: 93, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 93; and an LC CDR3 of SEQ ID NO: 208. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 208, and (ii) the HC CDR1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 10; the HC CDR1 of SEQ ID NO: 200. CDR2 of SEQ ID NO: 191 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 200; and HC CDR3 of SEQ ID NO: 191 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 191.

[0353] In some embodiments, the GDF15 antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 212, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 212; an LC CDR2 of SEQ ID NO: 102, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 102; and an LC CDR3 of SEQ ID NO: 103. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 103, and (ii) HC CDR1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 22; HC CDR1 of SEQ ID NO: 23 CDR2 of SEQ ID NO:23 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:23; and HC CDR3 of SEQ ID NO:24 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:24.

[0354] In some embodiments, the GDF15 antibody agent comprises (i) an LC CDR1 of SEQ ID NO: 101, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 101; an LC CDR2 of SEQ ID NO: 102, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 102; and an LC CDR3 of SEQ ID NO: 217. CDR3, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 217, and (ii) HC CDR1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 22; ...2, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 22; CDR2 of SEQ ID NO:23 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:23; and HC CDR3 of SEQ ID NO:24 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:24.

[0355] In some embodiments, the GDF15 antibody agent comprises a light chain polypeptide (LC polypeptide) described herein.

[0356] In some embodiments, the GDF15 antibody agent comprises a heavy chain polypeptide (HC polypeptide) described herein. In some embodiments, the HC polypeptide in the GDF15 antibody agent does not comprise a terminal lysine.

[0357] In some embodiments, the GDF15 antibody agent comprises a light chain polypeptide (LC polypeptide) described herein and a heavy chain polypeptide (HC polypeptide) described herein. In some embodiments, the HC polypeptide in the GDF15 antibody agent does not comprise a terminal lysine.

[0358] In some embodiments, the GDF15 antibody agent comprises a light chain (VL) comprising a variable region comprising three LC CDRs and one or more framework regions (e.g., as described herein), and a heavy chain (VH) comprising a variable region comprising three HC CDRs and one or more framework regions (e.g., as described herein).

[0359] In some embodiments, the VL and / or VH of the GDF15 antibody agent further comprise one or more framework regions (FRs), e.g., as described herein. In some embodiments, the VL and / or VH of the GDF15 antibody agent comprise one, two, three, or four FRs, e.g., as described herein. In some embodiments, the FRs comprise FRs derived from a human mature antibody, a human germline sequence, a non-human framework (e.g., a rodent framework); or a non-human framework that has been modified, e.g., immunodepleted or partially humanized, e.g., to remove antigenic or cytotoxic determinants, or a sequence having at least 85% sequence identity to the LC FR sequences described herein, or a sequence having at least 5, 10, or 20 changes relative to the LC FR sequences described herein.

[0360] In some embodiments, the VL and / or VH of the GDF15 antibody agent comprises (i) a FR sequence provided in Table 1 or Table 2, (ii) a sequence having at least 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a FR sequence provided in Table 1 or 2, or (iii) a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) compared to a FR sequence provided in Table 1 or 2.

[0361] In some embodiments, the VL and / or VH of the GDF15 antibody agent comprises an FR1 provided in Table 1 or 2, a sequence having at least 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the FR1 sequence provided in Table 1 or 2, or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) compared to the FR1 sequence provided in Table 1 or 2.

[0362] In some embodiments, the VL and / or VH of the GDF15 antibody agent comprises a FR2 provided in Table 1 or 2, a sequence having at least 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the FR2 sequence provided in Table 1 or 2, or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) compared to the FR2 sequence provided in Table 1 or 2.

[0363] In some embodiments, the VL and / or VH of the GDF15 antibody agent comprises a FR3 provided in Table 1 or 2, a sequence having at least 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the FR3 sequence provided in Table 1 or 2, or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) compared to the FR3 sequence provided in Table 1 or 2.

[0364] In some embodiments, the VL and / or VH of the GDF15 antibody agent comprises a FR4 provided in Table 1 or 2, a sequence having at least 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the FR4 sequence provided in Table 1 or 2, or a sequence having at least 5, 10, or 20 changes (e.g., substitutions, deletions, or insertions (e.g., conservative substitutions)) compared to the FR4 sequence provided in Table 1 or 2.

[0365] In some embodiments, the GDF15 antibody agent comprises a VL comprising the three LC CDRs and LC FR1, LC FR2, LC FR3, and LC FR4 of a GDF15 antibody agent provided in Table 1, or a sequence with at least 92% identity thereto; and / or a VH comprising the three HC CDRs and HC FR1, HC FR2, HC FR3, and HC FR4 of a GDF15 antibody agent provided in Table 2, or a sequence with at least 92% identity thereto.

[0366] In some embodiments, the GDF15 antibody agent comprises a VL sequence provided in Table 1, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto, and a VH sequence provided in Table 2, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto.

[0367] In some embodiments, the GDF15 antibody agent comprises (i) the sequence of SEQ ID NO: 99, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 99; and the sequence of SEQ ID NO: 8, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 8.

[0368] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 99, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 99; and the sequence of SEQ ID NO: 12, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 12.

[0369] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 99, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 99; and the sequence of SEQ ID NO: 16, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 16.

[0370] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 99, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 99; and the sequence of SEQ ID NO: 20, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 20.

[0371] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 107, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; and the sequence of SEQ ID NO: 29, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto.

[0372] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 115, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; and the sequence of SEQ ID NO: 38, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto.

[0373] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 115, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 115; and the sequence of SEQ ID NO: 47, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 47.

[0374] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 123, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 123; and the sequence of SEQ ID NO: 54, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 54.

[0375] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 107, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; and the sequence of SEQ ID NO: 58, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto.

[0376] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 107, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; and the sequence of SEQ ID NO: 61, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto.

[0377] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 127, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; and the sequence of SEQ ID NO: 66, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto.

[0378] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 127, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 127; and the sequence of SEQ ID NO: 71, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 71.

[0379] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 135, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 135; and the sequence of SEQ ID NO: 76, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 76.

[0380] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 135, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 135; and the sequence of SEQ ID NO: 80, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 80.

[0381] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 139, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 139; and the sequence of SEQ ID NO: 86, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 86.

[0382] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 139, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 139; and the sequence of SEQ ID NO: 90, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 90.

[0383] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 205, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto; and the sequence of SEQ ID NO: 12, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto.

[0384] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 209, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 209; and the sequence of SEQ ID NO: 201, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 201.

[0385] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 214, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 214; and the sequence of SEQ ID NO: 29, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 29.

[0386] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 218, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 218; and the sequence of SEQ ID NO: 29, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 29.

[0387] In some embodiments, the GDF15 antibody agent comprises a light chain comprising three LC CDRs, one or more framework regions (e.g., as described herein), and a constant region, and a heavy chain comprising three HC CDRs, one or more framework regions (e.g., as described herein), and at least one constant region.

[0388] In some embodiments, the light chain constant region comprises a light chain kappa or a light chain lambda constant region.

[0389] In some embodiments, the light chain kappa constant region comprises the sequence of SEQ ID NO: 175, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 175.

[0390] RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 175)

[0391] In some embodiments, the heavy chain constant region comprises a CH1, CH2, and / or CH3. In some embodiments, at least one constant region comprises an Fc domain. In some embodiments, the Fc domain comprises a mammalian Fc domain. In some embodiments, the Fc domain comprises a dog, cat, mouse, rat, rabbit, primate, or human Fc domain. In some embodiments, the Fc domain is selected from the Fc domains of immunoglobulin isotypes. In some embodiments, the immunoglobulin isotypes include IgA, IgD, IgG, IgM, or IgE. In some embodiments, the Fc domain comprises the Fc domain of an IgG, e.g., a human IgG. In some embodiments, the IgG is or comprises an IgG1, IgG2, IgG3, or IgG4.

[0392] In some embodiments, the GDF15 antibody agent disclosed herein comprises an Fc region, e.g., as described herein. In some embodiments, the Fc region is a wild-type Fc region, e.g., a wild-type human Fc region. In some embodiments, the Fc region comprises a variant, e.g., an Fc region, comprising an addition, substitution, or deletion of at least one amino acid residue within the Fc region, which, e.g., results in reduced or ablated affinity for at least one Fc receptor.

[0393] The Fc region of an antibody interacts with a number of receptors or ligands, including Fc receptors (e.g., FcyRI, FcyRIIA, FcyRIIIA), complement protein Clq, and other molecules such as proteins A and G. These interactions are essential for a variety of effector functions and downstream signaling events, including antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC).

[0394] In some embodiments, a GDF15 antibody agent comprising a variant Fc region has one or more of the following properties: (1) reduced effector function (e.g., reduced ADCC, ADCP, and / or CDC), (2) reduced binding to one or more Fc receptors, and / or (3) reduced binding to Clq complement. In some embodiments, the reduction in any one or all of properties (1)-(3) is compared to an otherwise similar antibody having a wild-type Fc region. In some embodiments, a GDF15 antibody agent comprising a variant Fc region has reduced affinity for human Fc receptors, e.g., FcγRI, FcγRII, and / or FcγRIII. Exemplary Fc region variants are disclosed in Saunders KO, (2019) Frontiers in Immunology; vol. 10, Article 296, the entire contents of which are incorporated herein by reference. For example, the Fc region variant is or includes the modifications provided in Table 3 of Saunders KO (2019). In some embodiments, the Fc region variant comprises a Leu234Ala / Leu235Ala (LALA) mutation, a Leu235Glu (LE) mutation, a Ser228Pro / Leu235Glu (SPLE) mutation, a Leu234Ala / Leu235Ala / Pro239Gly (LALA-PG) mutation, a Pro331Ser / Leu234Glu / Leu235Phe (TM) mutation, an Asp265Ala (DA) mutation, a Leu235Ala / Gly237Ala (LAGA) mutation, or a combination thereof.

[0395] In some embodiments, a GDF15 antibody agent disclosed herein comprises a Leu234Ala / Leu235Ala (LALA) mutation.

[0396] In some embodiments, the GDF15 antibody agents disclosed herein comprise Leu235Ala / Gly237Ala (LAGA) mutations.

[0397] In some embodiments, the Fc region variant comprises mutations to a wild-type Fc region, e.g., an IgG1 FcR wild-type region. In some embodiments, the hinge and CH2 sequence of the IgG1 FcR wild-type region comprises the following sequence: CPPCPAPELLGGPSVFLFPPK (SEQ ID NO: 176).

[0398] In some embodiments, the Fc region variant is, for example, SEQ ID NO: 177: [ka] In some embodiments, the GDF15 antibody agent comprises an Fc region with a LAGA mutation, for example, as provided in SEQ ID NO: 177.

[0399] In some embodiments, the Fc region variant is, for example, SEQ ID NO: 178: [ka] In some embodiments, the GDF15 antibody agent comprises an Fc region with a FEGG mutation, for example, as provided in SEQ ID NO: 178.

[0400] In some embodiments, the Fc region variant is, for example, SEQ ID NO: 179: [ka] In some embodiments, a GDF15 antibody agent comprises an Fc region with an AAGG mutation, for example, as provided in SEQ ID NO: 179.

[0401] In some embodiments, the Fc region variant is, for example, SEQ ID NO: 180: [ka] In some embodiments, the AAGA mutation is also referred to as Leu234Ala / Leu235Ala / Glu237Ala (LALAGA). In some embodiments, the GDF15 antibody agent comprises an Fc region with an AAGA mutation, for example, as provided in SEQ ID NO: 180.

[0402] In some embodiments, the Fc region variants comprising Fc mutations have reduced (e.g., no) binding to the neonatal Fc receptor (FcRn), e.g., when compared to an otherwise similar Fc region without the Fc mutations. In some embodiments, a GDF15 antibody agent comprising an Fc region with Fc mutations has reduced (e.g., no) binding to FcRn and reduced placental transfer, compared to an otherwise similar GDF15 antibody agent having an Fc region without the Fc mutations.

[0403] In some embodiments, the Fc region variants comprising LAGA, FEGG, AAGG, AAGA, LALA mutations, or combinations thereof, have reduced binding (e.g., no binding) to the neonatal Fc receptor (FcRn) compared to, for example, an otherwise similar Fc region without the LAGA, FEGG, AAGG, AAGA, LALA mutations, or combinations thereof.

[0404] In some embodiments, a GDF15 antibody agent comprising an Fc region having a LAGA mutation, a FEGG mutation, an AAGG mutation, an AAGA mutation, a LALA mutation, or a combination thereof, has reduced binding to FcRn (e.g., no binding) and reduced placental transfer compared to an otherwise similar GDF15 antibody agent having an Fc region without a LAGA mutation, a FEGG mutation, an AAGG mutation, an AAGA mutation, a LALA mutation, or a combination thereof.

[0405] In some embodiments, the Fc region variant comprising the I253A mutation, the H310A mutation, the H435R mutation, the H435A mutation, or a combination thereof, exhibits reduced binding (e.g., no binding) to the neonatal Fc receptor (FcRn), e.g., compared to an otherwise similar Fc region without the I253A mutation, the H310A mutation, the H435R mutation, the H435A mutation, or a combination thereof.

[0406] In some embodiments, a GDF15 antibody agent comprising an Fc region having an I253A mutation, an H310A mutation, an H435R mutation, an H435A mutation, or a combination thereof, has reduced binding to FcRn (e.g., no binding) and reduced placental transfer compared to an otherwise similar GDF15 antibody agent having an Fc region without an I253A mutation, an H310A mutation, an H435R mutation, an H435A mutation, or a combination thereof.

[0407] In some embodiments, the GDF15 antibody agent comprises an IgG1 Fc region comprising the sequence of SEQ ID NO: 181, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 181.

[0408] ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPEAAGA PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSREE MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPG (SEQ ID NO: 181)

[0409] In some embodiments, the GDF15 antibody agent comprises an IgG1 Fc region comprising the sequence of SEQ ID NO: 182, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 182.

[0410] ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPEAAGA PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSREE MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (SEQ ID NO: 182)

[0411] In some embodiments, the GDF15 antibody agent disclosed herein further comprises a half-life extender. In some embodiments, the half-life extender is or comprises albumin, such as human serum albumin. In some embodiments, the half-life extender comprises a modification that increases binding to neonatal Fc receptor (FcRn).

[0412] In some embodiments, the GDF15 antibody agents disclosed herein comprise an HC polypeptide comprising a CH3 domain or a variant thereof. In some embodiments, the CH3 variant, when introduced into the HC polypeptide, is characterized in that the half-life of the HC polypeptide is extended without reducing other desirable characteristics such as neutralizing potency, effector function, and / or generability. In some embodiments, the HC polypeptide having the CH3 variant has an extended half-life compared to an otherwise similar HC polypeptide without the CH3 variant.

[0413] In some embodiments, a CH3 variant has at least one amino acid residue addition, substitution, or deletion compared to a reference CH3 domain, eg, a wild-type CH3 domain.

[0414] In some embodiments, a CH3 variant has an amino acid residue at position 428 that differs from a reference CH3 domain, e.g., a wild-type CH3 domain. In some embodiments, a CH3 variant has an amino acid residue at position 434 that differs from a reference CH3 domain, e.g., a wild-type CH3 domain. In some embodiments, a CH3 variant has amino acid residues at positions 428 and 434 that differ from a reference CH3 domain, e.g., a wild-type CH3 domain.

[0415] In some embodiments, the CH3 variant has a leucine at position 428.

[0416] In some embodiments, the CH3 variant has an alanine at position 434.

[0417] In some embodiments, the CH3 variant has a leucine at position 428 and an alanine at position 434.

[0418] In some embodiments, the GDF15 antibody agent comprises a heavy chain (HC) provided in Table 2 (or a sequence having at least 85% identity thereto), and a light chain (HC) provided in Table 1 (or a sequence having at least 85% identity thereto).

[0419] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 143, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 143, and the sequence of SEQ ID NO: 159, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 159.

[0420] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 143 without the terminal lysine, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 143 without the terminal lysine, and the sequence of SEQ ID NO: 159, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 159.

[0421] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 144, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 144, and the sequence of SEQ ID NO: 159, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 159.

[0422] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 144 without the terminal lysine, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 144 without the terminal lysine, and the sequence of SEQ ID NO: 159, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 159.

[0423] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 145, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 145, and the sequence of SEQ ID NO: 159, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 159.

[0424] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 145 without the terminal lysine, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 145 without the terminal lysine, and the sequence of SEQ ID NO: 159, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 159.

[0425] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 146, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 146, and the sequence of SEQ ID NO: 159, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 159.

[0426] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 146 without the terminal lysine, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 146 without the terminal lysine, and the sequence of SEQ ID NO: 159, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 159.

[0427] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 147, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 147, and the sequence of SEQ ID NO: 163, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 163.

[0428] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 147 without the terminal lysine, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 147 without the terminal lysine, and the sequence of SEQ ID NO: 163, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 163.

[0429] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 148, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto, and the sequence of SEQ ID NO: 164, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto.

[0430] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 148 without the terminal lysine, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 148 without the terminal lysine, and the sequence of SEQ ID NO: 164, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 164.

[0431] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 149, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 149, and the sequence of SEQ ID NO: 164, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 164.

[0432] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 149 without the terminal lysine, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 149 without the terminal lysine, and the sequence of SEQ ID NO: 164, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 164.

[0433] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 150, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 150, and the sequence of SEQ ID NO: 166, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 166.

[0434] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 150 without the terminal lysine, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 150 without the terminal lysine, and the sequence of SEQ ID NO: 166, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 166.

[0435] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 151, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 151, and the sequence of SEQ ID NO: 163, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 163.

[0436] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 151 without the terminal lysine, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 151 without the terminal lysine, and the sequence of SEQ ID NO: 163, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 163.

[0437] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 152, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto, and the sequence of SEQ ID NO: 163, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions thereto.

[0438] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 152 without the terminal lysine, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 152 without the terminal lysine, and the sequence of SEQ ID NO: 163, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 163.

[0439] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 153, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 153, and the sequence of SEQ ID NO: 169, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 169.

[0440] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 153 without the terminal lysine, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 153 without the terminal lysine, and the sequence of SEQ ID NO: 169, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 169.

[0441] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 154, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 154, and the sequence of SEQ ID NO: 169, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 169.

[0442] In some embodiments, the GDF15 antibody agent comprises the sequence of SEQ ID NO: 154 without the terminal lysine, or a sequence havi...

Claims

1. An antibody agent comprising a polypeptide that binds to human growth differentiation factor 15 (GDF15), the antibody agent comprising a light chain comprising a light chain variable region (VL) comprising light chain complementarity determining region 1 (LC CDR1), LC CDR2, and LC CDR3 provided in Table 1, and a heavy chain comprising a heavy chain variable region (VH) comprising heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and HC CDR3 provided in Table 2.

2. The antibody agent is (i) intact IgA, IgG, IgD, IgE or IgM antibodies; (ii) antibody fragment, (iii) a single chain Fv, or (iv) The antibody agent of claim 1, which is or comprises a polypeptide comprising an antigen-binding domain specifically fused to an Fc domain.

3. The antibody agent described in claim 1, which is capable of specifically binding to GDF15.

4. (i) an LC CDR1 of SEQ ID NO: 92, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 92; an LC CDR2 of SEQ ID NO: 93, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 93; and an LC CDR3 of SEQ ID NO: 94, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:

94. (ii) an LC CDR1 of SEQ ID NO: 101, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 101; an LC CDR2 of SEQ ID NO: 102, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 102; and an LC CDR3 of SEQ ID NO: 103, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:

103. (iii) an LC CDR1 of SEQ ID NO: 92, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 92; an LC CDR2 of SEQ ID NO: 93, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 93; and an LC CDR3 of SEQ ID NO: 110, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:

110. (iv) an LC CDR1 of SEQ ID NO: 117, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 117; an LC CDR2 of SEQ ID NO: 93, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 93; and an LC CDR3 of SEQ ID NO: 118, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:

118. (v) an LC CDR1 of SEQ ID NO: 125, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 125; an LC CDR2 of SEQ ID NO: 102, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 102; and an LC CDR3 of SEQ ID NO: 126, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:

126. (vi) an LC CDR1 of SEQ ID NO: 129, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 129; an LC CDR2 of SEQ ID NO: 130, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 130; and an LC CDR3 of SEQ ID NO: 131, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:

131. (vii) an LC CDR1 of SEQ ID NO: 137, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 137; an LC CDR2 of SEQ ID NO: 102, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 102; and an LC CDR3 of SEQ ID NO: 138, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:

138. (viii) an LC CDR1 of SEQ ID NO: 92, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 92; an LC CDR2 of SEQ ID NO: 93, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 93; and an LC CDR3 of SEQ ID NO: 204, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:

204. (ix) an LC CDR1 of SEQ ID NO: 92, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 92; an LC CDR2 of SEQ ID NO: 93, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 93; and an LC CDR3 of SEQ ID NO: 208, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:

208. (x) an LC CDR1 of SEQ ID NO: 212, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 212; an LC CDR2 of SEQ ID NO: 102, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 102; and an LC CDR3 of SEQ ID NO: 103, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 103; or (xi) The antibody agent of claim 1, comprising: an LC CDR1 of SEQ ID NO: 101, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 101; an LC CDR2 of SEQ ID NO: 102, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 102; and an LC CDR3 of SEQ ID NO: 217, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:

217.

5. (i) HC CDR1 of SEQ ID NO: 1, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 1; HC CDR2 of SEQ ID NO: 2, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 2; and HC CDR3 of SEQ ID NO: 3, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:

3. (ii) an HC CDR1 of SEQ ID NO: 10, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 10; an HC CDR2 of SEQ ID NO: 11, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 11; and an HC CDR3 of SEQ ID NO: 191, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:

191. (iii) an HC CDR1 of SEQ ID NO: 14, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 14; an HC CDR2 of SEQ ID NO: 15, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 15; and an HC CDR3 of SEQ ID NO: 192, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:

192. (iv) HC CDR1 of SEQ ID NO: 18, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 18; HC CDR2 of SEQ ID NO: 19, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 19; and HC CDR3 of SEQ ID NO: 193, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:

193. (v) HC CDR1 of SEQ ID NO:22, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:22; HC CDR2 of SEQ ID NO:23, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:23; and HC CDR3 of SEQ ID NO:24, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:

24. (vi) HC CDR1 of SEQ ID NO: 31, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 31; HC CDR2 of SEQ ID NO: 32, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 32; and HC CDR3 of SEQ ID NO: 33, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:

33. (vii) HC CDR1 of SEQ ID NO: 40, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 40; HC CDR2 of SEQ ID NO: 32, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 32; and HC CDR3 of SEQ ID NO: 42, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:

42. (viii) HC CDR1 of SEQ ID NO: 49, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 49; HC CDR2 of SEQ ID NO: 50, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 50; and HC CDR3 of SEQ ID NO: 51, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:

51. (ix) a HC CDR1 of SEQ ID NO: 56, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 56; a HC CDR2 of SEQ ID NO: 57, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 57; and a HC CDR3 of SEQ ID NO: 24, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:

24. (x) an HC CDR1 of SEQ ID NO: 22, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 22; an HC CDR2 of SEQ ID NO: 60, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 60; and an HC CDR3 of SEQ ID NO: 24, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:

24. (xi) a HC CDR1 of SEQ ID NO: 63, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 63; a HC CDR2 of SEQ ID NO: 64, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 64; and a HC CDR3 of SEQ ID NO: 65, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:

65. (xii) HC CDR1 of SEQ ID NO: 68, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 68; HC CDR2 of SEQ ID NO: 69, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 69; and HC CDR3 of SEQ ID NO: 70, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:

70. (xiii) a HC CDR1 of SEQ ID NO: 73, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 73; a HC CDR2 of SEQ ID NO: 74, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 74; and a HC CDR3 of SEQ ID NO: 75, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:

75. (xiv) HC CDR1 of SEQ ID NO: 78, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 78; HC CDR2 of SEQ ID NO: 79, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 79; and HC CDR3 of SEQ ID NO: 75, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:

75. (xv) HC CDR1 of SEQ ID NO: 82, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 82; HC CDR2 of SEQ ID NO: 83, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 83; and HC CDR3 of SEQ ID NO: 84, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:

84. (xvi) a HC CDR1 of SEQ ID NO: 88, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 88; a HC CDR2 of SEQ ID NO: 57, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 57; and a HC CDR3 of SEQ ID NO: 89, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 89; or (xvii) HC CDR1 of SEQ ID NO: 10, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 10; HC CDR2 of SEQ ID NO: 200, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 200; and HC CDR3 of SEQ ID NO: 191, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:

191. The antibody agent of claim 1 , comprising:

6. The heavy chain further comprises the sequence of at least one constant region (CH), wherein the at least one constant region comprises: (a) an Fc domain selected from the Fc domains of immunoglobulin isotypes; (b) an Fc domain comprising a mutation disclosed herein, or (c) CH3 domain and optionally, the CH3 domain comprises a leucine at position 428 or an alanine at position 434.

7. 7. The antibody agent of claim 6, wherein the Fc domain comprises an IgG Fc domain, and the IgG constant region comprises one or more modifications that modulate one or more properties of the antibody agent, and the one or more modifications comprise a LAGA mutation, a FEGG mutation, an AAGG mutation, an AAGA mutation, a LALA mutation, or any combination thereof.

8. The antibody agent is (i) the sequence of SEQ ID NO: 99, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 99; and the sequence of SEQ ID NO: 8, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 8; (ii) the sequence of SEQ ID NO: 99, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 99; and the sequence of SEQ ID NO: 12, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 12; (iii) the sequence of SEQ ID NO: 99, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 99; and the sequence of SEQ ID NO: 16, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 16; (iv) the sequence of SEQ ID NO: 99, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 99; and the sequence of SEQ ID NO: 20, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 20; (v) the sequence of SEQ ID NO: 107, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 107; and the sequence of SEQ ID NO: 29, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 29; (vi) the sequence of SEQ ID NO: 115, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 115; and the sequence of SEQ ID NO: 38, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 38; (vii) the sequence of SEQ ID NO: 115, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 115; and the sequence of SEQ ID NO: 47, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 47; (viii) the sequence of SEQ ID NO: 123, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 123; and the sequence of SEQ ID NO: 54, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 54, (ix) the sequence of SEQ ID NO: 107, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 107; and the sequence of SEQ ID NO: 58, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 58; (x) the sequence of SEQ ID NO: 107, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 107; and the sequence of SEQ ID NO: 61, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 61; (xi) the sequence of SEQ ID NO: 127, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 127; and the sequence of SEQ ID NO: 66, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 66; (xii) the sequence of SEQ ID NO: 127, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 127; and the sequence of SEQ ID NO: 71, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 71; (xiii) the sequence of SEQ ID NO: 135, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 135; and the sequence of SEQ ID NO: 76, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 76; (xiv) the sequence of SEQ ID NO: 135, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 135; and the sequence of SEQ ID NO: 80, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 80; (xv) the sequence of SEQ ID NO: 139, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 139; and the sequence of SEQ ID NO: 86, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 86; (xvi) the sequence of SEQ ID NO: 139, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 139; and the sequence of SEQ ID NO: 90, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 90; (xvii) the sequence of SEQ ID NO: 205, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 205; and the sequence of SEQ ID NO: 12, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 12; (xviii) the sequence of SEQ ID NO: 209, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 209; and the sequence of SEQ ID NO: 201, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 201; (xix) the sequence of SEQ ID NO: 214, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 214; and the sequence of SEQ ID NO: 29, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 29; or (xx) the sequence of SEQ ID NO: 218, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 218; and the sequence of SEQ ID NO: 29, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:

29. The antibody agent of claim 1 , comprising:

9. The antibody agent is (i) the sequence of SEQ ID NO: 143, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 143; and the sequence of SEQ ID NO: 159, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 159; (ii) the sequence of SEQ ID NO: 144, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 144; and the sequence of SEQ ID NO: 159, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 159; (iii) the sequence of SEQ ID NO: 145, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 145; and the sequence of SEQ ID NO: 159, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 159; (iv) the sequence of SEQ ID NO: 146, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 146; and the sequence of SEQ ID NO: 159, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 159; (v) the sequence of SEQ ID NO: 147, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 147; and the sequence of SEQ ID NO: 163, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 163; (vi) the sequence of SEQ ID NO: 148, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 148; and the sequence of SEQ ID NO: 164, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 164; (vii) the sequence of SEQ ID NO: 149, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 149; and the sequence of SEQ ID NO: 164, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 164; (viii) the sequence of SEQ ID NO: 150, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 150; and the sequence of SEQ ID NO: 166, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 166; (ix) the sequence of SEQ ID NO: 151, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 151; and the sequence of SEQ ID NO: 163, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 163; (x) the sequence of SEQ ID NO: 152, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 152; and the sequence of SEQ ID NO: 163, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 163; (xi) the sequence of SEQ ID NO: 153, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 153; and the sequence of SEQ ID NO: 169, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 169; (xii) the sequence of SEQ ID NO: 154, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 154; and the sequence of SEQ ID NO: 169, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 169; (xiii) the sequence of SEQ ID NO: 155, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 155; and the sequence of SEQ ID NO: 171, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 171; (xiv) the sequence of SEQ ID NO: 156, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 156; and the sequence of SEQ ID NO: 171, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 171; (xv) the sequence of SEQ ID NO: 157, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 157; and the sequence of SEQ ID NO: 173, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 173; (xvi) the sequence of SEQ ID NO: 158, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 158; and the sequence of SEQ ID NO: 173, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 173; (xvii) the sequence of SEQ ID NO: 144, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 144; and the sequence of SEQ ID NO: 206, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 206; (xviii) the sequence of SEQ ID NO: 202, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 202, and the sequence of SEQ ID NO: 210, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions with respect to SEQ ID NO: 210; (xix) the sequence of SEQ ID NO: 147, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 147; and the sequence of SEQ ID NO: 215, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 215; or (xx) the sequence of SEQ ID NO: 147, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO: 147; and the sequence of SEQ ID NO: 219, or a sequence having at least 85% identity thereto, or a sequence having at least 5, 10, or 20 substitutions relative to SEQ ID NO:

219. The antibody agent of claim 1 , comprising:

10. The antibody agent has a binding affinity (K Ｄ The antibody agent according to claim 1, which binds to human GDF15 at the amino acid sequence (A).

11. The antibody agent of claim 1, wherein the antibody agent reduces the activity and / or level of GDF15 by about 5% or more.

12. 2. The antibody agent of claim 1, wherein the antibody agent does not bind to or has minimal binding affinity to one or more TGF beta superfamily members other than GDF15.

13. The antibody agent of claim 1 , wherein the antibody agent is produced in mammalian cells.

14. An isolated nucleic acid encoding the antibody agent of claim 1.

15. 1. An isolated nucleic acid comprising a GDF15 antibody agent sequence, said nucleic acid comprising: (a) a variable heavy (VH) sequence selected from SEQ ID NO:9, SEQ ID NO:13, SEQ ID NO:17, SEQ ID NO:21, SEQ ID NO:30, SEQ ID NO:39, SEQ ID NO:48, SEQ ID NO:55, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:67, SEQ ID NO:72, SEQ ID NO:77, SEQ ID NO:81, SEQ ID NO:87, SEQ ID NO:91, SEQ ID NO:203, or a sequence having at least 85% identity to any one of the foregoing; and (b) the isolated nucleic acid comprises a variable light (VL) sequence selected from SEQ ID NO:100, SEQ ID NO:108, SEQ ID NO:116, or SEQ ID NO:124, SEQ ID NO:128, SEQ ID NO:136, SEQ ID NO:140, SEQ ID NO:207, SEQ ID NO:211, SEQ ID NO:216, SEQ ID NO:220, or a sequence having at least 85% identity to any one of the foregoing.

16. A vector comprising the isolated nucleic acid of claim 14 or 15.

17. A host cell comprising the vector of claim 16.

18. A method for producing an antibody agent that binds to GDF15, comprising culturing a host cell described in claim 17 under conditions in which the GDF15 antibody agent is expressed by the host cell.

19. A composition comprising the GDF15 antibody drug polypeptide of claim 1.

20. A pharmaceutical composition comprising the GDF15 antibody drug polypeptide of claim 19.

21. The GDF15 pharmaceutical composition of claim 20 for use in a method, wherein the method comprises contacting the pharmaceutical composition with a cell, tissue or subject.

22. The GDF15 pharmaceutical composition of claim 21, wherein the contacting comprises administering the GDF15 pharmaceutical composition to the cell, tissue, or subject, and the subject has a condition or disorder associated with increased GDF15.

23. 23. The GDF15 pharmaceutical composition of claim 22, wherein the condition or disorder is selected from nausea, vomiting, cancer, anorexia, immunosuppression, fibrosis, aging, senescence, mitochondrial dysfunction, chronic kidney disease, chronic heart failure, growth impairment, cytokine storm, cytokine release syndrome, COPD, cyclic vomiting syndrome (CVS), cannabinoid hyperemesis syndrome (CHS), migraine-associated nausea / vomiting (MAN / V), hyperemesis gravidarum, chemotherapy-induced nausea and / or vomiting, or radiation-induced nausea and / or vomiting.

24. 22. The GDF15 pharmaceutical composition of claim 21, wherein the method improves symptoms of a disorder in a subject, the symptoms being nausea, weight loss, vomiting, loss of appetite, fatigue, muscle loss, immunosuppression, fibrosis, mitochondrial dysfunction, senescence, and / or aging.

25. 21. The GDF15 pharmaceutical composition of claim 20 for use in a method for inhibiting GDF15, said method comprising: contacting a cell, tissue, or subject with the GDF15 pharmaceutical composition; thereby inhibiting GDF15 in said cell, tissue or subject.

26. (a) inhibition of GDF15 comprises a decrease in the activity, level, and / or stability of GDF15; and / or 26. The GDF15 pharmaceutical composition of claim 25, wherein (b) the contacting comprises administering the GDF15 pharmaceutical composition to the cell, tissue, or subject.

27. 26. The GDF15 pharmaceutical composition of claim 25, wherein the subject has previously been diagnosed with or has a cancer or hyperproliferative disorder, and the cancer is associated with increased levels and / or activity of GDF15.

28. (i) the cancer has been partially or completely removed from the subject; and / or 28. The GDF15 pharmaceutical composition of claim 27, wherein (ii) the subject has previously undergone cancer therapy.

29. (i) the cancer therapy increases the level and / or activity of GDF15 in the subject compared to before administration of the cancer therapy; and / or (ii) The GDF15 pharmaceutical composition of claim 28, wherein the cancer therapy comprises radiation therapy, chemotherapy, immunotherapy, antibody therapy, or a small molecule, or any combination thereof.

30. The cancer is (i) a solid tumor or a hematological cancer; and / or (ii) The GDF15 pharmaceutical composition of claim 27, wherein the cancer is selected from gastric cancer, sarcoma, lymphoma, leukemia, head and neck cancer, thymic cancer, epithelial cancer, salivary cancer, liver cancer, stomach cancer, thyroid cancer, lung cancer, ovarian cancer, breast cancer, prostate cancer, esophageal cancer, pancreatic cancer, glioma, leukemia, lymphoma, multiple myeloma, renal cell carcinoma, bladder cancer, cervical cancer, choriocarcinoma, colon cancer, oral cancer, skin cancer, melanoma, endometrial cancer, myelofibrosis, bone cancer or brain cancer.

31. The object is (i) pregnant and / or have pregnancy-related nausea (hyperemesis gravidarum); (ii) have lower body weight or appetite compared to a comparator; and / or (iii) A GDF15 pharmaceutical composition according to claim 21 or 25, having an increased level and / or activity of GDF15.

32. A GDF15 pharmaceutical composition for use in a method, the method comprising: (i) assessing the level and / or activity of GDF15 in a sample from a subject; (ii) administering the GDF15 pharmaceutical composition to the subject if the level of GDF15 is higher than that of a comparator drug.

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