Engineered FC-prolactin fusions to increase lactation

Abstract

The technology described herein relates to compositions, kits and methods designed to promote milk production in a subject.

Description

ENGINEERED FC-PROLACTIN FUSIONS TO INCREASE LACTATIONCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63 / 599,295, filed November 15, 2023, contents of which are incorporated herein by reference in their entirety.TECHNICAL FIELD

[0002] The technology described herein relates to compositions, kits and methods designed to promote milk production in a subject.SEQUENCE LISTING

[0003] The instant application contains a Sequence Listing which has been submitted electronically in XML file format and is hereby incorporated by reference in its entirety. Said XML copy, created on November 15, 2024, is named 002806-000100WOPT_SL.xml and is 374,965 bytes in size.BACKGROUND

[0004] At least 15% of new mothers suffer from lactation insufficiency (LI), resulting in low milk supply and poor infant weight gain. These women turn towards supplemental infant formula or donor milk for their infants and galactagogues with poor clinical efficacy.

[0005] However, infant formula is a poor artificial milk substitute with well-established infant and maternal health risks. Formula feeding is associated with higher infant risks of ear infections, gastrointestinal infections, asthma, childhood obesity, type 2 diabetes, leukemia, necrotizing enterocolitis, and sudden infant death syndrome. Additionally, formula feeding is linked to higher maternal risks of breast cancer, ovarian cancer, and post-partum depression.

[0006] There remains a need in the art for treatments for improving lactation inefficiency that has improved clinical efficacy over glactagogues. In particular, there is a medical need for a composition that improves the production of milk in humans. The present disclosure addresses this need.SUMMARY

[0007] The technology described herein relates to compositions and methods for promoting increased lactation.

[0008] One aspect as described herein relates to an Fc-PRL fusion protein comprising aprolactin (PRL) polypeptide linked to an antibody Fc region. In some embodiments, the prolactin polypeptide in the Fc-PRL fusion protein lacks at least one carbohydrate that is present in a wild-type prolactin polypeptide. For example, the prolactin polypeptide comprises at least one mutation that eliminates a glycosylation site present in a wild-type prolactin polypeptide. The Fc-PRL fusion protein comprising a prolactin (PRL) polypeptide linked to an antibody Fc region is also referred to as a “Fc-PRL fusion protein” herein.

[0009] It is noted that the Fc-PRL fusion protein described herein can be a monomer or multimeric. Accordingly, in another aspect provided herein is a multimeric molecule comprising an Fc-PRL fusion protein described herein. Generally, the multimeric molecule comprises an Fc-PRL fusion protein described herein and a second polypeptide comprising at least an antibody Fc region. The Fc region of the Fc-PRL fusion protein and the Fc region of the polypeptide are capable of pairing with each other to form a dimer. Accordingly, in some embodiments of any one of the aspects described herein, the multimeric molecule is a dimer.

[0010] In some embodiments of any one of the aspects described herein, the second polypeptide in the multimeric molecule is a second Fc-PRL fusion protein described herein. In other words, the multimeric molecule comprises a first Fc-PRL fusion protein and a second Fc- PRL fusion protein described herein. It is noted that the first Fc-PRL fusion protein and the second Fc-PRL fusion protein in the multimeric compound can be same or different.

[0011] In some embodiments of any one of the aspects described herein, the second polypeptide in the multimeric molecule does not comprise a prolactin polypeptide linked to the antibody Fc region of the second polypeptide.

[0012] Another aspect as described herein relates to a nucleic acid, e.g., a polynucleotide encoding an Fc-PRL fusion protein or a multimeric molecule comprising an Fc-PRL fusion described herein.

[0013] Also provided herein is a pharmaceutical composition comprising an Fc-PRL fusion protein or a polynucleotide encoding an Fc-PRL fusion protein described herein. Generally, the pharmaceutical composition comprises an Fc-PRL fusion protein described herein, or a multimeric molecule comprising an Fc-PRL fusion protein described herein, and a pharmaceutically acceptable carrier or excipient.

[0014] In some embodiments the pharmaceutical composition comprises a nucleic acid encoding an Fc-PRL fusion protein described herein, or a multimeric molecule comprising an Fc-PRL fusion protein described herein, and a pharmaceutically acceptable carrier or excipient.

[0015] Also provided herein is a cell comprising an Fc-PRL fusion protein or a nucleic acid encoding an Fc-PRL fusion protein described herein. Generally, the cell comprises an Fc-PRLfusion protein described herein, or a multimeric molecule comprising an Fc-PRL fusion protein described herein, and a pharmaceutically acceptable carrier or excipient.

[0016] In some embodiments the cell comprises a nucleic acid encoding an Fc-PRL fusion protein described herein, or a multimeric molecule comprising an Fc-PRL fusion protein described herein, and a pharmaceutically acceptable carrier or excipient.

[0017] In another aspect, provided herein is a kit comprising: (i) an Fc-PRL fusion protein described herein or a polynucleotide encoding the same; or (ii) a multimeric molecule described herein or polynucleotide encoding the multimeric molecule.

[0018] The Fc-PRL fusion proteins are useful for increasing mammalian milk production. Accordingly, in another aspect, provided herein is a method for treating lactation insufficiency in a subject. The method comprises administering an effective amount of an Fc-PRL fusion protein described herein to a subject in need thereof.

[0019] In another aspect provided herein is a method for increasing milk production in a subject. The method comprises administering an effective amount of an Fc-PRL fusion protein described herein, or a polynucleotide encoding the Fc-PRL fusion protein, to a subject in need thereof.

[0020] It is noted that the Fc-PRL fusion protein can be administered as a monomer or as a multimeric molecule. Accordingly, in some embodiments of a method described herein, method comprises administering an effective amount of a multimeric molecule comprising an Fc-PRL protein described herein, or polynucleotide encoding the multimeric molecule.

[0021] In some embodiments of any one of the aspects described herein, the subject is human.

[0022] In some embodiments of any one of the aspects described herein, the subject is nonhuman. For example, the subject is a livestock animal.

[0023] In some embodiments, the method for treating lactation insufficiency or increasing milk production in a subject can comprise a step of diagnosing or selecting the subject for treatment.

[0024] In some embodiments, the method for treating lactation insufficiency or increasing milk production can comprise a step of determining lactation activity or level in the subject prior to administering the Fc-PRL fusion protein. A decreased activity and / or level indicates a subject is in need of treatment.

[0025] In some embodiments, the method for treating lactation insufficiency or increasing milk production can comprise a step of obtaining or receiving results of an assay indicating determining lactation activity or level prior to onset of administration.

[0026] In some administering is intravenous (IV), intraperitoneal (IP) administration, subcutaneous (SC) administration, or intramuscular (IM) administration.

[0027] In a preferred embodiment, a human patient is treated with an Fc-PRL fusion protein at a dose of 500 mgs per day by intravenous infusion over 1 hour, 4 hours, or longer periods of time. In a preferred embodiment, a human patient is treated with an Fc-PRL fusion protein at a dose of at least 500 mgs per day. In another preferred embodiment, a human patient is treated with an Fc-PRL fusion protein at a dose of at least 1 gram per day. In another preferred embodiment, a human patient is treated with an Fc-PRL fusion protein at a dose of at least 2.5 grams per day. In another preferred embodiment, a human patient is treated with an Fc-PRL fusion protein at a dose of at least 20 mgs per day. In another preferred embodiment, a human patient is treated with an Fc-PRL fusion protein at a dose of at least 10 mgs per day. In another preferred embodiment, a human patient is treated with an Fc-PRL fusion protein at a dose of at least 5 mgs per day. In another preferred embodiment, a human patient is treated with an Fc-PRL fusion protein at a dose of at least 1 mg per day. In another preferred embodiment, a human patient is treated with an Fc-PRL fusion protein at a dose of at least 100 pg per day.BRIEF DESCRIPTION OF THE DRAWINGS

[0028] FIGs. 1 a-i-lF shows Prolactin-XL is designed to overcome the unique drug development challenges specific to the lactating person-infant dyad. The top performing long- acting prolactin, called Prolactin-XL, is designed with tailored pharmacological properties to create a biologic that shares the milk-stimulating effects of endogenous prolactin while addressing several disadvantages that prevent recombinant prolactin from being a viable treatment. (FIG. 1 a-i) endogenous prolactin which is secreted by the pituitary in response to infant suckling. (FIG. 1 a-ii) Prolactin-XL is a long-acting injectable consisting of Fc, a subdomain of an IgGl antibody, fused to the endogenously active, deglycosylated prolactin mutant N59D. Prolactin-XL is likely compatible with self-administered subcutaneous injections. (FIG. 1 b-i) Prolactin stimulates mammary alveolar cells to produce milk. (FIG. 1 b-ii) Likewise, Prolactin-XL maintains prolactin-receptor-signaling-induced milk production in mammary alveolar cells. (FIG. 1 c-i) Milk proteins, including endogenous Prolactin, are digested by gastrointestinal proteases in the infant’s stomach. (FIG. 1 c-ii) Prolactin-XL is engineered to be more digestible by gastrointestinal proteases to decrease the oral bioavailability in the infant. (FIG. 1 d-i) Prolactin is a small 23kDa protein that is quickly excreted by the kidneys. (FIG. 1 d-ii) Prolactin-XL is a large 75kDa protein that is not excretedby the kidneys. (FIG. le) pH-dependent binding to the neonatal Fc receptor (FcRn), which salvages Prolactin-XL from endosomal degradation. (FIG. If) Prolactin-XL has been mutated to prevent off-target binding to Fc receptors on immune cells.

[0029] FIGs 2A-2J shows Prolactin-XL is the top performing variant in in vitro screens and has longest in vivo serum half-life. (FIG. 2A) A cartoon of Prolactin-XL compared to human WT prolactin. (FIG. 2B) A cartoon of a Fc-prolactin fusions binding to prolactin receptor (PRLR) to activate the JAK / Stat proliferation on mammary alveolar cells. Human WT His- tagged Prolactin was used as a positive control. (FIG. 2C) A cell-based assay measuring Fc- prolactin fusions induction of in vitro signaling via human PRLR stably expressed in Ba / F3 cells. Data are represented as mean ± SEM of triplicates, and PRISM was used to fit non-linear curves. (FIG. 2D) A cartoon of FcRn-mediated recycling of Fc-prolactin fusions. (FIG. 2E) Binding of Fc-prolactin fusions to human FcRn:P2m at pH 7.4 or pH 5.8 measured by ELISA. Data are represented as mean ± SEM of triplicates. (FIG. 2F) A cartoon of Fc-prolactin fusions interacting with Fc receptors to activate immune effector cells. (FIG. 2G) Binding of Fc- prolactin fusions to human FcyRI, human FcyRIIa, human FcyRIIb, or human FcyRIIIa measured by ELISA. Data are represented as mean ± SEM of triplicates. IgG isotype control or Prolactin-XL were digested by Trypsin at a ratio 1 : 1000 (enzyme: protein). The percent of the remaining fusion were analyzed by SDS-PAGE (FIG. 21) and measured by densitometry (FIG. 2H). Data are represented as mean ± SEM of triplicates. (FIG. 2J) Nulliparous Tg276 mice were injected with 5mg / kg I.V. of Prolactin-XL (n=4) and PRL N59D (n=5). Blood was collected by tail nick post inj ection, and the concentration of the fusions in serum was measured by ELISA. The data are depicted as mean ± SEM. PRISM was used to fit either a one-phase decay (PRL N59D) or a two-phase decay (Prolactin-XL).

[0030] FIGs. 3A-3L shows Prolactin-XL restores pharmacologically-ablated lactation. (FIG. 3A) A timeline of a repeat dose experiment where the B6 dams are dosed with BR or vehicle (0.2mg tartaric acid dissolved in PBS with 20% ethanol) twice-daily (S.C.) and administered S.C. Prolactin-XL or vehicle (PBS) every other day. The dose groups are Vehicle (n=8), BR + 5mg / kg Prolactin-XL (n=6), or BR (n=8). The pups reach endpoint when they weigh 20% less than the pups in the vehicle control group. (FIG. 3B) The percentage of pups remaining in the study each day was recorded. The data are depicted as mean ± SE. (FIG. 3C) The weight of the pups was measured daily starting on day 7 post-partum (n=40 for Vehicle, n=30 for BR + 5mg / kg of Prolactin-XL, and n=40 for BR) and (FIG. 3D) the z-score for each pup was calculated. For (FIG. 3C and 3D), the data are depicted as mean ± SEM. A Two-way ANOVA with Bonferroni correction for multiple comparison was used to calculate thestatistical significance of pup weight gain, and the p-values are listed in Table 5. (FIG. 3E) A timeline of a repeat dose experiment where the B6 dams are dosed with BR or vehicle (0.2mg tartaric acid dissolved in PBS with 20% ethanol) S.C. twice-daily and S.C. administered Prolactin-XL, Prolactin N59D, or vehicle (PBS) every other day. The dose groups are Vehicle (n=8), Br + 5mg / kg Prolactin N59D (n=6), BR + 0.5mg / kg Prolactin-XL (n=6), BR + 0.05mg / kg Prolactin-XL (n=6), BR+ 5mg / kg Prolactin-XL (n=6), or BR (n=8). The pups reach endpoint when they weigh 20% less than the pups in the vehicle control group. (FIG. 3F) The percentage of pups remaining in the study was recorded each day. The data are depicted as mean ± SE. (FIG. 3G, 31, and 3K) The weight of the pups was measured daily starting on day 7 post-partum (n=40 for Vehicle, n=30 for BR + 5mg / kg of Prolactin N59D, n=30 for BR + 0.05mg / kg of Prolactin-XL, n=30 for BR + 0.5mg / kg of Prolactin-XL, n=30 for BR + 5mg / kg of Prolactin-XL, and n=40 for BR) and the z-score for each pup was calculated (FIG. 3H, 3 J, and 3L). For FIG. 3G-3L, the data are depicted as mean ± SEM. A Two-way ANOVA with Bonferroni correction for multiple comparison was used to calculate the statistical significance of pup weight gain, and the p-values are listed in Table 7.

[0031] FIGs. 4A-4F shows Prolactin-XL increases milk supply in mice with uncomplicated lactation. (FIG. 4A) A timeline of single dose experiment where B6 dams are given a single dose of subcutaneous or intravenous 5mg / kg Prolactin-XL or vehicle (PBS) on day 7 postpartum. The dose groups are vehicle (n=6), 5mg / kg I.V. Prolactin-XL (n=5), or 5mg / kg S.C. Prolactin-XL (n=7). (FIG. 4B) The weight of the pups was measured daily starting on day 7 post-partum (n=30 for vehicle, n=25 for I.V. 5mg / kg Prolactin-XL, and n=35 for S.C. Prolactin-XL) and (FIG. 4C) the z-score for each pup was calculated. For (FIG. 4B and 4C), the data are depicted as mean ± SEM. A Two-way ANOVA with Bonferroni correction for multiple comparison was used to calculate the statistical significance of pup weight gain, and the p-values are listed in Table 6. On day 9 post-partum, the weight of pups fed by I.V. Prolactin-XL-dosed dams are significantly higher than the weight of pups fed by vehicle control dams. (FIG. 4D) A timeline of a repeat dose experiment where B6 dams are dosed with subcutaneously administered Prolactin-XL or vehicle every other day (n=6 and n=7, respectively). FIG. 4E the weight of the pups was measured daily starting on day 7 postpartum (n=30 for Prolactin-XL and n=35 for vehicle), and (FIG. 4F) the z-score for each pup was calculated. For (FIG. 4E and 4F), the data are depicted as mean ± SEM. Multiple unpaired t- tests with Bonferroni correction for multiple comparison were used to calculate the statistical significance of pup weight gain, and the p-values are listed in Table 8.

[0032] FIGs. 5A-5C shows Prolactin-XL induces transient changes in mammary tissue inmice with uncomplicated lactation. (FIG. 5A) Examples of lactating (left) and involuting (right) mammary glands stained with H&E (scale bai=0.2mm). (For FIG. 5B-5C), lactating mice (n=3) were repeatedly dosed with subcutaneously administered vehicle (PBS) or Prolactin-XL (5mg / kg) every other day beginning on the 7thday postpartum. Litters were normalized (n=5) on the 7thday postpartum. Mammary glands from the lactating mice were collected on 8d, 9d, lOd, 14d, 18d, 21d post-partum for subsequent analysis. Pups are weaned on the 21stday postpartum. Whole mammary glands were formalin-fixed, paraffin-embedded, and stained with H&E (n=3 per time point). Representative images are depicted in (FIG. 5B) (scale bar = 0.2mm) and (FIG. 5C) (scale bar = 50um).

[0033] FIG. 6 shows a schematic of prolactin pharmacokinetics in the postpartum period.

[0034] FIGs. 7A-7F shows Reducing and Non-reducing SDS-PAGE gels of purified Fc- Prolactin variants. The proteins were expressed in HEK 293F cells by transient transfection and purified by Protein A (Fc-PRL- 1, 3, 5-7, 9-17, 19, 22-29) or His-Tag (Fc-PRL- 2, 4, 8, 18, 20-21). 250nM of each fusion protein was analyzed by reducing (FIG. 7A, 7C, and 7E) and non-reducing (FIG. 7B, 7D, and 7F) 4-20% Tris glycine SDS-Page gel. Molecular weights were verified by reducing SDS-PAGE gels and / or western blots (data not shown).

[0035] FIGs. 8A-8F shows Fc-Prolactin variants with differential expression titers were (FIG. 8A) expressed transiently in Hek293F cells and purified either by Protein A (Fc-PRL- 1, 3, 5-7, 9-17, 19, 22-29) or His-Tag (Fc-PRL- 2, 4, 8, 18, 20-21). Molecular weights were verified by reducing SDS-PAGE gels and / or western blots (data not shown). Protein concentration was determined by BCA. (FIG. 8B-8E) FPLC analysis of top 4 Fc-prolactin fusions using size-exclusion chromatography columns was performed to determine purity and aggregation. The SEC prolife (FIG. 8B) Fc-PRL-3, (FIG. 8C) Fc-PRL-7, (FIG. 8D) Fc-PRL- 13, (FIG. 8E) Fc-PRL-17, and (FIG. 8F) overlay) and the abundance (percentage) is presented for the different fusions.

[0036] FIGs 9A-9F shows Production of high titer Prolactin-XL. (FIG. 9A) Pichia pastoris clones of Fc-PRL-13, called Prolactin-XL, were grown in 3mL scout cultures of and expression titers were determined via ELISA (i.e., capture prolactin and detect Fc). Clone 6 was identified as the highest expressing clone and was used to produce protein for in vivo studies. (FIG. 9B) Clone 6 was grown in 3ml and lOmL cultures and expression titers were determined via ELISA. Data is depicted as mean ± SEM. (FIG. 9C-9F) Prolactin-XL was purified via Protein A purification, and its molecular weight (expected 25 and 50 kDa) was verified via running lOug on reducing 12% Bis Tris SDS-PAGE (FIG. 9C) and Western Blot (FIG. 9E). lOug were also run on non-reducing 12% Bis Tris SDS-PAGE (FIG. 9D) and anti-human IgGl FcWestern blots (FIG. 9F) to analyze overproduction of the Fc only monomer (expected molecular weight 50 or 25 kDa).

[0037] FIGs. 10A-10DD shows Dose response curves demonstrating bioactivity of Fc- prolactin variants via human PRLR signaling. Fc-prolactin variants were assayed in an in vitro cell-based signaling assay previously described79. WT human His-tagged Prolactin was used as a positive control. PRISM was used to fit a non-linear curve and calculate Log(EC50) and Emax. Data is depicted as mean ± SEM.

[0038] FIGs. 11A-11O shows Dose response curves demonstrating bioactivity of Fc- prolactin variants via mouse PRLR signaling. Fc-prolactin variants were assayed in an in vitro cell-based signaling assay previously described79. WT mouse His-tagged Prolactin was used as a positive control. PRISM was used to fit a non-linear curve and calculate Log(EC50) and Emax. Data is depicted as mean ± SEM.

[0039] FIGs 12A-12C shows Binding of human Fc-prolactin variants to human or mouse FcRn by ELISA. The binding of the fusions to human FcRn (FIG. 12A-12B) or mouse FcRn (FIG. 12C) was measured via ELISA. For positive controls, we used IgG isotype control and Protein 1, which is a glycosylated Fc fused to PRL (N59D). Data is depicted at mean ± SEM triplicates except Fc-PRL-7 (n=2 for mouse FcRn), Fc-PRL-24 (n=2 for human FcRn), and Fc- PRL-29 (n=2 for human FcRn).

[0040] FIGs. 13A-13I shows Binding of human Fc-prolactin variants to human or mouse Fc receptors by ELISA. The binding of the fusions to hFcyRI (a), hFcyRI with competing IgGl isotype control (FIG. 13B), hFcyRIIa (FIG. 13C), hFcyRIIb (FIG. 13D), hFcyRIIIa (FIG. 13E), mFcyRI (FIG. 13F), mFcyRIIb (FIG. 13G), mFcyRIII (FIG. 13H), and mFcyRIV (FIG. 131) was measured via ELISA. For positive controls, we used IgG isotype control and Protein 1, which is a glycosylated Fc fused to PRL (N59D). Data is depicted at mean ± SEM triplicates except Fc-PRL-24 (n=2 for human receptors and n=l for mouse receptors) and Fc- PRL-29 (n=2 for human and mouse receptors).

[0041] FIGs. 14A-14C shows Gastrointestinal protease degradation of Fc-prolactin variants by SDS-PAGE gels. Fc-prolactin variants were incubated with GI proteases trypsin (FIG. 14B), chymotrypsin (FIG. 14A), and pepsin (FIG. 14C) at 1: 1000, 1 : 100, and 1 :5000 and 37C, 25C, and 37C respectively. Aliquots were taken from the reaction at different time points, and the percent of the fusion remaining in each aliquot was measured by SDS-PAGE (FIG. 14A- 14C). For positive controls, we used IgGisotype control and Protein 1, which is a glycosylated Fc fused to PRL (N59D). The arrows indicate bands that were used to calculate the percent remaining for each fusion on representative gels.

[0042] FIGs. 15A-15F shows Percent of Fc-prolactin variants remaining after gastrointestinal protease degradation. Fc-prolactin variants were incubated with GI proteases trypsin, chymotrypsin, and pepsin at 1: 1000, 1 : 100, and 1 :5000 and 37C, 25C, and 37C respectively. Aliquots were taken from the reaction at different time points, and the percent of the fusion remaining in each aliquot was measured by SDS-PAGE (Supplemental Figure 8) and densitometry (FIG. 15A-15F). For positive controls, we used IgG isotype control and Protein 1, which is a glycosylated Fc fused to PRL (N59D). Experiments were conducted in triplicate. Data is depicted as mean ± SEM of triplicates.

[0043] FIGs. 16A-16C shows In vitro serum protease degradation of Prolactin-XL. Prolactin-XL and Fc-PRL-1 were incubated with serum diluted 1 :2 at 37C. Aliquots were taken from the reaction at different time points, and the percent of the fusion remaining in each aliquot was measured by anti-human IgGl Fc Western Blot (FIG. 16A-16B) and densitometry (FIG. 16C). For positive controls, we used Fc-PRL-1, which is a glycosylated Fc fused to PRL (N59D). Experiments were conducted in duplicate. Data is depicted as mean (FIG. 16C).

[0044] FIGs. 17A-17D shows Pharmacokinetic profiles of top 4 Fc-Prolactin variants in Tg276 mice. (FIG. 17A) Nulliparous Tg276 mice were injected with 5mg / kg I.V. of Fc- prolactin fusions (n=4) and PRL N59D (n=5). Blood was collected by tail nick post injection, and the concentration of the fusions in serum was measured by ELISA. The data are depicted as mean ± SEM. PRISM was used to fit either a one-phase decay (PRL N59D) or a two-phase decay (Fc-prolactin fusions). The Pharmacokinetic parameters are listed in the Table in FIG. 17D. (FIG. 17B) On the 7thday postpartum, the litters of lactating Tg276 mice were normalized to n=5, and the dams (n=3) were injected with 5mg / kg I.V. of Prolactin-XL (Fc-PRL-13). Blood was collected by tail nick post injection, and the concentration of the fusion in serum was measured by ELISA. The data are depicted as mean ± SEM. PRISM was used to fit a one- phase decay a two-phase decay. The Pharmacokinetic parameters are listed in the Table in FIG. 17D. (FIG. 17C) Nulliparous Tg276 mice were administered 5mg / kg of Fc-PRL-13, IVIG, or PRL N59D fusions (n=8) via oral gavage. Blood was collected by tail nick post injection, and the concentration of the proteins in serum was measured by ELISA. PRL N59D was undetectable (<50ng / mL), and Fc-PRL-13 was undetectable (<100ng / mL). The data for Fc- PRL-13 and IVIG are depicted as individual data points.

[0045] FIGs. 18A-18E shows Pharmacokinetic profiles of Fc-PRL-13 in C57Bl / 6j mice. (FIG. 18A) C57bl / 6j mice were injected with I.V. or S.C. administered 5mg / kg of Fc-PRL-13 on the 7thday post-partum, and litters were normalized to n=5. Dose groups consist of nulliparous (N.P.) or lactating (Lac) mice (n=5 for I.V. PRL N59D (N.P.), n=8 for S.C. Fc-PRL-13 (N.P.), n=5 forI.V. Fc-PRL-13 (N.P.), n=5 forI.V. Fc-PRL-13 (Lac), and n=7 for S.C. Fc-PRL-13 (Lac)). Blood was collected by tail nick post injection, and the concentration of Fc- PRL-13 in serum was measured by ELISA. The data are depicted as mean ± SEM. PRISM was used to fit either a one-phase decay (PRL N59D or S.C. administered S.C.) or a two-phase decay (I V. administered Fc-prolactin fusions). The relevant pharmacokinetic parameters are listed in FIG. 18E. (FIG. 18B) Nulliparous C57bl / 6j mice were administered 5mg / kg of Fc- PRL-13, IVIG, or PRL N59D fusions (n=8) via oral gavage. Blood was collected by tail nick post injection, and the concentration of the proteins in serum was measured by ELISA. Fc- PRL-13 was undetectable (<100ng / mL). The data are depicted as individual data points. (FIG. 18C) Lactating C57bl / 6j mice (litters normalized to n=5) were administered S.C. 5mg / kg of Fc-PRL-13 every other day. Mice were sacrificed at 6 different time points (n=3), and blood was collected by cardiac puncture. The concentration of Fc-PRL-13 in serum was measured by ELISA. The data are depicted as mean ± SEM. (FIG. 18D) The pups of the dams repeatedly dosed were also sacrificed (n=15), and their blood was collected by decapitation. The concentration of the fusions in serum was measured by ELISA. The data are depicted as mean ± SEM.

[0046] FIGs. 19A-19B shows Western blots of Fc-PRL-13 in mouse maternal serum. Lactating C57bl / 6j mice (litters normalized to n=5) were administered S.C. 5mg / kg of Fc-PRL- 13 every other day. Mice were sacrificed at 6 different time points (n=3), and blood was collected by cardiac puncture. The molecular weight of Fc-PRL-13 (expected 25 & 50 kDa) in serum (diluted 1 :5) was measured by an anti -human IgGl Fc Western Blot.

[0047] FIGs. 20A-20F shows Western blots of Fc-PRL-13 in serum from pups fed by Fc- PRL-13-dosed dams. Lactating C57bl / 6j mice (litters normalized to n=5) were administered S.C. 5mg / kg of Fc-PRL-13 every other day. The pups of the dams repeatedly dosed were sacrificed (n=15), and their blood was collected by decapitation. The molecular weight of Fc- PRL-13 (expected 25 & 50 kDa) in serum (diluted 1 :5) was measured by an ant-human IgGl Fc Western Blot.

[0048] FIGs. 21A-21O shows Biomarker analysis of mammary glands. Lactating C57bl / 6j mice were administered S.C. 5mg / kg of Fc-PRL-13 every other day. Mice were sacrificed at 6 different time points (n=3). Their abdominal mammary glands were collected, homogenized in RIPA buffer with protease and phosphatase inhibitors, and stored at -20C. (FIG. 20A) The concentration of Fc-PRL-13 in serum was measured by ELISA. The data are depicted as mean ± SEM. Expression of prolactin receptor (FIG. 21B and 21J), P-casein (FIG. 21C and 21K), STAT5 (FIG. 21D and 21L), pSTAT5 (FIG. 21E and 21M), STAT3 (FIG. 21G and 21N),and pSTAT3 (FIG. 21H and 210) were analyzed by western blot and measured by densitometry. Intensity was normalized to an P-actin loading control. The data are depicted as mean ± SEM. The percent of phosphorylated STAT5 to total STAT5 and the percent of phosphorylated STAT3 to total STAT3 is depicted in FIG. 21F and 211, respectively. Multiple unpaired t-tests with Bonferroni correction for multiple comparison were used to calculate the statistical. All comparisons were not statistically significant (alpha = 0.05).

[0049] FIGs. 22A-22C shows Prolactin-XL does not cause pathological mammary gland growth (FIG. 22A) Whole mount mammary glands were carmine-stained from (n=3 except for 9d Prolactin-XL and 14d vehicle where n=2). (FIG. 22B) The area of the same whole mount, carmine-stained mammary glands as in (FIG. 22B) was measured using Qupath. The data are depicted as mean ± SD. (FIG. 22C) Representative images are depicted.

[0050] FIG. 23 shows Organ-level view of IHC-stained, CK18+ cells in mammary glands. Theses representative images are from a single experiment where B6 dams were dosed with subcutaneously administered Fc-PRL-13 (5mg / kg) or PBS every other day starting on the 7thday postpartum. Litters were normalized (n=5) on the 7thday postpartum. Mammary glands were collected from each mouse (time points= 8d, 9d, lOd, 14d, 18d, and 21d postpartum; n=3 mice per time point) for immunohistochemical staining of CK18.

[0051] FIG. 24 shows Tissue-level view of IHC-stained, CK18+ cells in mammary glands. Theses representative images are from a single experiment where B6 dams were dosed with subcutaneously administered Fc-PRL-13 (5mg / kg) or PBS every other day starting on the 7thday postpartum. Litters were normalized (n=5) on the 7thday postpartum. Mammary glands were collected from each mouse (time points= 8d, 9d, lOd, 14d, 18d, and 21d postpartum; n=3 mice per time point) for immunohistochemical staining of CK18.

[0052] FIG. 25 shows Cellular-level view of IHC-stained, CK18+ cells in mammary glands. Theses representative images are from a single experiment where B6 dams were dosed with subcutaneously administered Fc-PRL-13 (5mg / kg) or PBS every other day starting on the 7thday postpartum. Litters were normalized (n=5) on the 7thday postpartum. Mammary glands were collected from each mouse (time points= 8d, 9d, lOd, 14d, 18d, and 21d postpartum; n=3 mice per time point) for immunohistochemical staining of CK18.

[0053] FIGs. 26A-26G shows Immunohistochemistry analysis of CK18+ cells in mammary glands. The following data (FIG. 26A-26G) are from a single experiment where B6 dams were dosed with subcutaneously administered Fc-PRL-13 (5mg / kg) or PBS every other day starting on the 7thday postpartum. Litters were normalized (n=5) on the 7thday postpartum. Mammary glands were collected from each mouse (time points= 8d, 9d, lOd, 14d, 18d, and 21dpostpartum; n=3 mice per time point) for immunohistochemical staining of CK18. Qupath was used to measure overall DAB staining, annotate the area of the mammary gland, and to perform cell segmentation. For each cell, Qupath measures a variety of morphology parameters including nuclear area, perimeter, and max calipers. Downstream analysis of the segmented cells was done in Python. For FIG. 26C-26I the data are depicted as mean ± SD. Multiple unpaired t-tests with Bonferroni correction for multiple comparison were used to calculate the statistical. Significant comparisons are labeled (green *, alpha = 0.05), otherwise the comparisons were not significant.

[0054] FIGs. 27A-27C shows Organ-, Tissue-, and Cellular-level view of IHC-stained, Ki67+ cells in mammary glands. Theses representative images are from a single experiment where B6 dams were dosed with subcutaneously administered Fc-PRL-13 (5mg / kg) or PBS every other day starting on the 7thday postpartum. Litters were normalized (n=5) on the 7thday postpartum. Mammary glands were collected from each mouse (time points= 8d, 9d, lOd, 14d, 18d, and 21d postpartum; n=3 mice per time point) for immunohistochemical staining ofKi67.

[0055] FIGs. 28A-28G shows Immunohistochemistry analysis of Ki67+ mammary glands. The following histological and biomarkers analyses are from a single experiment where B6 dams were dosed with subcutaneously administered Fc-PRL-13 (5mg / kg) or PBS every other day starting on the 7thday postpartum. Litters were normalized (n=5) on the 7thday postpartum. Mammary glands were collected from each mouse (time points= 8d, 9d, lOd, 14d, 18d, and 21d postpartum; n=3 mice per time point) for immunohistochemical staining of Ki67. Qupath was used to measure overall DAB staining, annotate the area of the mammary gland, and to perform cell segmentation. For each cell, Qupath measures a variety of morphology parameters including nuclear area, perimeter, and max calipers. Downstream analysis of the segmented cells was done in Python. For FIG. 28A-28G, the data are depicted as mean ± SD. Multiple unpaired t-tests with Bonferroni correction for multiple comparison were used to calculate the statistical. Significant comparisons are labeled (green *, alpha = 0.05), otherwise the comparisons were not significant.

[0056] FIGs. 29A-29C shows Organ-, Tissue-, and Cellular-level view of IHC-stained, pSTAT3+ cells in mammary glands. Theses representative images are from a single experiment where B6 dams were dosed with subcutaneously administered Fc-PRL-13 (5mg / kg) or PBS every other day starting on the 7thday postpartum. Litters were normalized (n=5) on the 7thday postpartum. Mammary glands were collected from each mouse (time points= 8d, 9d, lOd, 14d, 18d, and 21d postpartum; n=3 mice per time point) for immunohistochemical staining of pSTAT3.

[0057] FIGs. 30A-30G shows Immunohistochemistry analysis of phosphorylated Stat3+ cells in mammary glands. The following histological and biomarkers analyses are from a single experiment where B6 dams were dosed with subcutaneously administered Fc-PRL-13 (5mg / kg) or PBS every other day starting on the 7thday postpartum. Litters were normalized (n=5) on the 7thday postpartum. Mammary glands were collected from each mouse (time points= 8d, 9d, lOd, 14d, 18d, and 21d postpartum; n=3 mice per time point) for immunohistochemical staining of pSTAT3. Qupath was used to measure overall DAB staining, annotate the area of the mammary gland, and to perform cell segmentation. For each cell, Qupath measures a variety of morphology parameters including nuclear area, perimeter, and max calipers. Downstream analysis of the segmented cells was done in Python. For FIG. 30 A- 30G, the data are depicted as mean ± SD. Multiple unpaired t-tests with Bonferroni correction for multiple comparison were used to calculate the statistical. Significant comparisons are labeled (green *, alpha = 0.05), otherwise the comparisons were not significant.

[0058] FIGs. 31A-31C shows Organ-, Tissue-, and Cellular-level view of IHC-stained, CK14+ cells in mammary glands. Theses representative images are from a single experiment where B6 dams were dosed with subcutaneously administered Fc-PRL-13 (5mg / kg) or PBS every other day starting on the 7thday postpartum. Litters were normalized (n=5) on the 7thday postpartum. Mammary glands were collected from each mouse (time points= 8d, 9d, lOd, 14d, 18d, and 21d postpartum; n=3 mice per time point) for immunohistochemical staining ofCK14.

[0059] FIGs. 32A-32C shows Organ-, Tissue-, and Cellular-level view of IHC-stained, SMA+ cells in mammary glands. Theses representative images are from a single experiment where B6 dams were dosed with subcutaneously administered Fc-PRL-13 (5mg / kg) or PBS every other day starting on the 7thday postpartum. Litters were normalized (n=5) on the 7thday postpartum. Mammary glands were collected from each mouse (time points= 8d, 9d, lOd, 14d, 18d, and 21d postpartum; n=3 mice per time point) for immunohistochemical staining of SMA.

[0060] FIGs. 33A-33C shows Organ-, Tissue-, and Cellular-level view of IHC-stained, CD45+ cells in mammary glands. Theses representative images are from a single experiment where B6 dams were dosed with subcutaneously administered Fc-PRL-13 (5mg / kg) or PBS every other day starting on the 7thday postpartum. Litters were normalized (n=5) on the 7thday postpartum. Mammary glands were collected from each mouse (time points= 8d, 9d, lOd, 14d, 18d, and 21d postpartum; n=3 mice per time point) for immunohistochemical staining ofCD45.

[0061] FIGs. 34A-34C shows Organ-, Tissue-, and Cellular-level view of TUNEL-stained mammary glands. Theses representative images are from a single experiment where B6 dams were dosed with subcutaneously administered Fc-PRL-13 (5mg / kg) or PBS every other daystarting on the 7thday postpartum. Litters were normalized (n=5) on the 7thday postpartum. Mammary glands were collected from each mouse (time points= 8d, 9d, lOd, 14d, 18d, and 21d postpartum; n=3 mice per time point) for immunohistochemical staining with TUNEL.

[0062] FIGs. 35A-35D shows Immunohistochemistry analysis of CK14+, SMA+, CD45+, or Tunel+ stained mammary glands. The following histological and biomarkers analyses are from a single experiment where B6 dams were dosed with subcutaneously administered Fc- PRL-13 (5mg / kg) or PBS every other day starting on the 7thday postpartum. Litters were normalized (n=5) on the 7thday postpartum. Mammary glands were collected from each mouse (time points= 8d, 9d, lOd, 14d, 18d, and 21d postpartum; n=3 mice per time point) for immunohistochemical staining of CK14 (FIG. 35A), smooth muscle actin (SMA) (FIG. 35B), CD45 (FIG. 35C) and TUNEL (FIG. 35D). Qupath was used to measure overall DAB staining and annotate the area of the mammary gland. For FIG. 35A-35D, the data are depicted as mean ± SD. Multiple unpaired t-tests with Bonferroni correction for multiple comparison were used to calculate the statistical. Significant comparisons are labeled (green *, alpha = 0.05), otherwise the comparisons were not significant.

[0063] FIGs. 36A-36G shows Bulk RNA transcriptomic analysis of mammary glands. The following RNA transcriptomic analyses are from a single experiment where B6 dams were dosed with subcutaneously administered Fc-PRL-13 (5mg / kg) or PBS every other day starting on the 7thday postpartum. Litters were normalized (n=5) on the 7thday postpartum. Mammary glands were collected from each mouse (time points= 8d, 9d, lOd, 14d, 18d, and 21d postpartum; n=3 mice per time point) for bulk RNA sequencing. DeSeq2 was used to identify differentially expressed genes across time and within treatments (FIG. 36A-36C) and between treatments at the same time point (FIG. 36D-36G). Identified differentially expressed genes were compared to previously lactation and involution gene sets(FIG. 36C and 36F)48.

[0064] FIG. 37A-37X displays rationally designed Fc-PRL fusion proteins. 29 molecules were constructed, consisting of PRL fused to Fc (Proteins 1-29) using rational engineering and structural information from solved structures of PRL, PRLR, and homologous hormones and receptors in highly similar complexes (If6f45, 3d4846, lrw547). Fc was also modified with various sets of mutations from literature to increase half-life, reduce immune activation, create heterodimers, or purify out unwanted Fc species.

[0065] FIG. 38 depicts the top 5 candidate fusion proteins. From the 19 constructed Fc-PRL fusions, 5 were selected (3, 7, 13, 17, 29) based on expression, PRLR-mediated signaling, and mutations to enhance FcRn binding, abolish FcR immune effector functions, and unwanted Fc homodimers. Half-life and FcR binding are confirmed in the next series of assays.DETAILED DESCRIPTION

[0066] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. Herein, the use of the singular includes the plural unless specifically stated otherwise. As used herein, the use of “or” means “and / or” unless stated otherwise. Furthermore, the use of the term “including” as well as other forms, such as “includes” and “included”, is not limiting. Also, terms such as “element” or “component” encompass both elements and components comprising one unit and elements and components that comprise more than one subunit, unless specifically stated otherwise.

[0067] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including, but not limited to, patents, patent applications, articles, books, and treatises, are hereby expressly incorporated by reference in their entirety for any purpose.

[0068] In one aspect provided herein is an Fc-PRL fusion protein comprising a prolactin (PRL) polypeptide linked to an antibody Fc region, wherein the prolactin polypeptide comprises at least one mutation that eliminates a glycosylation site present in a wild-type prolactin polypeptide.

[0069] As used herein, the term “glycosylation site” refers in particular to any amino acid sequence that can be recognized by an enzyme capable of catalyzing the binding of a monosaccharide unit or a carbohydrate chain to a peptide or polypeptide chain. Preferably, the glycosylation site includes the amino acid residue to which the monosaccharide unit or a carbohydrate chain is attached. It is noted that a glycosylation site can be an N-glycosylation sites or an O-glycosylation site. Generally, N-glycosylation sites comprise an asparagine residue as a binding site for the monosaccharide unit or carbohydrate chain, and O- glycosylation sites comprise a serine or threonine residue as a binding site for the monosaccharide unit or carbohydrate chain. In some embodiments, an N-glycosylation site comprises the amino acid sequence Asn Xaa Ser / Thr (SEQ ID NO: 1), wherein Xaa is any amino acid preferably except Pro. This amino acid sequence refers to a sequence of three consecutive amino acids, wherein the first amino acid residue is an asparagine residue, the second amino acid residue may be any amino acid residue, in particular, any naturally occurring amino acid residue, except proline, and the third amino acid residue is a serine or threonine. When glycosylated, the carbohydrate chain binds to the asparagine residue. In some embodiments of any one of the aspects described herein, the glycosylation site of the prolactinpolypeptide comprises the amino acid sequence of asparagine-lysine-serine.Prolactin

[0070] The Fc-PRL fusion protein comprises a prolactin polypeptide. Prolactin is a peptide hormone, encoded by the PRL gene. It is secreted from the pituitary gland in response to eating, mating, estrogen treatment, ovulation and nursing. Prolactin plays an essential role in metabolism, regulation of the immune system and pancreatic development. In humans, three smaller (4, 16, and 23 kDa) and several larger (so-called big and big-big) variants exist. Prolactin is produced at least in the anterior pituitary, decidua, myometrium, breast, lymphocytes, leukocytes and prostate.

[0071] During pregnancy, high circulating concentrations of estrogen and progesterone increase prolactin levels by 10- to 20-fold. Estrogen and progesterone inhibit the stimulatory effects of prolactin on milk production. The abrupt drop of estrogen and progesterone levels following delivery allow prolactin — which temporarily remains high — to induce lactation.

[0072] Sucking on the nipple offsets the fall in prolactin as the internal stimulus for them is removed. The sucking activates mechanoreceptors in and around the nipple. These signals are carried by nerve fibers through the spinal cord to the hypothalamus, where changes in the electrical activity of neurons that regulate the pituitary gland increase prolactin secretion. The suckling stimulus also triggers the release of oxytocin from the posterior pituitary gland, which triggers milk let-down: Prolactin controls milk production (lactogenesis) but not the milkejection reflex; the rise in prolactin fills the breast with milk in preparation for the next feed.

[0073] Deficiencies in prolactin (hypoprolactinemia) are defined as prolactin levels below 3 pg / L in women and 5 pg / L in men. Hypoprolactinemia, or serum prolactin deficiency, is associated with ovarian dysfunction in women and and arteriogenic erectile dysfunction, premature ejaculation, oligozoospermia, asthenospermia, hypofunction of seminal vesicles and hypoandrogenism in men. Hypoprolactinemia can result from hypopituitarism, excessive dopaminergic action in the tuberoinfundibular pathway and ingestion of D2 receptor agonists such as bromocriptine.

[0074] Human prolactin precursor [NM 000948.6, Homo sapiens, Gene ID: 5617] (SEQ ID NO: 2)1 gtgagacttc cagatcttct ctggtgaagt gtgtttcctg caacgatcac gaacatgaac61 atcaaaggat cgccatggaa agggtccctc ctgctgctgc tggtgtcaaa cctgctcctg121 tgccagagcg tggccccctt gcccatctgt cccggcgggg ctgcccgatg ccaggtgacc181 cttcgagacc tgtttgaccg cgccgtcgtc ctgtcccact acatccataa cctctcctca241 gaaatgttca gcgaattcga taaacggtat acccatggcc gggggttcat taccaaggcc301 atcaacagct gccacacttc ttcccttgcc acccccgaag acaaggagca agcccaacag361 atgaatcaaa aagactttct gagcctgata gtcagcatat tgcgatcctg gaatgagcct421 ctgtatcatc tggtcacgga agtacgtggt atgcaagaag ccccggaggc tatcctatcc481 aaagctgtag agattgagga gcaaaccaaa cggcttctag agggcatgga gctgatagtc541 agccaggttc atcctgaaac caaagaaaat gagatctacc ctgtctggtc gggacttcca601 tccctgcaga tggctgatga agagtctcgc ctttctgctt attataacct gctccactgc661 ctacgcaggg attcacataa aatcgacaat tatctcaagc tcctgaagtg ccgaatcatc721 cacaacaaca actgctaagc ccacatccat ttcatctatt tctgagaagg tccttaatga781 tccgttccat tgcaagcttc ttttagttgt atctcttttg aatccatgct tgggtgtaac841 aggtctcctc ttaaaaaata aaaactgact ccttagagac atcaaaatct aaaa

[0075] Human prolactin precursor [NP 000939.1, Homo sapiens, Gene ID: 5617] (SEQID NO: 3)1 mnikgspwkg slllll vsnl llcqsvaplp icpggaarcq vtlrdlfdra vvlshyihnl61 ssemfsefdk rythgrgfit kainschtss latpedkeqa qqmnqkdfls livsilrswn121 eplyhlvtev rgmqeapeai Iskaveieeq tkrllegmel ivsqvhpetk eneiypvwsg181 Ipslqmadee srlsayynll hclrrdshki dnylkllkcr iihnnnc

[0076] Human prolactin precursor [NM 001163558.3, Homo sapiens, Gene ID: 5617](SEQ ID NO: 4)1 aggtcataag aaccttcatt ccagaagtac cctcaaagac agagacacca agaagaatcg61 gaacatacag gctttgatat caaaggttta taaagccaat atctgggaaa gagaaaaccg121 tgagacttcc agatcttctc tggtgaagtg tgtttcctgc aacgatcacg aacatgaaca181 tcaaaggatc gccatggaaa gggtccctcc tgctgctgct ggtgtcaaac ctgctcctgt241 gccagagcgt ggcccccttg cccatctgtc ccggcggggc tgcccgatgc caggtgaccc301 ttcgagacct gtttgaccgc gccgtcgtcc tgtcccacta catccataac ctctcctcag361 aaatgttcag cgaattcgat aaacggtata cccatggccg ggggttcatt accaaggcca421 tcaacagctg ccacacttct tcccttgcca cccccgaaga caaggagcaa gcccaacaga481 tgaatcaaaa agactttctg agcctgatag tcagcatatt gcgatcctgg aatgagcctc541 tgtatcatct ggtcacggaa gtacgtggta tgcaagaagc cccggaggct atcctatcca601 aagctgtaga gattgaggag caaaccaaac ggcttctaga gggcatggag ctgatagtca661 gccaggttca tcctgaaacc aaagaaaatg agatctaccc tgtctggtcg ggacttccat721 ccctgcagat ggctgatgaa gagtctcgcc tttctgctta ttataacctg ctccactgcc781 tacgcaggga ttcacataaa atcgacaatt atctcaagct cctgaagtgc cgaatcatcc841 acaacaacaa ctgctaagcc cacatccatt tcatctattt ctgagaaggt ccttaatgat901 ccgttccatt gcaagcttct tttagttgta tctcttttga atccatgctt gggtgtaaca961 ggtctcctct taaaaaataa aaactgactc cttagagaca tcaaaatcta aaa

[0077] Human prolactin precursor [NP 001157030.1, Homo sapiens, Gene ID: 5617](SEQ ID NO: 5)1 mnikgspwkg slllll vsnl llcqsvaplp icpggaarcq vtlrdlfdra vvlshyihnl61 ssemfsefdk rythgrgfit kainschtss latpedkeqa qqmnqkdfls livsilrswn121 eplyhlvtev rgmqeapeai Iskaveieeq tkrllegmel ivsqvhpetk eneiypvwsg181 Ipslqmadee srlsayynll hclrrdshki dnylkllkcr iihnnnc

[0078] Cow prolactin precursor [NM_173953.2, Bos taurus, Gene ID: 28901] (SEQ IDNO: 6)1 tgcttggctg aggagccata ggacgagagc ttcctggtga agtgtgtttc ttgaaatcat61 caccaccatg gacagcaaag gttcgtcgca gaaagggtcc cgcctgctcc tgctgctggt121 ggtgtcaaat ctactcttgt gccagggtgt ggtctccacc cccgtctgtc ccaatgggcc181 tggcaactgc caggtatccc ttcgagacct gtttgaccgg gcagtcatgg tgtcccacta241 catccatgac ctctcctcgg aaatgttcaa cgaatttgat aaacggtatg cccagggcaa301 agggttcatt accatggccc tcaacagctg ccatacctcc tcccttccta ccccggaaga361 taaagaacaa gcccaacaga cccatcatga agtccttatg agcttgattc ttgggttgct421 gcgctcctgg aatgaccctc tgtatcacct agtcaccgag gtacggggta tgaaaggagc481 cccagatgct atcctatcga gggccataga gattgaggaa gaaaacaaac gacttctgga541 aggcatggag atgatatttg gccaggttat tcctggagcc aaagagactg agccctaccc601 tgtgtggtca ggactcccgt ccctgcaaac taaggatgaa gatgcacgtt attctgcttt661 ttataacctg ctccactgcc tgcgcaggga ttcaagcaag attgacactt accttaagct721 cctgaattgc agaatcatct acaacaacaa ctgctaagcc cacattccat cctatccatt781 tctgagatgg ttcttaatga tccattccct ggcaaacttc tctgagcttt atagctttgt841 aatgcatgct tggctctaat gggtttcatc ttaaataaaa acagactctg tagcgatgtc901 aaaatct

[0079] Cow prolactin precursor [NP 776378.2, Bos taurus, Gene ID: 28901] (SEQ ID NO: 7)1 mdskgssqkg srlllllvvs nlllcqgvvs tpvcpngpgn cqvslrdlfd ravmvshyih61 dlssemfnef dkryaqgkgf itmalnscht sslptpedke qaqqthhevl mslilgllrs121 wndplyhlvt evrgmkgapd ailsraieie eenkrllegm emifgqvipg aketepypvw181 sglpslqtkd edarysafyn llhclrrdss kidtylklln criiynnnc

[0080] Goat prolactin precursor [NM 001285547.1, Capra hircus, Gene ID: 100861193] (SEQID NO: 8)1 aggacgagag cttcctggtg aagtgtgttt cttgaaatca tcaccaccat ggacagcaaa61 ggttcagcgc agaaagggtc ccgcctgctc ctgctgctgg tggtgtcaaa tctactcttg121 tgtcagggtg tggtctccac ccccgtctgt cccaatgggc ctggcaactg ccaggtgtcc181 cttcgagacc tgtttgaccg ggcagtcatg gtgtcccact acatccataa cctctcctcg241 gaaatgttca atgaatttga taaacggtac gcccagggca aagggtacat taccatggcc301 ctcaacagct gccatacctc ctcccttcct acccctgaag acaaagaaca agcccaacag361 acccaccatg aagtccttat gagcttgatt cttgggttgc tgcgctcctg gaatgaccct421 ctgtatcacc tagtcacaga ggtgcggggt atgaaaggag tcccagatgc tatcctatcg481 agggccatag agattgagga agaaaacaaa cgacttctgg aaggcatgga gatgatattg541 ggccaggtta ttcctggagc caaagagact gagccctacc ctgtgtggtc aggactccca601 tccctgcaaa ctaaggatga agaggcacgt cattctgctt tttacaacct gctccactgc661 ctgcgcaggg attcaagcaa gattgacact taccttaagc tcctgaattg cagaatcatc721 tacaacaaca actgctaagc ccacattcat cctatccatt tctgagatgg ttcttaatga781 tccattccct ggcaaacttc tctgagcttt atagcttttt aatgcatgct tggctctaat841 ggttt

[0081] Goat prolactin precursor [NP 001272476.1, Capra hircus, Gene ID: 100861193] (SEQ ID NO: 9)1 mdskgsaqkg srlllllvvs nlllcqgvvs tpvcpngpgn cqvslrdlfd ravmvshyih61 nlssemfnef dkryaqgkgy itmalnscht sslptpedke qaqqthhevl mslilgllrs121 wndplyhlvt evrgmkgvpd ailsraieie eenkrllegm emilgqvipg aketepypvw181 sglpslqtkd eearhsafyn llhclrrdss kidtylklln criiynnnc

[0082] Sheep prolactin precursor [NM_001009306.1, Ovis aries, Gene ID: 443317] (SEQ IDNO: 10)1 gtccgaaagg gtggtgatga tttcaagaaa cacactttct gcgctgaacc tttgctgtcc61 atggtggtga tgatttcaag aaacacactt caccaggaca gcaaaggttc agcgcagaaa121 gggtcccgcc tgctcctgct gctggtggtg tcaaatctac tcttgtgtca gggtgtggtc181 tccacccctg tctgtcccaa tgggcctggc gactgtcagg tgtcccttcg agacctgttt241 gaccgggcag tcatggtgtc ccactacatt cataacctct cctcggaaat gttcaatgaa 301 tttgataaaa ggtatgccca gggcaaaggg ttcattacca tggccctcaa cagctgccac 361 acctcctccc ttcctacccc tgaagacaaa gaacaagccc aacagaccca ccatgaagtc 421 cttatgagct tgattcttgg gttgctgcgc tcctggaatg accctctgta tcacctagtc 481 acagaggtgc ggggtatgaa aggagtccca gatgctattc tatcgagggc tatagagatt 541 gaggaagaaa acaaacgact tctggaaggc atggagatga tatttggcca agttattcct 601 ggagccaaag agactgagcc ctaccctgtg tggtcaggac tcccatccct gcaaactaag 661 gatgaagatg cacgtcattc tgctttttac aacctgcttc actgcctgcg cagggattca 721 agcaagattg acacttacct taagctcctg aattgcagaa tcatctacaa caacaactgc 781 taagcccaca ttccatccta tccatttctg agatggttct taatgatcca ttccctggca 841 aacttctctg agctttatag ctttttaatg catgcttggc tctaatgggt ttcatcttaa 901 ataaaaacag actctgtaga aatgtc

[0083] Sheep prolactin precursor [NP 001009306.1, Ovis aries, Gene ID: 443317] (SEQ ID NO: 11)1 mvvmisrntl hqdskgsaqk gsrlllllvv snlllcqgvv stpvcpngpg dcqvslrdlf 61 dravmvshyi hnlssemfne fdkryaqgkg fitmalnsch tsslptpedk eqaqqthhev 121 Imslilgllr swndplyhlv tevrgmkgvp dailsraiei eeenkrlleg memifgqvip 181 gaketepypv wsglpslqtk dedarhsafy nllhclrrds skidtylkll ncriiynnnc

[0084] In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence selected from the group consisting ofLPICPGGAARCQVTLRDLFDRAVVLSHYIHNLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRIIHNNNC (SEQ ID NO: 12 (human PRL 29-227));LPICPGGAARCQVTLRDLFDRAVVLSHYIHDLSSEMFSEFDKRYTHGRGFITKAINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQEAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRIIHNNNC (SEQ ID NO: 13 (human PRL 29-227, N59D));LPICPGGAARCQVTLRDLFDRAVVLSHYIHNLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHKIDNYLKLLKSRIIHNNNC (SEQ ID NO: 14 (human PRL 29-227, C219S));LPICPGGAARCQVTLRDLFDRAVVLSHYIHNLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRIIHNNNS (SEQ ID NO: 15 (human PRL 29-227, C227S));LPICPGGAARCQVTLRDLFDRAVVLSHYIHDLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHKIDNYLKLLKSRIIHNNNC (SEQ ID NO: 16 (human PRL 29-227, N59D, C219S));LPICPGGAARCQVTLRDLFDRAVVLSHYIHDLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRIIHNNNS (SEQ ID NO: 17 (human PRL 29-227, N59D, C227S));LPICPGGAARCQVTLRDLFDRAVVLSHYIHDLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHKIDNYLKLLKSRIIHNNNS (SEQ ID NO: 18 (human PRL 29-227, N59D, C219S, C227S));TPVCPNGPGNCQVSLRDLFDRAVMVSHYIHDLSSEMFNEFDKRYAQGKGFIT MALNSCHTSSLPTPEDKEQAQQTHHEVLMSLILGLLRSWNDPLYHLVTEVRG MKGAPDAILSRAIEIEEENKRLLEGMEMIFGQVIPGAKETEPYPVWSGLPSLQT KDEDARYSAFYNLLHCLRRDSSKIDTYLKLLNCRIIYNNNC (SEQ ID NO: 19 (Cow PRL 31-229 WT));TPVCPNGPGNCQVSLRDLFDRAVMVSHYIHNLSSEMFNEFDKRYAQGKGYIT MALNSCHTSSLPTPEDKEQAQQTHHEVLMSLILGLLRSWNDPLYHLVTEVRG MKGVPDAILSRAIEIEEENKRLLEGMEMILGQVIPGAKETEPYPVWSGLPSLQT KDEEARHSAFYNLLHCLRRDSSKIDTYLKLLNCRIIYNNNC (SEQ ID NO: 20 (Goat PRL 31-229 WT));TPVCPNGPGNCQVSLRDLFDRAVMVSHYIHDLSSEMFNEFDKRYAQGKGYIT MALNSCHTSSLPTPEDKEQAQQTHHEVLMSLILGLLRSWNDPLYHLVTEVRG MKGVPDAILSRAIEIEEENKRLLEGMEMILGQVIPGAKETEPYPVWSGLPSLQT KDEEARHSAFYNLLHCLRRDSSKIDTYLKLLNCRIIYNNNC (SEQ ID NO: 21 (Goat PRL 31-229, N62D));TPVCPNGPGDCQVSLRDLFDRAVMVSHYIHNLSSEMFNEFDKRYAQGKGFIT MALNSCHTSSLPTPEDKEQAQQTHHEVLMSLILGLLRSWNDPLYHLVTEVRG MKGVPDAILSRAIEIEEENKRLLEGMEMIFGQVIPGAKETEPYPVWSGLPSLQT KDEDARHSAFYNLLHCLRRDSSKIDTYLKLLNCRIIYNNNC (SEQ ID NO: 22 (Sheep PRL 42-240 WT));TPVCPNGPGNCQVSLRDLFDRAVMVSHYIHDLSSEMFNEFDKRYAQGKGFIT MALNSCHTSSLPTPEDKEQAQQTHHEVLMSLILGLLRSWNDPLYHLVTEVRG MKGVPDAILSRAIEIEEENKRLLEGMEMIFGQVIPGAKETEPYPVWSGLPSLQT KDEDARHSAFYNLLHCLRRDSSKIDTYLKLLNCRIIYNNNC (SEQ ID NO: 23 (Sheep PRL 42-240, N61D))LPICSAGDCQTSLRELFDRWILSHYIHTLYTDMFIEFDKQYVQDREFMVKVINDCPTSSLATPEDKEQALKVPPEVLLNLILSLVQSSSDPLFQLITGVGGIQEAPEYILSRAKEIEEQNKQLLEGVEKIISQAYPEAKGNGIYFVWSQLPSLQGVDEESKILSLRNTIRCLRRDSHKVDNFLKVLRCQIAHQNNC (SEQ ID NO: 24 (mousePRL WT))Wild- types

[0085] In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from SEQ ID NO: 12, 19, 20 or 22. In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 12, 19, 20, or 22. In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises an amino acid sequence having at least 97%, 98% or 99% sequence identity to SEQ ID NO: 12, 19, 20, or 22. In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises an amino acid sequence having 100% sequence identity to SEQ ID NO: 12, 19, 20, or 22

[0086] In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 12. In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 12. In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises an amino acid sequence having at least 97%, 98% or 99% sequence identity to SEQ ID NO: 12.

[0087] In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises a substitution at a position corresponding to position 59 of SEQ ID NO: 3 or 5. For example, the PRL polypeptide in the Fc-PRL fusion protein comprises anN to D substitution at a position corresponding to position 59 of SEQ ID NO: 3 or 5.

[0088] In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises a substitution at a position corresponding to position 219 of SEQ ID NO: 3 or 5. For example, the PRL polypeptide in the Fc-PRL fusion protein comprises an C to S substitution at a position corresponding to position 219 of SEQ ID NO: 3 or 5.

[0089] In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises a substitution at a position corresponding to position 227of SEQ ID NO: 3 or 5. For example, the PRL polypeptide in the Fc-PRL fusion protein polypeptide in the Fc-PRL fusion protein comprises an C to S substitution at a position corresponding to position 227 of SEQ ID NO: 3 or 5.

[0090] In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises a substitution at positions corresponding to positions 59 and 219 of SEQ ID NO: 3 or 5. For example, the PRL polypeptide in the Fc-PRL fusion protein comprises an N to D substitution at a position corresponding to position 59, and an C to S substitution at a position corresponding to position 219 of SEQ ID NO: 3 or 5.

[0091] In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises a substitution at positions corresponding to positions 59 and 227of SEQ ID NO: 3 or 5. For example, the PRL polypeptide in the Fc-PRL fusion protein comprises an N to D substitution at a position corresponding to position 59, and an C to S substitution at a position corresponding to position 227of SEQ ID NO: 3 or 5.

[0092] In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises a substitution at positions corresponding to positions 59, 219and 227 of SEQ ID NO: 3 or 5. For example, the PRL polypeptide in the Fc-PRL fusion protein comprises an N to D substitution at a position corresponding to position 59, an C to S substitution at position 219, and an C to S substitution at a position corresponding to position 227of SEQ ID NO: 3 or 5.

[0093] In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 19. In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 19. In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises an amino acid sequence having at least 97%, 98% or 99% sequence identity to SEQ ID NO: 19.

[0094] In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 20. In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 20. In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises an amino acid sequence having at least 97%, 98% or 99% sequence identity to SEQ ID NO: 20.

[0095] In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises a substitution at a position corresponding to position 59 of SEQ ID NO: 20. For example, the PRL polypeptide in the Fc-PRL fusion protein comprises an N to D substitution at a position corresponding to position 59 of SEQ ID NO: 20.

[0096] In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 22. In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 22. In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises an amino acid sequence having at least 97%, 98% or 99% sequence identity to SEQ ID NO: 22.

[0097] In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises a substitution at a position corresponding to position 59 of SEQ ID NO: 22. For example, the PRL polypeptide in the Fc-PRL fusion protein comprises an N to D substitution at a position corresponding to position 59 of SEQ ID NO: 22.

[0098] In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises a substitution at a position corresponding to position 31 of SEQ ID NO: 12. For example, the PRL polypeptide in the Fc-PRL fusion protein comprises an N to D substitution at a position corresponding to position 31 of SEQ ID NO: 12.

[0099] In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises a substitution at a position corresponding to position 191 of SEQ ID NO: 12. For example, the PRL polypeptide in the Fc-PRL fusion protein comprises an C to S substitution at a position corresponding to position 191 of SEQ ID NO: 12.

[0100] In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises a substitution at a position corresponding to position 199 of SEQ ID NO: 12. For example, the PRL polypeptide in the Fc-PRL fusion protein polypeptide in the Fc-PRL fusion protein comprises an C to S substitution at a position corresponding to position 199 of SEQ ID NO:12

[0101] In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises a substitution at positions corresponding to positions 31 and 191 of SEQ ID NO: 12. For example, the PRL polypeptide in the Fc-PRL fusion protein comprises an N to D substitution at a position corresponding to position 31, and an C to S substitution at a position corresponding to position 191 of SEQ ID NO: 12.

[0102] In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises a substitution at positions corresponding to positions 31 and 199 of SEQ ID NO: 12. For example, the PRL polypeptide in the Fc-PRL fusion protein comprises an N to D substitution at a position corresponding to position 31, and an C to S substitution at a position corresponding to position 199 of SEQ ID NO: 12.

[0103] In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises a substitution at positions corresponding to positions 31, 191 and 199 of SEQ ID NO: 12. For example, the PRL polypeptide in the Fc-PRL fusion protein comprises an N to D substitution at a position corresponding to position 59, an C to S substitution at position 191, and an C to S substitution at a position corresponding to position 199 of SEQ ID NO: 12.Mutated PRLs

[0104] Accordingly, in some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence: SEQ ID NO: 13-18, 21, 23 or 24. In some embodiments, the PRL polypeptide comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 13-18, 21, 23 or 24. In some embodiments, the PRL polypeptide comprises an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 13-18, 21, 23 or 24. In some embodiments, the PRL polypeptide comprises an amino acid sequence having at least 97%, 98% or 99% sequence identity to SEQ ID NO: 13-18, 21, 23 or 24. In some embodiments, the PRL polypeptide comprises an amino acid sequence having 100% sequence identity to SEQ ID NO: 13-18, 21, 23 or 24.

[0105] In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 13. In some embodiments, the PRL polypeptide comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 13. In some embodiments, the PRL polypeptide comprises an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 13. In some embodiments, the PRL polypeptide comprises an amino acid sequence having at least 97%, 98% or 99% sequence identity to SEQ ID NO: 13

[0106] In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises the amino acid sequence of SEQ ID NO: 13. In some embodiments, the PRL polypeptide comprises an amino acid sequence having 100% sequence identity to SEQ ID NO: 13.

[0107] In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises the amino acid sequence of SEQ ID NO: 17.

[0108] In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises the amino acid sequence of SEQ ID NO: 18.

[0109] In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence: SEQ ID NO: 13-18, 21, 23 or 24, and provided that the PRL polypeptide comprises aspartic acid at a position corresponding to position 59, serine at a position corresponding to position 219, and / or serine at position corresponding to a position 227 of SEQ ID NO: 13-18, 21, 23 or 24. In some embodiments, the PRL polypeptide comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 13-18, 21, 23 or 24, and provided that the PRL polypeptide comprises aspartic acid at a position corresponding to position 59, serine at a position corresponding to position 219, and / or serine at position corresponding to a position 227 of SEQ ID NO: 13-18, 21, 23 or 24. In some embodiments, the PRL polypeptide comprises an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 13-18, and provided that the PRL polypeptide comprises aspartic acid at a position corresponding to position 59, serine at a position corresponding to position 219, and / or serine at position corresponding to a position 227 of SEQ ID NO: 13-18, 21, 23 or 24. In some embodiments, the PRL polypeptide comprises an amino acid sequence having at least 97%, 98% or 99% sequence identity to SEQ ID NO: 13-18, 21, 23 or 24, and provided that the PRL polypeptide comprises aspartic acid at a position corresponding to position 59, serine at a position corresponding to position 219, and / or serine at position corresponding to a position 227 of SEQ ID NO: 13-18, 21, 23 or 24

[0110] In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence: SEQ ID NO: 13, and provided that the PRL polypeptide comprises aspartic acid at a position corresponding to position 59, serine at a position corresponding to position 219, and / or serine at position corresponding to a position 227 of SEQ ID NO: 13. In some embodiments, the PRL polypeptide comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 13, and provided that the PRL polypeptide comprises aspartic acid at a position corresponding to position 59, serine at a position corresponding to position 219, and / or serine at position corresponding to a position 227 of SEQ ID NO: 13. In someembodiments, the PRL polypeptide comprises an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 13-18, and provided that the PRL polypeptide comprises aspartic acid at a position corresponding to position 59, serine at a position corresponding to position 219, and / or serine at position corresponding to a position 227 of SEQ ID NO: 13. In some embodiments, the PRL polypeptide comprises an amino acid sequence having at least 97%, 98% or 99% sequence identity to SEQ ID NO: 13, and provided that the PRL polypeptide comprises aspartic acid at a position corresponding to position 59, serine at a position corresponding to position 219, and / or serine at position corresponding to a position 227 of SEQ ID NO: 13.

[0111] In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence: SEQ ID NO: 13-18, 21, 23 or 24, and provided that the PRL polypeptide comprises aspartic acid at a position corresponding to position 31, serine at a position corresponding to position 191, and / or serine at position corresponding to a position 227 of SEQ ID NO: 13-18, 21, 23 or 24. In some embodiments, the PRL polypeptide comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 13-18, 21, 23 or 24, and provided that the PRL polypeptide comprises aspartic acid at a position corresponding to position 31, serine at a position corresponding to position 191, and / or serine at position corresponding to a position 199 of SEQ ID NO: 13-18, 21, 23 or 24. In some embodiments, the PRL polypeptide comprises an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 13-18, and provided that the PRL polypeptide comprises aspartic acid at a position corresponding to position 31, serine at a position corresponding to position 191, and / or serine at position corresponding to a position 199 of SEQ ID NO: 13-18, 21, 23 or 24. In some embodiments, the PRL polypeptide comprises an amino acid sequence having at least 97%, 98% or 99% sequence identity to SEQ ID NO: 13-18, 21, 23 or 24, and provided that the PRL polypeptide comprises aspartic acid at a position corresponding to position 31, serine at a position corresponding to position 191, and / or serine at position corresponding to aposition 199 of SEQ ID NO: 13-18, 21, 23 or 24In some embodiments, the PRL polypeptide in the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence: SEQ ID NO: 13, and provided that the PRL polypeptide comprises aspartic acid ata position corresponding to position 31, serine at a position corresponding to position 191, and / or serine at position corresponding to a position 199 of SEQ ID NO: 13. In some embodiments, the PRL polypeptide comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 13, and provided that the PRL polypeptide comprises aspartic acid at a position corresponding to position 31, serine at a position corresponding to position 191, and / or serine at position corresponding to a position 199 of SEQ ID NO: 13. In some embodiments, the PRL polypeptide comprises an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 13-18, and provided that the PRL polypeptide comprises aspartic acid at a position corresponding to position 31, serine at a position corresponding to position 191, and / or serine at position corresponding to a position 199 of SEQ ID NO: 13. In some embodiments, the PRL polypeptide comprises an amino acid sequence having at least 97%, 98% or 99% sequence identity to SEQ ID NO: 13, and provided that the PRL polypeptide comprises aspartic acid at a position corresponding to position 31, serine at a position corresponding to position 191, and / or serine at position corresponding to a position 199 of SEQ ID NO: 13Fc Region

[0112] Fusion of other protein domains to an Fc region of antibody is a routine tool for protein engineering, but an extremely large number of protein domain configurations, in combination with mutations that might be made in the Fc region, are possible and it is difficult to predict which configurations are optimal for a given application. In particular, levels of protein expression, secretion, aggregation of the resulting product, pharmacokinetic behavior, and steric hindrance of a fusion partner by an Fc element can all affect with fusion protein utility. Thus, preparing an Fc-PRL fusion protein with desired properties is not routine.

[0113] In some embodiments, a polypeptide as described herein can comprise one or more types of modifications and / or moieties, e.g. 1 type of modification, 2 types of modifications, 3 types of modifications, or more types of modifications. In some embodiments, the modification modifies the pharmacokinetics (PK) of a polypeptide described herein. In some embodiments, the modification modifies in particular the in vivo half-life and distribution of a polypeptide disclosed herein. In one embodiment, the PK modifying modification increases the half-life of the polypeptide containing the modified amino acid as compared with one containing an otherwise identical unmodified amino acid. Non-limiting examples ofmodifications and / or moieties include PEGylation; PASylation, glycosylation; HESylation; ELPylation; lipidation; acetylation; amidation; end-capping modifications; cyano groups; phosphorylation; albumin, cyclization, and / or substitution (e.g., of the amino group, the carboxylic acid group, one or more protons, and / or the hydroxyl group) as compared with the general structure. In some embodiments, such modification does not significantly alter a relevant activity of a polypeptide containing the modified amino acid, as compared with one containing an otherwise identical unmodified amino acid.

[0114] As used herein, an “Fc region” or “Fc element” is a protein sequence that comprises at least a CH3 domain of an IgG antibody element, and more preferably a CH2 and CH3 domain, and in some cases a hinge region as well. The following are typical Fc regions that are useful in constructing Fc-PRL fusion proteins and that consist of a few amino acids from the CHI domain, a hinge region, a CH2 domain, and a CH3 domain. Fc regions are related to each other through sequence similarity and are defined herein as sequences that can be aligned using BLAST (blast.ncbi.nlm.nih.gov / Blast.cgi) with one of the sequences below to give an “Expect” score of at most le-100 (with lower scores indicating greater similarity). Fc region is also referred to as an Fc domain herein.

[0115] Generally, the “Fc domain” is the polypeptide comprising the constant region of an antibody excluding the first constant region immunoglobulin domain and, in some cases, part or all of the hinge. Thus, an Fc domain refers to the non-antigen binding portion of an antibody, whether in monomeric or multimeric form. The Fc domain can be from any vertebrate source, including mammals such as primates (e.g., humans), non-human primates (e.g. Chimpanzee, Macaque) and rodents (e.g. a mouse, rat, rabbit, guinea pig). Preferably, the antibody from which the Fc domain arises is of human origin.

[0116] An Fc domain includes the hinge region of the heavy chain. By “hinge” or “hinge region” or “antibody hinge region” or “immunoglobulin hinge region” herein is meant the flexible polypeptide comprising the amino acids between the first and second constant domains of an antibody, just upstream of the papain cleavage. Accordingly, for IgG, an Fc domain comprises immunoglobulin domains CH2 and CH3 and the hinge region between CHI and CH2. Although the boundaries of the Fc region may vary, the human IgG heavy chain Fc region is usually defined to include residues C226 or P230 to its carboxyl-terminus, wherein the numbering is according to the EU index and in Kabat. In some embodiments, as is more fully described below, amino acid modifications are made to the Fc region, for example to alter binding to one or more FcyR receptors or to the FcRn receptor.

[0117] It is noted that when a position is indicated with EU numbering of Kabat, the position corresponds to the position in the full length wild-type sequence. When a position is indicated with reference to specific sequence, such position corresponds to the position in the specified sequence.

[0118] Accordingly, in certain embodiments, the term Fc domain includes the hinge region which may be truncated, modified by replacement, deletion and / or insertion and further the modified or unmodified hinge region may be the site of attachment of a linker domain.

[0119] An “analog of an Fc domain” refers to a molecule or sequence that is modified from the native Fc but still comprises a binding site for the salvage receptor. The term analog of an Fc domain includes a molecule or sequence that is humanized from a non-human native Fc. The term analog of an Fc domain also includes a molecule or sequence that lacks, or has modifications of, one or more native Fc residues that affect or are involved in disulfide formation, incompatibility with a host cell, N-terminal heterogeneity upon expression, stability, glycosylation, interaction with a complement, binding to an Fc salvage receptor and / or interaction with an Fey receptor.

[0120] The terms “fragments of the Fc domain” or “fragment of the Fc domain” refers to a native Fc from which one or more sites have been removed where the removed site(s) does not constitute structural features or functional activity that is required by the Fc-PRL fusion proteins of the present invention. Fragments of the Fc domain include deleting residues from the native Fc or truncating the native Fc and may include substitutions of the remaining residues. The inserted or altered residues (e.g., the substituted residues) may be natural amino acids or altered amino acids, peptidomimetics, unnatural amino acids, or D-amino acids.

[0121] Generally, the Fc domain includes a sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to IgGl, IgG2, IgG3, IgG4, IgD, IgA, IgE, or IgM, in particular human IgGl or IgG3.

[0122] In some embodiments, the Fc domain comprises at least a hinge domain (upper, middle, and / or lower hinge region), a CH2 domain (or a variant or fragment thereof), and a CH3 domain (or a variant or fragment thereof). In some embodiments, the Fc domain consists of a hinge domain (upper, middle, and / or lower hinge region), a CH2 domain (or a variant or fragment thereof), and a CH3 domain (or a variant or fragment thereof). In some embodiments, the Fc domain consists of a hinge domain (upper, middle, and / or lower hinge region), a CH2 domain (or a variant or fragment thereof), a CH3 domain (or a variant or fragment thereof), and a CH4 domain (or a variant or fragment thereof). In some embodiments, the Fc domain consists of a hinge domain (upper, middle, and / or lower hinge region) and a CH2 domain. Insome embodiments, the Fc domain consists of a hinge domain (upper, middle, and / or lower hinge region) and a CH3 domain (or a variant or fragment thereof). In some embodiments, the Fc domain consists of a CH2 domain (or a variant or fragment thereof), and a CH3 domain (or a variant or fragment thereof). In some embodiments, the Fc domain consists of a complete CH2 domain and a complete CH3 domain. In some embodiments, the Fc domain consists of a complete CH2 domain and a complete CH3 domain. In some embodiments, the Fc domain comprises at least the portion of an Fc molecule known in the art to be required for FcRn binding. In some embodiments, the Fc domain comprises at least the portion of an Fc molecule known in the art to be required for FcyR binding. In some embodiments, the Fc domain comprises at least the portion of an Fc molecule known in the art to be required for Protein A binding. In some embodiments, the Fc domain comprises at least the portion of an Fc molecule known in the art to be required for Protein G binding.

[0123] As described herein, an Fc domain generally refers to a polypeptide comprising all or part of the Fc domain of an immunoglobulin heavy chain. As discussed above, this includes, but is not limited to polypeptides comprising the entire hinge region, CHI, CH2, and / or CH3 domains as well as fragments of such peptides comprising, for example, the hinge, CH2 and CH3 domains. The Fc domain may be derived from any immunoglobulin of any species and / or subtype, including but not limited to, a human IgGl, IgG2, IgG3, IgG4, IgD, IgA, IgE, or IgM antibody. The Fc domain includes the last two constant region immunoglobulin domains of IgA, IgD, and IgG, the last three constant region immunoglobulin domains of IgE and IgM, and the flexible hinge N-terminal to these domains. For IgA and IgM, Fc may include the J chain.

[0124] The Fc domain as used herein encompasses native Fc and Fc variant molecules. As with the Fc variants and native Fc proteins, the term Fc domain includes molecules in monomeric and multimeric form, whether digested from an antibody or produced by other means.

[0125] It is noted that any Fc domain may be modified such that it varies in amino acid sequence from the native Fc domain of a naturally occurring immunoglobulin molecule. In some embodiments, the Fc domain retains an effector function, for example, FcRN and / or FcyR binding.

[0126] It is also noted that the Fc domain can be derived from different immunoglobulin molecules. For example, the Fc domain can comprise a CH2 and / or CH3 domain derived from one type or subtype of immunoglobulin and a hinge region from a different type or subtype ofimmunoglobulin, such as a CH2 and / or CH3 domain derived from IgGl and a hinge region derived from IgG3 or vice-versa.

[0127] In some embodiments of the various aspects described herein, the Fc domain comprises a hinge region, an IgG CH2 domain and an IgG CH3 domain.

[0128] In some embodiments, the hinge region of the Fc domain has a length of about 10 to about 20 amino acids.

[0129] In some embodiments of the various aspects described herein, the Fc domain is of human origin. In some embodiments, the Fc region extends from Cys226, or from Pro230, to the carboxyl-terminus of the heavy chain of a human IgG.

[0130] The hinge-region between the CH2 and CH3 domains of IgG is able to bind several proteins beyond protein A, such as the neonatal Fc receptor (FcRn). Without wishing to be bound by a theory, FcRn functions to salvage IgG from the lysosomal degradation pathway, resulting in reduced clearance and increased half-life. The FcRn is a heterodimeric protein consisting of two polypeptides: a 50 kDa class I major histocompatibility complex-like protein (a-FcRn) and a 15 kDa B2-microglobulin (P2m). FcRn binds with high affinity to the CH2- CH3 portion of the Fc-region of IgG. The interaction between IgG and FcRn is strictly pH dependent and occurs in a 1 :2 stoichiometry, with one IgG binding to two FcRn molecules via its two heavy chains (Huber, A. H, et al., J. Mol. Biol. 230 (1993) 1077-1083). FcRn binding occurs in the endosome at acidic pH (pH < 6. 5) and IgG is released at the neutral cell surface (pH of about 7. 4). The pH-sensitive nature of the interaction facilitates the FcRn mediated protection of IgGs pinocytosed into cells from intracellular degradation by binding to the receptor within the acidic environment of endosomes. FcRn then facilitates the recycling of IgG to the cell surface and subsequent release into the blood stream upon exposure of the FcRn IgG complex to the neutral pH environment outside the cell.

[0131] Accordingly, in some embodiments, the Fc-PRL fusion protein includes a wild-type Fc domain that can allow the Fc-PRL fusion protein to undergo endocytosis after binding FcRn. For example, the Fc-PRL fusion protein described herein comprises the FcRn binding portion of the Fc of an immunoglobulin. The term “FcRn binding portion of an Fc region” denotes the part of an antibody heavy chain polypeptide that extends approximately from EU position 243 to EU position 261, and approximately from EU position 275 to EU position 293, and approximately from EU position 302 to EU position 319, and approximately from EU position 336 to EU position 348, and approximately from EU position 367 to EU position 393, and EU position 408, and approximately from EU position 424 to EU position 440.

[0132] In some embodiments of the various aspects described herein, one or more of the following amino acid residues, in the Fc domain, according to the EU numbering of Kabat are altered C220, C226, C229, L234, L235, F243, P244, P245, K246, P247, K248, D249, T250, L251, M252, 1253, S254, R255, T256, P257, E258, V259, 1260, C261, V264, F275, N276, W277, Y278, V279, D280, V282, E283, V284, H285, N286, A287, K288, T289, K290, P291, R292, E293, N297, V302, V303, S304, V305, L306, T307, V308, L309, H310, 0311, Q311, D312, W313, L314, N315, G316, K317, E318, Y319, P329, 1336, S337, K338, A339, K340, G341, Q342, P343, R344, E345, P346, Q347, V348, T350, L351, T366, C367, L368, V369, F372, Y373, P374, S375, D376, 1377, A378, V379, E380, W381, E382, S383, N384, G385, Q386, P387, E388, N389, Y391, K392, T393, T394, F405, Y407, S408, S424, C425, S426, V427, M428, H429, E430, A431, L432, H433, N434, H435, Y436, T437, Q438, K439, S440, and K447 (EU numbering).

[0133] In some embodiments of the various aspects described herein, one or more of the following amino acid residues, in the Fc domain, according to the EU numbering of Kabat are altered C220, C226, C229, L234, L235, M252, S254, T256, V264, N297, L309, P329, T350, L351, T366, L368, K392, T394, F405, Y407, , N434, H435, Y436, and K447 (EU numbering of Kabat).Wild-type Fc

[0134] In some embodiments of the various aspects described herein, the Fc domain comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence selected from the group consisting ofEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 25, human IgGl);KTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRWSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 26, human IgG2);ELKTPLGDTTHTCPRCPEPKSCDTPPPCPRCPEPKSCDTPPPCPRCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFKWYVDGVEVHNAKTKPWEEQYNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAMEWESSGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNIFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 27, human IgG3);KVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG NVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 28, human IgG4);GEKMGDGCVREPSVFIFPPKPKDTLMITGTPEVTCWVNVGHDNPEVQFSWFVDDVEVHTARTKPREEQFNSTYRVVSALPIQHQDWTGGKEFKCKVNNKGLSAPIVRIISRSKGPAREPQVYVLDPPKEELSKSTLSVTCMVTGFYPEDVAVEWQRNRQTESEDKYRTTPPQLDTDRSYFLYSKLRVDRNSWQEGDTYTCVVMHEALHNHYTQKSTSKSAGK (SEQ ID NO: 29, Cow IgGl Fc WT (Uniprot A0A3Q1N3I9))TCPKCPGKSAEPLGGLSVFIFPPKPKDTLTISGTPEVTCVVVDVGQDDPEVQFSWFMDNVEVHTARTTPREEQFNSTFRVVSALPIQHKDWLQGKEFKCKVHNEGLPAPIIRTISRAKGQAREPQVYVLAPPREELSKSTLSVTCLITGFYPEEVDVEWQRDGQPESEDKYHTAPPQLDADGSYFLYSRLRVNKSSWQEGDTYTCAVMHEALRNHYKEKSISKSPGK (SEQ ID NO: 30, Goat IgGl Fc WT (Uniprot A0A452EKB3))EPGCPDPCKHCRCPPPELPGGPSVFIFPPKPKDTLTISGTPEVTCVVVDVGQDDPEVQFSWFVDNVEVRTARTKPREEQFNSTFRVVSALPIQHQDWTGGKEFKCKVHNEALPAPIVRTISRTKGQAREPQVYVLAPPQEELSKSTLSVTCLVTGFYPDYIAVEWQKNGQPESEDKYGTTTSQLDADGSYFLYSRLRVDKNSWQEGDTYACVVMHEALHNHYTQKSISKPPGK (SEQ ID NO: 31, Sheep IgGl Fc WT (GB accession X69797))EPRVPITQNPCPPLKECPPCAAPDLLGGPSVFIFPPKIKDVLMISLSPMVTCVVV DVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMS GKEFKCKVNNRALPSPIEKTISKPRGPVRAPQVYVLPPPAEEMTKKEFSLTCMI TGFLPAEIAVDWTSNGRTEQNYKNTATVLDSDGSYFMYSKLRVQKSTWERG SLFACSVVHEGLHNHLTTKTISRSLGK (SEQ ID NO: 32, mouse IgA2 heavy chain).KTTPPSVYPLAPGCGDTTGSSVTLGCLVKGYFPESVTVTWNSGSLSSSVHTFP ALLQSGLYTMSSSVTVPSSTWPSQTVTCSVAHPASSTTVDKKLEPSGPISTINP CPPCKECHKCPAPNLEGGPSVFIFPPNIKDVLMISLTPKVTCVVVDVSEDDPDV QISWFVNNVEVHTAQTQTHREDYNSTIRWSTLPIQHQDWMSGKEFKCKVN NKDLPSPIERTISKIKGLVRAPQVYILPPPAEQLSRKDVSLTCLVVGFNPGDISVEWTSNGHTEENYKDTAPVLDSDGSYFIYSKLNMKTSKWEKTDSFSCNVRHE GLKNYYLKKTISRSPG (SEQ ID NO: 93, mouse IgG2b FC)Mutated Fc

[0135] It is often useful to introduce mutations in the Fc region. For example, one or more of the following amino acid residues, in the Fc region, according to the EU numbering of Kabat are altered C220, N297, and / or K447. In some embodiments, the Fc region comprises one or more mutations selected from C220S, N297D, N297E, and K447A. For example, the Fc region comprises an amino acid sequence where the sequence EPKSCDKTHTCP (SEQ ID NO: 33) is mutated to EPKSSDKTHTCP (SEQ ID NO: 34); the sequence KTKPREEQYNSTYRVVSVLT (SEQ ID NO: 35) is mutated to KTKPREEQYDSTYRVVSVLT (SEQ ID NO: 36) or KTKPREEQYQSTYRVVSVLT (SEQ ID NO: 37); and / or the sequence QKSLSLSLGK (SEQ ID NO: 38) is mutated to QKSLSLSLGA (SEQ ID NO: 39, Lys447Ala) or the sequence QKSLSLSPGK (SEQ ID NO: 250) is mutated to QKSLSLSPGA (SEQ ID NO: 251, Lys447Ala). In some embodiments, the Fc region comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence: SEQ ID NO: 25, and wherein the sequencecomprises an K to A substitution at a position corresponding to position 232 of SEQ ID NO: 25.

[0136] In some embodiments, the Fc region comprises at least one modification selected from the group consisting of: LALA; PG; VE; YTE; LS; DHS; and negative charge modifications. For example, a human Fc region (e.g., IgGl) comprises an amino acid sequence where one or more of the following amino acid residues are altered K218, S219, L234, L235, M252, S254, T256, V264, L309, Q311, P329, M428, N434, and K447 (EU numbering of Kabat). For example, a human Fc region (e.g., IgGl) comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence: SEQ ID NO: 25, and wherein the sequence comprises a mutation at a position corresponding to position 3, 4, 19, 20, 37, 39, 41, 49, 94, 96, 114, 213, 219, and / or 232 of the SEQ ID NO: 25. In some embodiments, a human Fc region (e.g., IgGl) comprises an amino acid sequence comprising at least one mutation selected from the group consisting of: K218E, S219E, L234A, L235A, M252Y, S254T, T256E, V264E, L309D, Q311H, P329G, M428L, N434S, and K447E (EU numbering of Kabat). For example, the Fc region comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence: SEQ ID NO: 25, and wherein the sequence comprises a K to E substation at a position corresponding to position 3, a S to E substitution at a position corresponding to position 4, a L to A substitution at a position corresponding to position 19, a L to A substitution at a position corresponding to position 20, a M to Y substitution at a position corresponding to position 37, a S to T substitution at a position corresponding to position 39, a T to E substitution at a position corresponding to position 41, a V to E substitution at a position 49, a L to D substitution at a position corresponding to position 94, a Q to H substitution at a position corresponding to position 96, a P to G substitution at a position 114, a M to L substitution at a position corresponding to position 213, a N to S substitution at a position corresponding to position 219, and / or an K to E substitution at a position corresponding to position 232 of SEQ ID NO: 25.

[0137] In some embodiments, a murine Fc region (e.g., IgG2b) comprises an amino acid sequence where one or more of the following amino acid residues are altered L241, E242, M259, S261, T263, V271, Q316, Q318, P336G, N431, and R435 (EU numbering of Kabat). For example, a murine FC region comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence: SEQ ID NO: 93, and wherein thesequence comprises a mutation at a position corresponding to position 122, 123, 140, 142, 144, 152, 197, 199, 217, 314, and / or 316 SEQ ID NO: 93. In some embodiments, a murine Fc region (e.g., IgG2b) comprises an amino acid sequence comprising at least one modification selected from the group consisting of L241A, E242A, M259Y, S261T, T263E, V271E, Q316D, Q318H, P336G, N431 S, and R435L (EU numbering of Kabat). For example, the murine Fc region comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence: SEQ ID NO: 93, and wherein the sequence comprises a L to A substitution at a position corresponding to position 122, a E to A substitution at a position corresponding to position 123, a M to Y substitution at a position corresponding to position 140, a S to T substitution at a position corresponding to position 142, a T to E substitution at a position corresponding to position 144, a V to E substitution at a position corresponding to position 152, a Q to D substitution at a position corresponding to position 197, a Q to H substitution at a position corresponding to position 199, a P to G substitution at a position corresponding to position 217, a N to S substitution at a position corresponding to position 314, and / or a R to L substitution at a position corresponding to position 316 of the SEQ ID NO: 93

[0138] In some embodiments, a “LALA” modification in a human Fc region (e.g., IgGl) comprises a mutation / substitution at one or more of positions L234 and L235 (EU numbering of Kabat). For example, in a human Fc region (e.g., IgGl) a LALA modification comprises a L234A and / or L235A mutation (EU numbering of Kabat), such as converting the sequence TCPPCPAPELLGGPSVFLFPPK (SEQ ID NO: 40) to TCPPCPAPEAAGGPSVFLFPPK (SEQ ID NO: 41; e.g., L234A, L235A) near the N-terminus of the Fc region.

[0139] In a murine IgG2b Fc, a “LALA” modification comprises a mutation at one or more of positions L241 and E242 (EU numbering of Kabat). For example, in murine IgG2B Fc, a LALA modification comprises a L241A and / or E242A mutation (EU numbering of Kabat), such as converting the sequence ECHKCPAPNLEGGPSVFIFPPN (SEQ ID NO: 42) to ECHKCPAPNAAGGPSVFIFPPN (SEQ ID NO: 43; e g., L241A, E242A) near the N- terminus of the Fc region.

[0140] In some embodiments, a “PG” modification in a human Fc region comprises a mutation at position P329 (EU numbering of Kabat). For example, a PG modification in a human Fc region comprises the modification P329G (EU numbering of Kabat), such as converting the sequence CKVSNKALPAPIEKTIS (SEQ ID NO: 44) to CKVSNKALGAPIEKTIS (SEQ ID NO: 45) in the human Fc region.

[0141] In a murine IgG2b Fc, a “PG” modification comprises a mutation at position P236 (EU numbering of Kabat). For example, a PG modification in a murine Ig2b Fc region comprises the modification P236G (EU numbering of Kabat), such as converting the sequence CKVNNKDLPSPIERTIS (SEQ ID NO: 46) to CKVNNKDLGSPIERTIS (SEQ ID NO: 47).

[0142] In some embodiments, a “VE” modification in human IgGl Fc region comprises a mutation at position V264. For example, a VE modification in a human IgGl Fc region comprises the modification V264E (EU numbering of Kabat), such as converting the sequence VTCWVDVS (SEQ ID NO: 48) to VTCVVEDVS (SEQ ID NO: 49) in a human IgGl near the N-terminus of the Fc region.

[0143] In some embodiments, a “VE” modification in a murine IgG2b Fc region comprises a mutation at position V271. For example, a VE modification in a murine IgG2b Fc region comprises the modification V271E (EU numbering of Kabat), such as converting the sequence VTCVWDVS (SEQ ID NO: 48) to VTCVVEDVS (SEQ ID NO: 49) in a murine IgG2b near the N-terminus of the Fc region.

[0144] In some embodiments, a “YTE” modification in a human IgGl Fc region comprises a mutation at position M252, S254, and / or T256 (EU numbering of Kabat). For example, a YTE modification in a human IgGl Fc region comprises the modification M252Y, S254T, and / or T256E (EU numbering of Kabat), such as converting the sequence DTLMISRTPE (SEQ ID NO: 50) to DTLYITREPE (SEQ ID NO: 51) near the N-terminus of the Fc region.

[0145] In a murine IgG2b Fc, a “YTE” modification comprises a mutation at position M259, S261, and / or T263 (EU numbering of Kabat). For example, a YTE modification in a murine IgG2b Fc comprises the modification M259Y, S261T, and / or T263E (EU numbering of Kabat), such as converting the sequence DVLMISLTPK (SEQ ID NO: 52) to DVLYITLEPK (SEQ ID NO: 53) near the N-terminus of the Fc region.

[0146] In some embodiments, a “LS” modification in a human Fc region comprises a mutation at position M428 and / or N434 (EU numbering of Kabat). For example, a LS modification in a human Fc region comprises the mutation M428L and / or N434S (EU numbering of Kabat), such as converting the sequence FSCSVMHEALHNHYT (SEQ ID NO: 54) to FSCSVLHEALHSHYT (SEQ ID NO: 55) near the C-terminus of the Fc region.

[0147] In a murine IgG2b Fc, a “LS” modification comprises a mutation at position R435 and / or N441 (EU numbering of Kabat). For example, a LS modification in a murine Fc region comprises the modification R435L and / or N441 S (EU numbering ofKabat), such as converting the sequence FSCNVRHEGLKNYYL (SEQ ID NO: 56) to FSCNVLHEGLKSYYL (SEQ ID NO: 57) near the C-terminus of the Fc region.

[0148] In a human IgGl Fc region, a “DHS” modification comprises a mutation at position L309, Q311, and / or N434 (EU numbering of Kabat). For example, a DHS modification in a human Fc region comprises the mutation L309D, Q311H, and / or N434S (EU numbering of Kabat), such as converting the sequence LTVLHQDWLN (SEQ ID NO: 58) to LTVDHHDWLN (SEQ ID NO: 59) near the middle of the Fc region and / or converting the sequence EALHNHYTQK (SEQ ID NO: 60) to EALHSHYTQK (SEQ ID NO: 61) near the C-terminus of the Fc region.

[0149] In a murine IgG2b Fc, a “DHS” modification comprises a mutation at position Q216, Q218, and / or N241 (EU numbering of Kabat). For example, a DHS modification in a human Fc region comprises the mutation Q216D, Q218H, and / or N241S (EU numbering of Kabat), such as converting the sequence LPIQHQDWMS (SEQ ID NO: 62) to LPIDHHDWMS (SEQ ID NO: 63) near the middle of the Fc region and / or converting the sequence EGLKNYYLKK (SEQ ID NO: 64) to EGLKSYYLKK (SEQ ID NO: 65) near the C-terminus of the Fc region.

[0150] It is noted that an “EDHS” modification comprises a “VE” modification combined with a “DHS” modification.

[0151] In some embodiments, a “negative charge” modification comprises modifying at least one amino acid to a negatively charged amino acid, such as aspartic acid (Asp, D) or glutamic acid (Glu, E) (acidic side chains).

[0152] For example, a “negative charge” modification in a human Fc region comprises a mutation at position K218, S219, and / or K447 (EU numbering of Kabat). For example, a negative charge modification in a human Fc region comprises the mutation K218E, S219E and / or K447E (EU numbering of Kabat), such as converting the sequence EPKSCDKTHT (SEQ ID NO: 66) to EPEECDKTHT. (SEQ ID NO: 67) at the N-terminus of the Fc region, and / or converting the sequence QKSLSLSPGK (SEQ ID NO: 68) to QKSLSLSPGE (SEQ ID NO: 69) at the C-terminus of the Fc region. In a murine IgG2b Fc, a “negative charge” modification comprises a mutation at K218E, S220E and / or K447E (EU numbering ofKabat). For example, a negative charge modification in a murine Fc region comprises the mutation K218E, S220E and / or K447E (EU numbering of Kabat), such as converting the sequence EPKSSPPCKE (SEQ ID NO: 70) to EPESEPPCKE (SEQ ID NO: 71) at the N-terminus of the Fc region, and / or converting the sequence TKTISRSLGK (SEQ ID NO: 72) to TKTISRSLGE (SEQ ID NO: 73) at the C-terminus of the Fc region.

[0153] Mutated Fc from the examples

[0154] In some embodiments of the various aspects described herein, one or more of the following amino acid residues, in the Fc domain, according to the EU numbering of Kabat are altered C220, N297, and K447 (EU numbering of Kabat).

[0155] In some embodiments of the various aspects described herein, the Fc domain comprises at least one mutation selected from the group consisting of: C220S, N297D, and K447A (EU numbering of Kabat).

[0156] In some embodiments of the various aspects described herein, one or more of the following amino acid residues, in the Fc domain, according to the EU numbering of Kabat are altered C220, N297, K447, L234, L235, V264, L309, Q311, and N434 (EU numbering of Kabat).

[0157] In some embodiments of the various aspects described herein, the Fc domain comprises at least one mutation selected from the group consisting of: C220S, N297D, K447A, L234A, L235A, V264E, L309D, Q311H, and N434S (EU numbering of Kabat).

[0158] In some embodiments of the various aspects described herein, one or more of the following amino acid residues, in the Fc domain, according to the EU numbering of Kabat are altered C220, N297, K447, L234, L235, P329, V264, L309, Q311, and N434 (EU numbering of Kabat).

[0159] In some embodiments of the various aspects described herein, the Fc domain comprises at least one mutation selected from the group consisting of: C220S, N297D, K447A, L234A, L235A, P329G, V264E, L309D, Q311H, and N434S (EU numbering of Kabat).

[0160] In some embodiments of the various aspects described herein one or more of the following amino acid residues, in the Fc domain, according to the EU numbering of Kabat are altered C220, N297, K447, L234, L235, M252, S254 and T256 (EU numbering of Kabat).

[0161] In some embodiments of the various aspects described herein, the Fc domain comprises at least one mutation selected from the group consisting of: C220S, N297D, K447A, L234A, L235A, M252Y, S254T and T256E (EU numbering of Kabat).

[0162] In some embodiments of any one of the aspects described herein, the Fc domain comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence selected from the group consisting of:EPKSsDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGa (SEQ ID NO: 74, Fc C220S, N297D and K447A);EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVDHHDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHSHYTQKSLSLSPGa (SEQ ID NO: 75, Fc C220S, N297D, K447A, L234A, L235A, V264E, L309D, Q311H, N434S);EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVDHHDWLNGKEY KCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHSHYTQKSLSLSPGa (SEQ ID NO: 76, Fc C220S, N297D, K447A, L234A, L235A, P329G, V264E, L309D, Q311H, N434S); andEPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITREPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGa (SEQ ID NO: 77, C220S, N297D, K447A, L234A, L235A, M252Y, S254T, T256E).

[0163] In some embodiments, the Fc domain comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 74-77. In some embodiments, the Fc domain comprises an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 74-77. In some embodiments, the Fc domain comprises an amino acid sequence having at least 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 74-77. In some embodiments, the PRL polypeptidein the Fc domain comprises an amino acid sequence having 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 74-77.

[0164] In some embodiments, the Fc domain comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 74-77, provided that the sequence comprises a S at a position corresponding to position 5, a D at a position corresponding to position 82, a A at a position corresponding to position 232, an A at a position corresponding to position 19, an A at a position corresponding to position 20, a Y at a position corresponding to position 37, a T at a position corresponding to position 39, an E at a position corresponding to position 41, a G at a position corresponding to position 114, an E at a position corresponding to position 49, a D at position 94, a H at a position corresponding to position 96, and / or an S at a position corresponding to position 219 of SEQ ID NO: 74-77.

[0165] In some embodiments, the Fc domain comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 74-77, provided that the sequence comprises a S at a position corresponding to position 220, a D at a position corresponding to position 297, a A at a position corresponding to position 447, an A at a position corresponding to position 234, an A at a position corresponding to position 235, a Y at a position corresponding to position 252, a T at a position corresponding to position 254, an E at a position corresponding to position 256, a G at a position corresponding to position 329, an E at a position corresponding to position 264, a D at position 309, a H at a position corresponding to position 311, and / or an S at a position corresponding to position 434 (EU numbering of Kabat).

[0166] In some embodiments, the Fc domain comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 74-77, provided that the sequence does not comprises a C at a position corresponding to position 5, a N at a position corresponding to position 82, a K at a position corresponding to position 232, an L at a position corresponding to position 19, an L at a position corresponding to position 20, a M at a position corresponding to position 37, a S at a position corresponding to position 39, a T at a position corresponding to position 41, a P at a position corresponding to position 114, a V at a position corresponding to position 49, a L at position 94, a Q at a position corresponding to position 96, and / or an N at a position corresponding to position 219 of SEQ ID NO: 74-77.

[0167] In some embodiments, the Fc domain comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequenceselected from the group consisting of SEQ ID NO: 74-77, provided that the sequence does not comprises a C at a position corresponding to position 220, a N at a position corresponding to position 297, a K at a position corresponding to position 447, an L at a position corresponding to position 234, an L at a position corresponding to position 235, a M at a position corresponding to position 252, a S at a position corresponding to position 254, an T at a position corresponding to position 256, a P at a position corresponding to position 329, an V at a position corresponding to position 264, a L at position 309, a Q at a position corresponding to position 311, and / or an N at a position corresponding to position 434 (EU numbering of Kabat).Fc A

[0168] In some embodiments of the various aspects described herein, one or more of the following amino acid residues, in the Fc domain, according to the EU numbering of Kabat are altered C220, L234, L235, M252, S254, T256, V264, N297, L309, Q311, P329, T350, L351, F405, Y407, N434, H435, Y436, and K447 (EU numbering of Kabat).

[0169] In some embodiments of the various aspects described herein, one or more of the following amino acid residues, in the Fc domain, according to the EU numbering of Kabat are altered C220, N297, K447, T350, L351, F405, and Y407 (EU numbering of Kabat).

[0170] In some embodiments of the various aspects described herein, one or more of the following amino acid residues, in the Fc domain, according to the EU numbering of Kabat are altered C220, N297, K447, L234, L235, V264, L309, Q311, and N434 (EU numbering of Kabat).

[0171] In some embodiments of the various aspects described herein, one or more of the following amino acid residues, in the Fc domain, according to the EU numbering of Kabat are altered L234, L235, V264, L309, Q311 and N434 (EU numbering of Kabat).

[0172] In some embodiments of the various aspects described herein, one or more of the following amino acid residues, in the Fc domain, according to the EU numbering of Kabat are altered C220, N297, K447, L234, L235, P329, V264, L309, Q311, N434, H435, and Y436 (EU numb eri ng of Kab at) .

[0173] In some embodiments of the various aspects described herein, one or more of the following amino acid residues, in the Fc domain, according to the EU numbering of Kabat are altered C220, N297, K447, T350, L351, F405, Y407, L234, L235, V264, L309, Q311, and N434 (EU numbering of Kabat).

[0174] In some embodiments of the various aspects described herein, one or more of the following amino acid residues, in the Fc domain, according to the EU numbering of Kabat are altered C220, N297, K447, T350, L351, F405, Y407, L234, L235, P329, V264, L309, Q311, and N434 (EU numbering of Kabat).

[0175] In some embodiments of the various aspects described herein, the Fc domain comprises at least one mutation selected from the group consisting of: C220S, N297D, K447A, T350V, L351Y, F405A, and Y407V (EU numbering of Kabat).

[0176] In some embodiments of the various aspects described herein, the Fc domain comprises at least one mutation selected from the group consisting of: C220S, N297D, K447A, L234A, L235A, V264E, L309D, Q311H, and N434S (EU numbering of Kabat).

[0177] In some embodiments of the various aspects described herein, the Fc domain comprises at least one mutation selected from the group consisting of: L234A, L235A, V264E, L309D, Q311H and N434S (EU numbering of Kabat).

[0178] In some embodiments of the various aspects described herein, the Fc domain comprises at least one mutation selected from the group consisting of: C220S, N297D, K447A, L234A, L235A, P329G, V264E, L309D, Q311H, N434S, H435R, and Y436F (EU numbering of Kabat).

[0179] In some embodiments of the various aspects described herein, the Fc domain comprises at least one mutation selected from the group consisting of: C220S, N297D, K447A, T350V, L351Y, F405A, Y407V, L234A, L235A, V264E, L309D, Q311H, and N434S (EU numb eri ng of Kab at) .

[0180] In some embodiments of the various aspects described herein, the Fc domain comprises at least one mutation selected from the group consisting of: C220S, N297D, K447A, T350V, L351Y, F405A, Y407V, L234A, L235A, P329G, V264E, L309D, Q311H, andN434S (EU numbering of Kabat).

[0181] In some embodiments, the Fc domain comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence selected from the group consisting of:EPKSsDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYVYPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFALVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGa (SEQ ID NO: 78, C220S, N297D, K447A, T350V, L351Y, F405A, Y407V);EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVDHHDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYVYPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFALVSKLTVDKSRWQQGNVFS CSVMHEALHSHYTQKSLSLSPGa (SEQ ID NO: 79, C220S, N297D, K447A, T350V, L351Y, F405A, Y407V, L234A, L235A, V264E, L309D, Q311H, N434S);PKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVEDVSHED PEVKFNWYVDGVEVHNAKTKPREEQYdSTYRWSVLTVDHHDWLNGKEYK CKVSNKALGAPIEKTISKAKGQPREPQVYVYPPSRDELTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFALVSKLTVDKSRWQQGNVFSC SVMHEALHSHYTQKSLSLSPGa (SEQ ID NO: 80, C220S, N297D, K447A, T350V, L351Y, F405A, Y407V, L234A, L235A, P329G, V264E, L309D, Q311H, N434S); andEPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITREPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYVYPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFALVSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGa (SEQ ID NO: 81, (C220S, N297D, K447A, T350V, L351Y, F405A, Y407V, L234A, L235A, M252Y, S254T, T256E).

[0182] In some embodiments, the Fc domain comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 78-81. In some embodiments, the Fc domain comprises an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 78-81. In some embodiments, the Fc domain comprises an amino acid sequence having at least 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 78-81. In some embodiments, the PRL polypeptide in the Fc domain comprises an amino acid sequence having 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 78-81.

[0183] In some embodiments, the Fc domain comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 78-81, provided that the sequence comprises a S at a position corresponding to position 5, a D at a position corresponding to position 82, a A at a position corresponding to position 232, an A at a position corresponding to position 19, an A at a position corresponding to position 20, a Y at a position corresponding to position 37, a T at a position corresponding to position 39, an E at a position corresponding to position 41, a G at a position corresponding to position 114, an E at a position corresponding to position 49, a D at position 94, a H at a position corresponding to position 96, and / or an S at a position corresponding to position 219, a V at a position corresponding to position 135, a Y at a position corresponding to position 136, an A at a position corresponding to position 190, and / or a V at a position corresponding to position 192 of SEQ ID NO: 78-81.

[0184] In some embodiments, the Fc domain comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 78-81, provided that the sequence comprises a S at a position corresponding to position 220, a D at a position corresponding to position 297, a A at a position corresponding to position 447, an A at a position corresponding to position 234, an A at a position corresponding to position 235, a Y at a position corresponding to position 252, a T at a position corresponding to position 254, an E at a position corresponding to position 256, a G at a position corresponding to position 329, an E at a position corresponding to position 264, a D at position 304, a H at a position corresponding to position 311, and / or an S at a position corresponding to position 434, a V at a position corresponding to position 350, a Y at a position corresponding to position 351, an A at a position corresponding to position 405, and / or a V at a position corresponding to position 407 of SEQ ID NO: 78-81

[0185] In some embodiments, the Fc domain comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 78-81, provided that the sequence does not comprise a S at a position corresponding to position 5, a D at a position corresponding to position 82, a A at a position corresponding to position 232, an A at a position corresponding to position 19, an A at a position corresponding to position 20, a Y at a position corresponding to position 37, a T at a position corresponding to position 39, an E at a position corresponding to position 41, a G at a position corresponding to position 114, an E at a position corresponding to position 49, a D at position 94, a H at a position corresponding to position 96, and / or an S ata position corresponding to position 219, a V at a position corresponding to position 135, a Y at a position corresponding to position 136, an A at a position corresponding to position 190, and / or a V at a position corresponding to position 192 of SEQ ID NO: 78-81.

[0186] In some embodiments, the Fc domain comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 78-81, provided that the sequence does not comprise a S at a position corresponding to position 220, a D at a position corresponding to position 297, a A at a position corresponding to position 447, an A at a position corresponding to position 234, an A at a position corresponding to position 235, a Y at a position corresponding to position 252, a T at a position corresponding to position 254, an E at a position corresponding to position 256, a G at a position corresponding to position 329, an E at a position corresponding to position 264, a D at position 304, a H at a position corresponding to position 311, and / or an S at a position corresponding to position 434, a V at a position corresponding to position 350, a Y at a position corresponding to position 351, an A at a position corresponding to position 405, and / or a V at a position corresponding to position 407 of SEQ ID NO: 78-81Fc B

[0187] In some embodiments of the various aspects described herein, one or more of the following amino acid residues, in the Fc domain, according to the EU numbering of Kabat are altered C220, L234, L235, M252, S254, T256, V264, N297, L309, Q311, P329, T350, T366, K392, T394, N434, H435, Y436, , and K447 (EU numbering of Kabat).

[0188] In some embodiments of the various aspects described herein, one or more of the following amino acid residues, in the Fc domain, according to the EU numbering of Kabat are altered C220, N297, K447, T350, T366, K392, and T394 (EU numbering of Kabat).

[0189] In some embodiments of the various aspects described herein, one or more of the following amino acid residues, in the Fc domain, according to the EU numbering of Kabat are altered C220, N297, K447, T350, T366, K392, T394, L234, L235, V264, L309, Q311, N434, H435, and Y436 (EU numbering of Kabat).

[0190] In some embodiments of the various aspects described herein, one or more of the following amino acid residues, in the Fc domain, according to the EU numbering of Kabat are altered C220, N297, K447, T350, T366, K392, T394, L234, L235, P329, V264, L309, Q311, N434, H435, and Y436 (EU numbering of Kabat).

[0191] In some embodiments of the various aspects described herein, one or more of the following amino acid residues, in the Fc domain, according to the EU numbering of Kabat are altered C220, N297, K447, T350, T366, K392, T394, L234, L235, M252, S254, T256, H435, and Y436 (EU numbering of Kabat).

[0192] In some embodiments of the various aspects described herein, the Fc domain comprises at least one mutation selected from the group consisting of: C220S, N297D, K447A, T350V, T366L, K392L, and T394W (EU numbering of Kabat).

[0193] In some embodiments of the various aspects described herein, the Fc domain comprises at least one mutation selected from the group consisting of: C220S, N297D, K447A, T350V, T366L, K392L, T394W, H435R, and Y436F (EU numbering of Kabat).

[0194] In some embodiments of the various aspects described herein, the Fc domain comprises at least one mutation selected from the group consisting of: C220S, N297D, K447A, T350V, T366L, K392L, T394W, L234A, L235A, P329G, V264E, L309D, Q311H, N434S, H435R, and Y436F (EU numbering of Kabat).

[0195] In some embodiments of the various aspects described herein, the Fc domain comprises at least one mutation selected from the group consisting of: C220S, N297D, K447A, T350V, T366L, K392L, T394W, L234A, L235 A, M252Y, S254T, T256E, H435R, and Y436F (EU numbering of Kabat).

[0196] In some embodiments of any one of the aspects described herein, the Fc domain comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence selected from the group consisting of:EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVDHHDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYVLPPSRDELTKNQVSLLCLVKGF YPSDI AVEWESNGQPENNYLTWPPVLD SDGSFFLYSKLTVDKSRWQQGNVF S CSVMHEALHSHYTQKSLSLSPGa (SEQ ID NO: 82, C220S, N297D, K447A, T350V, T366L, K392L, T394W, L234A, L235A, V264E, L309D, Q311H, N434S);EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVDHHDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYVLPPSRDELTKNQVSLLCLVKGF YPSDI AVEWESNGQPENNYLTWPPVLD SDGSFFLYSKLTVDKSRWQQGNVF SCSVMHEALHSRFTQKSLSLSPGa (SEQ ID NO: 83, C220S, N297D, K447A, T350V, T366L, K392L, T394W, L234A, L235A, V264E, L309D, Q311H, N434S, H435R, Y436F);EPKSsDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYVLPPSRDELTKNQVSLLCLVKGF YPSDI AVEWESNGQPENNYLTWPPVLD SDGSFFLYSKLTVDKSRWQQGNVF S CSVMHEALHNHYTQKSLSLSPGa (SEQ ID NO: 84, C220S, N297D, K447A, T350V, T366L, K392L, T394W);EPKSsDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYVLPPSRDELTKNQVSLLCLVKGF YPSDI AVEWESNGQPENNYLTWPPVLD SDGSFFLYSKLTVDKSRWQQGNVF S CSVMHEALHNRFTQKSLSLSPGa (SEQ ID NO: 85, C220S, N297D, K447A, T350V, T366L, K392L, T394W, H435R, Y436F);EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVDHHDWLNGKEY KCKVSNKALGAPIEKTISKAKGQPREPQVYVLPPSRDELTKNQVSLLCLVKGF YPSDI AVEWESNGQPENNYLTWPPVLD SDGSFFLYSKLTVDKSRWQQGNVF S CSVMHEALHSRFTQKSLSLSPGa (SEQ ID NO: 86, C220S, N297D, K447A, T350V, T366L, K392L, T394W, L234A, L235A, P329G, V264E, L309D, Q311H, N434S, H435R, Y436F); andEPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITREPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYVLPPSRDELTKNQVSLLCLVKGF YPSDI AVEWESNGQPENNYLTWPPVLD SDGSFFLYSKLTVDKSRWQQGNVF S CSVMHEALHNRFTQKSLSLSPGa (SEQ ID NO: 87, C220S, N297D, K447A, T350V, T366L, K392L, T394W, L234A, L235A, M252Y, S254T, T256E, H435R, Y436F).

[0197] In some embodiments, the Fc domain comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 82-87. In some embodiments, the Fc domain comprises an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 82-87. In some embodiments, the Fc domain comprises an amino acid sequence having at least 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 82-87. In some embodiments, the PRL polypeptide in the Fc domain comprises an amino acid sequence having 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 82-87.

[0198] In some embodiments, the Fc domain comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 82-87, provided that the sequence comprises a S at a position corresponding to position 5, a D at a position corresponding to position 82, a A at a position corresponding to position 232, an A at a position corresponding to position 19, an A at a position corresponding to position 20, a Y at a position corresponding to position 37, a T at a position corresponding to position 39, an E at a position corresponding to position 41, a G at a position corresponding to position 114, an E at a position corresponding to position 49, a D at position 94, a H at a position corresponding to position 96, and / or an S at a position corresponding to position 219, a V at a position corresponding to position 135, an L at a position corresponding to position 151, an L at a position corresponding to position 177, a W at a position corresponding to position 179, a R at a position corresponding to position 220, and / or a F at a position corresponding to position 221 of SEQ ID NO: 82-87.

[0199] In some embodiments, the Fc domain comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 82-87, provided that the sequence comprises a S at a position corresponding to position 220, a D at a position corresponding to position 297, a A at a position corresponding to position 447, an A at a position corresponding to position 234, an A at a position corresponding to position 235, a Y at a position corresponding to position 252, a T at a position corresponding to position 254, an E at a position corresponding to position 256, a G at a position corresponding to position 329, an E at a position corresponding to position 264, a D at position 309, a H at a position corresponding to position 311, and / or an S at a position corresponding to position 434, a V at a position corresponding to position 350, an L at a position corresponding to position 366, an L at a position corresponding to position 392, a W at a position corresponding to position 394, a R ata position corresponding to position 220, and / or a F at a position corresponding to position 436 of SEQ ID NO: 82-87

[0200] In some embodiments, the Fc domain comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 82-87, provided that the sequence does not comprise a S at a position corresponding to position 5, a D at a position corresponding to position 82, a A at a position corresponding to position 232, an A at a position corresponding to position 19, an A at a position corresponding to position 20, a Y at a position corresponding to position 37, a T at a position corresponding to position 39, an E at a position corresponding to position 41, a G at a position corresponding to position 114, an E at a position corresponding to position 49, a D at position 94, a H at a position corresponding to position 96, and / or an S at a position corresponding to position 219, a V at a position corresponding to position 135, an L at a position corresponding to position 151, an L at a position corresponding to position 177, a W at a position corresponding to position 179, a R at a position corresponding to position 220, and / or a F at a position corresponding to position 221 of SEQ ID NO: 82-87.

[0201] In some embodiments, the Fc domain comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 82-87, provided that the sequence does not comprise a S at a position corresponding to position 220, a D at a position corresponding to position 297, a A at a position corresponding to position 447, an A at a position corresponding to position 234, an A at a position corresponding to position 235, a Y at a position corresponding to position 252, a T at a position corresponding to position 254, an E at a position corresponding to position 256, a G at a position corresponding to position 329, an E at a position corresponding to position 264, a D at position 309, a H at a position corresponding to position 311, and / or an S at a position corresponding to position 434, a V at a position corresponding to position 350, an L at a position corresponding to position 366, an L at a position corresponding to position 392, a W at a position corresponding to position 394, a R at a position corresponding to position 220, and / or a F at a position corresponding to position 436 of SEQ ID NO: 82-87Fc knob

[0202] In some embodiments of the various aspects described herein, one or more of the following amino acid residues, in the Fc domain, according to the EU numbering of Kabat arealtered C220, C226, C229, L234, L235, M252, S254, T256, V264, N297, L309, Q311, T366, N434, and K447 (EU numbering of Kabat).

[0203] In some embodiments of the various aspects described herein, one or more of the following amino acid residues, in the Fc domain, according to the EU numbering of Kabat are altered C220, N297, K447, and T366 (EU numbering of Kabat).

[0204] In some embodiments of the various aspects described herein, one or more of the following amino acid residues, in the Fc domain, according to the EU numbering of Kabat are altered C220, N297, K447, T366, L234, L235, V264, L309, Q311, and N434 (EU numbering of Kabat).

[0205] In some embodiments of the various aspects described herein, one or more of the following amino acid residues, in the Fc domain, according to the EU numbering of Kabat are altered C220, N297, K447, T366, L234, L235, P329, V264, L309, Q311, and N434 (EU numb eri ng of Kab at) .

[0206] In some embodiments of the various aspects described herein, one or more of the following amino acid residues, in the Fc domain, according to the EU numbering of Kabat are altered C220, N297, K447, L234, L235, M252, S254, and T256 (EU numbering of Kabat).

[0207] In some embodiments of the various aspects described herein, one or more of the following amino acid residues, in the Fc domain, according to the EU numbering of Kabat are altered C220, C226, C229, N297, K447, and T366 (EU numbering of Kabat).

[0208] In some embodiments of the various aspects described herein, the Fc domain comprises at least one mutation selected from the group consisting of: C220S, N297D, K447A, and T366W (EU numbering of Kabat).

[0209] In some embodiments of the various aspects described herein, the Fc domain comprises at least one mutation selected from the group consisting of: C220S, N297D, K447A, T366W, L234A, L235A, V264E, L309D, Q311H, and N434S (EU numbering of Kabat).

[0210] In some embodiments of the various aspects described herein, the Fc domain comprises at least one mutation selected from the group consisting of: C220S, N297D, K447A, T366W, L234A, L235A, P329G, V264E, L309D, Q311H, and N434S (EU numbering of Kabat).

[0211] In some embodiments of the various aspects described herein, the Fc domain comprises at least one mutation selected from the group consisting of: C220S, N297D, K447A, L234A, L235A, M252Y, S254T, and T256E (EU numbering of Kabat).

[0212] In some embodiments of the various aspects described herein, the Fc domain comprises at least one mutation selected from the group consisting of: C220S, C226S, C229S, N297D, K447A, and T366W (EU numbering of Kabat).

[0213] In some embodiments of any one of the aspects described herein, the Fc domain comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence selected from the group consisting ofEPKSsDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGa (SEQ ID NO: 88, C220S, N297D, K447A, and T366W)EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVDHHDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHSHYTQKSLSLSPGa (SEQ ID NO: 89, C220S, N297D, K447A, T366W, L234A, L235A, V264E, L309D, Q311H, andN434S)EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVDHHDWLNGKEY KCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKG FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVF SCSVMHEALHSHYTQKSLSLSPGa (SEQ ID NO: 90, C220S, N297D, K447A, T366W, L234A, L235A, P329G, V264E, L309D, Q311H, andN434S)EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITREPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGa (SEQ ID NO: 91, C220S, N297D, K447A, T366W, L234A, L235A, M252Y, S254T, and T256E); andEPKSsDKTHTSPPSPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGa (SEQ ID NO: 92, C220S, C226S, C229S, N297D, K447A, and T366W).

[0214] In some embodiments, the Fc domain comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 88-92. In some embodiments, the Fc domain comprises an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 88-92. In some embodiments, the Fc domain comprises an amino acid sequence having at least 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 88-92. In some embodiments, the PRL polypeptide in the Fc domain comprises an amino acid sequence having 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 88-92.

[0215] In some embodiments, the Fc domain comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 88-92, provided that the sequence comprises a S at a position corresponding to position 5, a S D at a position corresponding to position 11, a S D at a position corresponding to position 14, a D at a position corresponding to position 82, a A at a position corresponding to position 232, an A at a position corresponding to position 19, an A at a position corresponding to position 20, a Y at a position corresponding to position 37, a T at a position corresponding to position 39, an E at a position corresponding to position 41, a G at a position corresponding to position 114, an E at a position corresponding to position 49, a D at position 94, a H at a position corresponding to position 96, and / or an S at a position corresponding to position 219, and / or an W at a position corresponding to position 151 of SEQ ID NO: 88-92

[0216] In some embodiments, the Fc domain comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 88-92, provided that the sequencecomprises a S at a position corresponding to position 220, a S D at a position corresponding to position 226, a S D at a position corresponding to position 229, a D at a position corresponding to position 297, a A at a position corresponding to position 447, an A at a position corresponding to position 234, an A at a position corresponding to position 235, a Y at a position corresponding to position 252, a T at a position corresponding to position 254, an E at a position corresponding to position 256, a G at a position corresponding to position 329, an E at a position corresponding to position 264, a D at position 309, a H at a position corresponding to position 311, and / or an S at a position corresponding to position 434, and / or an W at a position corresponding to position 366 of SEQ ID NO: 88-92.

[0217] In some embodiments, the Fc domain comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 88-92, provided that the sequence does not comprise a S at a position corresponding to position 5, a S D at a position corresponding to position 11, a S D at a position corresponding to position 14, a D at a position corresponding to position 82, a A at a position corresponding to position 232, an A at a position corresponding to position 19, an A at a position corresponding to position 20, a Y at a position corresponding to position 37, a T at a position corresponding to position 39, an E at a position corresponding to position 41, a G at a position corresponding to position 114, an E at a position corresponding to position 49, a D at position 94, a H at a position corresponding to position 96, and / or an S at a position corresponding to position 219, and / or an W at a position corresponding to position 151 of SEQ ID NO: 88-92

[0218] In some embodiments, the Fc domain comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 88-92, provided that the sequence does not comprise a S at a position corresponding to position 220, a S D at a position corresponding to position 226, a S D at a position corresponding to position 229, a D at a position corresponding to position 297, a A at a position corresponding to position 447, an A at a position corresponding to position 234, an A at a position corresponding to position 235, a Y at a position corresponding to position 252, a T at a position corresponding to position 254, an E at a position corresponding to position 256, a G at a position corresponding to position 329, an E at a position corresponding to position 264, a D at position 309, a H at a position corresponding to position 311, and / or an S at a position corresponding to position 434, and / or an W at a position corresponding to position 366 of SEQ ID NO: 88-92.Fc hole

[0219] In some embodiments of the various aspects described herein, one or more of the following amino acid residues, in the Fc domain, according to the EU numbering of Kabat are altered C220, L234, L235, M252, S254, T256, V264, N297, L309, Q311, P329, T366, L368, Y407, N434, H435, Y436, and K447 (EU numbering of Kabat).

[0220] In some embodiments of the various aspects described herein, one or more of the following amino acid residues, in the Fc domain, according to the EU numbering of Kabat are altered C220, N297, K447, T366, L368, and Y407 (EU numbering of Kabat).

[0221] In some embodiments of the various aspects described herein, one or more of the following amino acid residues, in the Fc domain, according to the EU numbering of Kabat are altered C220, N297, K447, T366, L368, Y407, H435, Y436, L234, L235, V264, L309, Q311, and N434 (EU numbering of Kabat).

[0222] In some embodiments of the various aspects described herein, one or more of the following amino acid residues, in the Fc domain, according to the EU numbering of Kabat are altered C220, N297, K447, T366, L368, Y407, H435, Y436, L234, L235, P329, V264, L309, Q311, and N434 (EU numbering of Kabat).

[0223] In some embodiments of the various aspects described herein, one or more of the following amino acid residues, in the Fc domain, according to the EU numbering of Kabat are altered C220, N297, K447, T366, L368, Y407, H435, Y436, L234, L235, M252, S254, and T256 (EU numbering of Kabat).

[0224] In some embodiments of the various aspects described herein, the Fc domain comprises at least one mutation selected from the group consisting of: C220S, N297D, K447A, T366S, L368A, and Y407V (EU numbering of Kabat).

[0225] In some embodiments of the various aspects described herein, the Fc domain comprises at least one mutation selected from the group consisting of: C220S, N297D, K447A, T366S, L368A, Y407V, H435R, Y436F, L234A, L235A, V264E, L309D, Q311H, andN434S (EU numbering of Kabat).

[0226] In some embodiments of the various aspects described herein, the Fc domain comprises at least one mutation selected from the group consisting of: C220S, N297D, K447A, T366S, L368A, Y407V, H435R, Y436F, L234A, L235A, P329G, V264E, L309D, Q311H, and N434S (EU numbering of Kabat).

[0227] In some embodiments of the various aspects described herein, the Fc domain comprises at least one mutation selected from the group consisting of: C220S, N297D, K447A,T366S, L368A, Y407V, H435R, Y436F, L234A, L235A, M252Y, S254T, and T256E (EU numb eri ng of Kab at) .

[0228] In some embodiments of any one of the aspects described herein, the Fc domain comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence selected from the group consisting ofEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYDSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLSCAVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGA (SEQ ID NO: 94, C220S, N297D, K447A, T366S, L368A, Y407V);EPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYDSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLSCAVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFS CSVMHEALHNRFTQKSLSLSPGA (SEQ ID NO: 95, C220S, N297D, K447A, T366S, L368A, Y407V, H435R, Y436F);EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHE DPEVI<FNWYVDGVEVHNAI<TI<PREEQYDSTYRVVSVLTVDHHDWLNGI<EY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLSCAVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFS CSVMHEALHSRFTQKSLSLSPGA (SEQ ID NO: 96, C220S, N297D, K447A, T366S, L368A, Y407V, H435R, Y436F, L234A, L235A, V264E, L309D, Q311H, N434S);EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHE DPEVI<FNWYVDGVEVHNAI<TI<PREEQYDSTYRVVSVLTVDHHDWLNGI<EY KCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLSCAVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFS CSVMHEALHSRFTQKSLSLSPGA (SEQ ID NO: 97, C220S, N297D, K447A,T366S, L368A, Y407V, H435R, Y436F, L234A, L235A, P329G, V264E, L309D,Q311H, and N434S); andEPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITREPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYDSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLSCAVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFS CSVMHEALHNRFTQKSLSLSPGA (SEQ ID NO: 98, C220S, N297D, K447A, T366S, L368A, Y407V, H435R, Y436F, L234A, L235A, M252Y, S254T, and T256E).

[0229] In some embodiments, the Fc domain comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 94-98. In some embodiments, the Fc domain comprises an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 94-98. In some embodiments, the Fc domain comprises an amino acid sequence having at least 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 94-98. In some embodiments, the PRL polypeptide in the Fc domain comprises an amino acid sequence having 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 94-98.

[0230] In some embodiments, the Fc domain comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 94-98, provided that the sequence comprises a S at a position corresponding to position 5, a D at a position corresponding to position 82, a A at a position corresponding to position 232, an A at a position corresponding to position 19, an A at a position corresponding to position 20, a Y at a position corresponding to position 37, a T at a position corresponding to position 39, an E at a position corresponding to position 41, a G at a position corresponding to position 114, an E at a position corresponding to position 49, a D at position 94, a H at a position corresponding to position 96, and / or an S at a position corresponding to position 219, a S at a position corresponding to position 151, an A at a position corresponding to position 153, a V at a position corresponding to position 182, an R at a position corresponding to position 220, and / or an F at a position corresponding to position 221 of SEQ ID NO: 94-98.

[0231] In some embodiments, the Fc domain comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 94-98, provided that the sequence comprises a S at a position corresponding to position 220, a D at a position corresponding to position 297, a A at a position corresponding to position 447, an A at a position corresponding to position 234, an A at a position corresponding to position 235, a Y at a position corresponding to position 252, a T at a position corresponding to position 254, an E at a position corresponding to position 256, a G at a position corresponding to position 329, an E at a position corresponding to position 264, a D at position 309, a H at a position corresponding to position 311, and / or an S at a position corresponding to position 434, a S at a position corresponding to position 366, an A at a position corresponding to position 368, a V at a position corresponding to position 397, an Rat a position corresponding to position 435, and / or an F at a position corresponding to position 436 of SEQ ID NO: 94-98.

[0232] In some embodiments, the Fc domain comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 94-98, provided that the sequence does not comprise a S at a position corresponding to position 5, a D at a position corresponding to position 82, a A at a position corresponding to position 232, an A at a position corresponding to position 19, an A at a position corresponding to position 20, a Y at a position corresponding to position 37, a T at a position corresponding to position 39, an E at a position corresponding to position 41, a G at a position corresponding to position 114, an E at a position corresponding to position 49, a D at position 94, a H at a position corresponding to position 96, and / or an S at a position corresponding to position 219, a S at a position corresponding to position 151, an A at a position corresponding to position 153, a V at a position corresponding to position 182, an R at a position corresponding to position 220, and / or an F at a position corresponding to position 221 of SEQ ID NO: 94-98.

[0233] In some embodiments, the Fc domain comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 94-98, provided that the sequence does not comprise a S at a position corresponding to position 220, a D at a position corresponding to position 297, a A at a position corresponding to position 447, an A at a position corresponding to position 234, an A at a position corresponding to position 235, a Y at a position corresponding to position 252, a T at a position corresponding to position 254, an E at a position corresponding to position 256, a G at a position corresponding to position 329, an E at aposition corresponding to position 264, a D at position 309, a H at a position corresponding to position 311, and / or an S at a position corresponding to position 434, a S at a position corresponding to position 366, an A at a position corresponding to position 368, a V at a position corresponding to position 397, an Rat a position corresponding to position 435, and / or an F at a position corresponding to position 436 of SEQ ID NO: 94-98.Multimeric molecules

[0234] In another aspect provided herein is a multimeric molecule. The multimeric molecule comprises a first Fc-PRL fusion protein described herein and a second polypeptide comprising an antibody Fc region. Generally, the Fc region of the Fc-PRL fusion protein and the Fc region of the polypeptide pair to form a dimer.

[0235] In some embodiments of any one of the aspects described herein, the Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide in the multimeric molecule have asymmetric complementary structures. As used herein, an “asymmetric complementary structure” means the Fc regions of the Fc region of the Fc-PRL fusion protein and the Fc region of the polypeptide in the multimeric molecule are different, i.e., the Fc regions form a heterodimer. The asymmetric complementary structure can be formed, for example, by the KiH (knobs-into-holes) technique.Fc A and Fc B

[0236] In some embodiments of any one of the aspects described herein, the Fc region of the second polypeptide in the multimeric molecule comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence selected from the group consisting of: SEQ ID NO: 78-81. For example, the Fc domain of the second polypeptide in the multimeric molecule comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 78-81. In some embodiments, the Fc domain of the second polypeptide in the multimeric molecule comprises an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 78-81. For example, the Fc domain of the second polypeptide in the multimeric molecule comprises an amino acid sequence having at least 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 78-81. In some embodiments, the Fc domain of the secondpolypeptide in the multimeric molecule comprises an amino acid sequence having 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 78-81.

[0237] In some embodiments of any one of the aspects described herein, the Fc region of the second polypeptide in the multimeric molecule comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence selected from the group consisting of: SEQ ID NO: 82-87. For example, the Fc domain of the second polypeptide in the multimeric molecule comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 82-87. In some embodiments, the Fc domain of the second polypeptide in the multimeric molecule comprises an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 82-87. For example, the Fc domain of the second polypeptide in the multimeric molecule comprises an amino acid sequence having at least 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 82-87. In some embodiments, the Fc domain of the second polypeptide in the multimeric molecule comprises an amino acid sequence having 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 82-87.

[0238] In some embodiments of any one of the aspects described herein, one of the Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide in the multimeric molecule comprises an comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence selected from the group consisting of: SEQ ID NO: 78-81 and the other Fc region comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence selected from the group consisting of: SEQ ID NO: 82-87.

[0239] For example, one of the Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide in the multimeric molecule comprises an comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence selected from the group consisting of: SEQ ID NO: 78-81 and the other Fc region comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence selected from the group consisting of: SEQ ID NO: 82-87.

[0240] In some embodiments of any one of the aspects described herein, one of the Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide in the multimeric molecule comprises an comprises an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence selected from the group consisting of: SEQ ID NO: 78-81 and the other Fc region comprises an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence selected from the group consisting of: SEQ ID NO: 82-87. For example, one of the Fc region of the Fc- PRL fusion protein and the Fc region of the second polypeptide in the multimeric molecule comprises an comprises an amino acid sequence having at least 97%, 98% or 99% sequence identity to an amino acid sequence selected from the group consisting of: SEQ ID NO: 78-81 and the other Fc region comprises an amino acid sequence having at least 97%, 98% or 99% sequence identity to an amino acid sequence selected from the group consisting of: SEQ ID NO: 82-87. In some embodiments of any one of the aspects described herein, one of the Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide in the multimeric molecule comprises an comprises an amino acid sequence having 100% sequence identity to an amino acid sequence selected from the group consisting of: SEQ ID NO: 78- 81 and the other Fc region comprises an amino acid sequence having 100% sequence identity to an amino acid sequence selected from the group consisting of: SEQ ID NO: 82-87.

[0241] In some embodiments of any one of the aspects described herein, one of the Fc regions (e.g., Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide) comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 78 and the and the other Fc region comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 85. For example, the Fc region of the Fc-PRL fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 78 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 85.

[0242] In some embodiments of any one of the aspects described herein, one of the Fc regions (e.g., Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide) comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 79 and the and the other Fc region comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 82. For example, the Fc region of the Fc-PRL fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 79 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 82.

[0243] In some embodiments of any one of the aspects described herein, one of the Fc regions (e.g., Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide) comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 79 and the and the other Fc region comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 83. For example, the Fc region of the Fc-PRL fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 79 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 83.

[0244] In some embodiments of any one of the aspects described herein, one of the Fc regions (e.g., Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide) comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 80 and the and the other Fc region comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 86. For example, the Fc region of the Fc-PRL fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 80 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 86.

[0245] In some embodiments of any one of the aspects described herein, one of the Fc regions (e.g., Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide) comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 81 and the and the other Fc region comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 87. For example, the Fc region of the Fc-PRL fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 81 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 87.Fc knob and Fc hole

[0246] In some embodiments of any one of the aspects described herein, the Fc region of the second polypeptide in the multimeric molecule comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence selected from the group consisting of: SEQ ID NO: 88-92. For example, the Fc domain of the second polypeptide in the multimeric molecule comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 88-92. In some embodiments, the Fc domain ofthe second polypeptide in the multimeric molecule comprises an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 88-92. For example, the Fc domain of the second polypeptide in the multimeric molecule comprises an amino acid sequence having at least 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 88-92. In some embodiments, the Fc domain of the second polypeptide in the multimeric molecule comprises an amino acid sequence having 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 88-92.

[0247] In some embodiments of any one of the aspects described herein, the Fc region of the second polypeptide in the multimeric molecule comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence selected from the group consisting of: SEQ ID NO: 94-98. For example, the Fc domain of the second polypeptide in the multimeric molecule comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 94-98. In some embodiments, the Fc domain of the second polypeptide in the multimeric molecule comprises an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 94-98. For example, the Fc domain of the second polypeptide in the multimeric molecule comprises an amino acid sequence having at least 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 94-98. In some embodiments, the Fc domain of the second polypeptide in the multimeric molecule comprises an amino acid sequence having 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 94-98.

[0248] In some embodiments of any one of the aspects described herein, one of the Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide in the multimeric molecule comprises an comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence selected from the group consisting of: SEQ ID NO: 88-92 and the other Fc region comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence selected from the group consisting of: SEQ ID NO: 94-98.

[0249] For example, one of the Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide in the multimeric molecule comprises an comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequenceidentity to an amino acid sequence selected from the group consisting of: SEQ ID NO: 88-92 and the other Fc region comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence selected from the group consisting of: SEQ ID NO: 94-98.

[0250] In some embodiments of any one of the aspects described herein, one of the Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide in the multimeric molecule comprises an comprises an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence selected from the group consisting of: SEQ ID NO: 88-92 and the other Fc region comprises an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence selected from the group consisting of: SEQ ID NO: 94-98. For example, one of the Fc region of the Fc- PRL fusion protein and the Fc region of the second polypeptide in the multimeric molecule comprises an comprises an amino acid sequence having at least 97%, 98% or 99% sequence identity to an amino acid sequence selected from the group consisting of: SEQ ID NO: 88-92 and the other Fc region comprises an amino acid sequence having at least 97%, 98% or 99% sequence identity to an amino acid sequence selected from the group consisting of: SEQ ID NO: 94-98. In some embodiments of any one of the aspects described herein, one of the Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide in the multimeric molecule comprises an comprises an amino acid sequence having 100% sequence identity to an amino acid sequence selected from the group consisting of: SEQ ID NO: 88- 92 and the other Fc region comprises an amino acid sequence having 100% sequence identity to an amino acid sequence selected from the group consisting of: SEQ ID NO: 94-98.

[0251] In some embodiments of any one of the aspects described herein, one of the Fc regions (e.g., Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide) comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 88 and the and the other Fc region comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 94. For example, the Fc region of the Fc-PRL fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 88 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 94.

[0252] In some embodiments of any one of the aspects described herein, one of the Fc regions (e.g., Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide) comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 88 and the and the other Fc region comprises an amino acid sequence having at least85% sequence identity to SEQ ID NO: 95. For example, the Fc region of the Fc-PRL fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 88 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 95.

[0253] In some embodiments of any one of the aspects described herein, one of the Fc regions (e.g., Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide) comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 89 and the and the other Fc region comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 96. For example, the Fc region of the Fc-PRL fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 89 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 96.

[0254] In some embodiments of any one of the aspects described herein, one of the Fc regions (e.g., Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide) comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 90 and the and the other Fc region comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 97 For example, the Fc region of the Fc-PRL fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 90 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 97.

[0255] In some embodiments of any one of the aspects described herein, one of the Fc regions (e.g., Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide) comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 91 and the and the other Fc region comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 98. For example, the Fc region of the Fc-PRL fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 91 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 98.

[0256] In some embodiments of any one of the aspects described herein, one of the Fc regions (e.g., Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide) comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 92 and the and the other Fc region comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 95. For example, the Fc region of the Fc-PRL fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ IDNO: 92 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 95.

[0257] In some embodiments of any one of the aspects described herein, one of the Fc regions (e.g., Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide) comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 89 and the and the other Fc region comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 96. For example, the Fc region of the Fc-PRL fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 89 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 96.

[0258] In some embodiments of any one of the aspects described herein, one of the Fc regions (e.g., Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide) comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 90 and the and the other Fc region comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 97. For example, the Fc region of the Fc-PRL fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 87 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 97.

[0259] In some embodiment of any one of the aspects described herein, the second polypeptide in the multimeric molecule does not comprise a prolactin polypeptide linked to the antibody Fc region.

[0260] In some other embodiments of any one of the aspects described herein, the second polypeptide comprising an antibody Fc region in the multimeric molecule further comprises prolactin polypeptide linked to the Fc region. For example, the second polypeptide comprising an antibody Fc region in the multimeric molecule is a second Fc-PRL fusion protein described herein. It is noted that the first and second Fc-PRL fusion proteins in a multimeric molecule can be same or different. Accordingly, in some embodiments of any one of the aspects described herein, the first and second Fc-PRL fusion proteins in the multimeric molecule are same. In some other embodiments of any one of the aspects described herein, the first and second Fc-PRL fusion proteins in the multimeric molecule are different.

[0261] In some embodiments of the multimeric compound described herein, the Fc-PRL fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 120 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 94. In some embodiments of the multimeric compounddescribed herein, the Fc-PRL fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 121 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 95. In some embodiments of the multimeric compound described herein, the Fc-PRL fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 122 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 96. In some embodiments of the multimeric compound described herein, the Fc-PRL fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 123 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 97. In some embodiments of the multimeric compound described herein, the Fc-PRL fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 124 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 98. In some embodiments of the multimeric compound described herein, the Fc-PRL fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 125 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 85. In some embodiments of the multimeric compound described herein, the Fc-PRL fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 126 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 82. In some embodiments of the multimeric compound described herein, the Fc-PRL fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 127 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 83. In some embodiments of the multimeric compound described herein, the Fc-PRL fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 128 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 86. In some embodiments of the multimeric compound described herein, the Fc-PRL fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 129 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 87. In some embodiments of the multimeric compound described herein, the Fc-PRL fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 130 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 95. In some embodiments of the multimeric compound described herein, the Fc-PRL fusion protein comprises an aminoacid sequence having at least 85% sequence identity to SEQ ID NO: 131 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 95. In some embodiments of the multimeric compound described herein, the Fc-PRL fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 132 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 95. In some embodiments of the multimeric compound described herein, the Fc-PRL fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 133 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 95. In some embodiments of the multimeric compound described herein, the Fc-PRL fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 134 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 96. In some embodiments of the multimeric compound described herein, the Fc-PRL fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 135 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 97. In some embodiments of the multimeric compound described herein, the Fc-PRL fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 136 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 98. In some embodiments of the multimeric compound described herein, the Fc-PRL fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 137 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 85. In some embodiments of the multimeric compound described herein, the Fc-PRL fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 138 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 82. In some embodiments of the multimeric compound described herein, the Fc-PRL fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 139 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 83. In some embodiments of the multimeric compound described herein, the Fc-PRL fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 140 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 86. In some embodiments of the multimeric compound described herein, the Fc-PRL fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQID NO: 141 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 87.

[0262] In some embodiments of the multimeric compound described herein, the Fc fusion protein comprises an amino acid sequence having at least 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 125 and the second polypeptide comprises an amino acid sequence having at least 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 85. In some embodiments of the multimeric compound described herein, the Fc fusion protein comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 125 and the second polypeptide comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 85. In some embodiments of the multimeric compound described herein, the Fc fusion protein comprises an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 125 and the second polypeptide comprises an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 85. In some embodiments of the multimeric compound described herein, the Fc fusion protein comprises an amino acid sequence having 100% sequence identity to SEQ ID NO: 125 and the second polypeptide comprises an amino acid sequence having 100% sequence identity to SEQ ID NO: 85.Orientation and linkers

[0263] The prolactin polypeptide and the Fc domain can be present in any order in the Fc- PRL fusion protein. For example, the C-terminus of the prolactin polypeptide can be linked to the N-terminus of the Fc domain. In another non-limiting example, example, the N-terminus of the prolactin polypeptide can be linked to the C-terminus of the Fc domain.

[0264] It is noted the Fc domain and the PRL polypeptide can be linked via a direct bond (such as a single peptide bond, e.g., linked directly to each other) or a linker. The linker can be a chemical linker or a peptide linker containing one or more amino acid residues (e.g. with an intervening amino acid or amino acid sequence between the Fc domain and the PRL polypeptide).

[0265] In some embodiments, the Fc domain and the PRL polypeptide are linked via a peptide linker. The term “peptide linker” as used herein denotes a peptide with amino acid sequences, which is in some embodiments of synthetic origin. It is noted that peptide linkers may affect folding of a given Fc-PRL fusion protein, and may also react / bind with otherproteins, and these properties can be screened for by known techniques. Exemplary peptide linkers include those that consist of glycine and serine residues, the so-called Gly-Ser polypeptide linkers. As used herein, the term “Gly-Ser polypeptide linked’ refers to a peptide that consists of glycine and serine residues. In some embodiments, the peptide linker comprises the amino acid sequence (GxS)n with G is glycine, S is serine, where x is 3, 4 or 5 and n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, SEQ ID NO: 99. In some embodiments, x is 3 and, n is 8, 9 or 10. In some embodiments, x is 4 and n is 6, 7, or 8. In some embodiments, x is 4 and n is 6 or 7. In some embodiments, x is 4 and n is 7. In some embodiments, the peptide linker comprises the amino acid sequence Ser(Gly4Ser)nwherein n is an integer 1 to 10, SEQ ID NO: 100 respectively. In some embodiments, the peptide linker comprises the amino acid sequence (G4S)6G2(SEQ ID NO: 101) In some embodiments, the peptide linker comprises the amino acid sequence GSGGGSGGGGSGGGGS (SEQ ID NO: 102). In some embodiments, the peptide linker comprises the amino acid sequence GGSGG (SEQ ID NO: 103).

[0266] In some embodiments, the peptide linker comprises the amino acid sequence (X)n, where each X is independently aspartic acid (D) or glutamic acid (E), and n ranges from 1 to up to 10 or more (SEQ ID NO: 104).

[0267] Exemplary linkers, in addition to those described herein, include a string of histidine residues, e.g., His6 (SEQ ID NO: 105); sequences made up of Ala and Pro, varying the number of Ala-Pro pairs to modulate the flexibility of the linker; and sequences made up of charged amino acid residues e.g., mixing Glu and Lys. Flexibility can be controlled by the types and numbers of residues in the linker. See, e.g., Perham, 30 Biochem. 8501 (1991); Wriggers et al., 80 Biopolymers 736 (2005).

[0268] Chemical linkers can comprise a direct bond or an atom such as oxygen or sulfur, a unit such as NH, C(O), C(O)NH, SO, SO2, SO2NH, or a chain of atoms, such as substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C5-C12 heteroaryl, substituted or unsubstituted C5-C12 heterocyclyl, substituted or unsubstituted C3-C12 cycloalkyl, where one or more methylenes can be interrupted or terminated by O, S, S(O), SO2, NH, or C(O). The linker can be 1 amino acid or more, 5 amino acids or more, 10 amino acids or more, 15 amino acids or more, 20 amino acids or more, 25 amino acids or more, 30 amino acids or more, 35 amino acids or more, 40 amino acids or more, 45 amino acids or more, 50 amino acids or more and beyond.

[0269] In some embodiments, the linker can be a cleavable linker. For example, the linker comprises a cleavable group. A cleavable group is one which is sufficiently stable under a firstset of conditions and can be cleaved to release the two parts the cleavable group is holding together. In a preferred embodiment, the cleavable group is cleaved at least 10 times or more, preferably at least 100 times faster under a first reference condition (which can, e.g., be selected to mimic or represent intracellular conditions) than under a second reference condition (which can, e.g., be selected to mimic or represent conditions found in the blood or serum).

[0270] Cleavable groups are susceptible to cleavage agents, e.g., pH, redox potential or the presence of degradative molecules. Generally, cleavage agents are more prevalent or found at higher levels or activities at the desired site of action of the molecule comprising the cleavable group. Examples of such degradative agents include: redox agents which are selected for particular substrates or which have no substrate specificity, including, e.g., oxidative or reductive enzymes or reductive agents such as mercaptans, present in cells, that can degrade a redox cleavable linking group by reduction; esterases; amidases; endosomes or agents that can create an acidic environment, e.g., those that result in a pH of five or lower; enzymes that can hydrolyze or degrade an acid cleavable linking group by acting as a general acid, peptidases (which can be substrate specific) and proteases, and phosphatases.

[0271] Exemplary cleavable groups include, but are not limited to peptide-based cleavable groups, (e.g., groups that are cleaved by enzymes such as peptidases and proteases, e.g., - NHCHRAC(O)NHCHRBC(O)-, where RAand RBare the R groups of the two adjacent amino acids); redox cleavable groups (e.g., -S-S- and -C(R)2-S-S-, wherein R is H or Ci-Ce alkyl and at least one R is Ci-Ce alkyl such as CHs or CH2CH3); phosphate-based cleavable linking groups (e g., -O-P(O)(OR)-O-, -O-P(S)(OR)-O-, -O-P(S)(SR)-O-, -S-P(O)(OR)-O-, -O- P(O)(OR)-S-, -S-P(O)(OR)-S-, -O-P(S)(ORk)-S-, -S-P(S)(OR)-O-, -O-P(O)(R)-O-, -O- P(S)(R)-O-, -S-P(O)(R)-O-, -S-P(S)(R)-O-, -S-P(O)(R)-S-, -O-P(S)( R)-S-, . -O-P(O)(OH)-O- , -O-P(S)(OH)-O-, -O-P(S)(SH)-O-, -S-P(O)(OH)-O-, -O-P(O)(OH)-S-, -S-P(O)(OH)-S-, -O- P(S)(OH)-S-, -S-P(S)(OH)-O-, -O-P(O)(H)-O-, -O-P(S)(H)-O-, -S-P(O)(H)-O-, -S-P(S)(H)-O- , -S-P(O)(H)-S-, and -O-P(S)(H)-S-, wherein R is optionally substituted linear or branched Ci- C10 alkyl); acid cleavable groups (e.g., hydrazones, esters, and esters of amino acids, -C=NN- and -OC(O)-); and ester-based cleavable groups (e.g., -C(O)O-).

[0272] In some embodiments, the linker comprises a peptide based cleavable group comprises two or more amino acids.Ta#

[0273] In some embodiments of the various aspects described herein, the Fc-PRL fusion protein comprises one or more epitopes or affinity tags. Without wishing to be bound a theory,the epitope of affinity tag can provide a convenient means for isolating or purifying the Fc- PRL fusion protein. When present, the epitope or affinity tag can be located anywhere in the Fc-PRL fusion protein. For example, the epitope or affinity tag can be at the N-terminal, C- terminal or at an internal position of the Fc-PRL fusion protein. In some embodiments, an epitope or affinity tag is at a position N-terminal of the Fc domain. In some embodiments, an epitope or affinity tag is at a position C-terminal of the Fc domain. In some embodiments, an epitope or affinity tag is at a position N-terminal of the prolactin polypeptide. In some embodiments, an epitope or affinity tag is at a position C-terminal of the prolactin polypeptide.

[0274] In some embodiments, an epitope or affinity tag is at a position N-terminal of the Fc-PRL fusion protein. In some embodiments, an epitope or affinity tag i at a position Citerminal of the Fc-PRL. fusion protein.

[0275] A number of epitope or affinity tags are known in the art. These are usually divided into 3 classes according to their size: small tags have a maximum of 12 amino acids, mediumsized ones have a maximum of 60 and large ones have more than 60. The small tags include the Arg-tag, the His-tag, the avidin biotin, or streptavidin (Strep)-tag, the Flag-tag, the T7-tag, the V5-peptide-tag and the c-Myc-tag, the medium-sized ones include the S-tag, the HAT -tag, the calmodulin-binding peptide, the chitin-binding domain (CBD) and some cellulose-binding domains. The latter can contain up to 189 amino acids and are then regarded, like the glutathione-S-transferase (GST)-and maltose binding protein (MBP)-tag, as large affinity tags.

[0276] Some exemplary affinity tag sequences include, but are not limited to, 6-FHS tag (HHHHHH (SEQ ID NO: 105), c-Myc epitope (EQKLISEEDL, SEQ ID NO: 106), Flag-tag (DYKDDDDK, SEQ ID NO: 107), AU1 HA tag (YPYDVPDYA, SEQ ID NO: 108), and tag (DTYRYI, SEQ ID NO: 109). In some preferred embodiments, the affinity tag comprises the sequence EQKLISEEDLNSAVD (SEQ ID NO: 110) or NSAVDHHHHHH (SEQ ID NO: 111) In some embodiments, the affinity tag comprises the sequence EQKLISEEDLNSAVDHHHHHH (SEQ ID NO: 112).Exemplary Fc-PRL fusion proteins

[0277] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting ofEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKLPICPGGAARCQVTLRDLFDRAWLSHYIHDLSSEMFSEFDKRYTHGRGFITKAINSCHTSSLATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHLVTEVRGMQEAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMADEESRLSAYYNLLHCLRRDSHKIDNYLKL LKCRIIHNNNC (SEQ ID NO: 113);EPKSsDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGaLPICPGGAARCQVTLRDLFDRAVVLSHYIHNLSSEMFSEFDKRYTHGRGFITKAINSCHTSSLATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHLVTEVRGMQEAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMADEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRIIHNNNCEQKLISEEDLNSAVDHHHHHH (SEQ ID NO: 114);EPKSsDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGaLPICPGGAARCQVTLRDLFDRAVVLSHYIHDLSSEMFSEFDKRYTHGRGFITKAINSCHTSSLATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHLVTEVRGMQEAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMADEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRHHNNNC (SEQ ID NO: 115);EPKSsDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGaGGsGGLPICPGGAARCQVTLRDLFDRAW LSHYIHDLSSEMFSEFDKRYTHGRGFITKAINSCHTSSLATPEDKEQAQQMNQ KDFLSLIVSILRSWNEPLYHLVTEVRGMQEAPEAILSKAVEIEEQTKRLLEGME LIVSQVHPETKENEIYPVWSGLPSLQMADEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRIIHNNNCEQKLISEEDLNSAVDHHHHHH (SEQ ID NO: 116);EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVDHHDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGaLPICPGGAARCQVTLRDLFDRAVVLSHYIH DLSSEMFSEFDKRYTHGRGFITKAINSCHTSSLATPEDKEQAQQMNQKDFLSL IVSILRSWNEPLYHLVTEVRGMQEAPEAILSKAVEIEEQTKRLLEGMELIVSQV HPETKENEIYPVWSGLPSLQMADEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRHHNNNC (SEQ ID NO: 117);EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVDHHDWLNGKEY KCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGaLPICPGGAARCQVTLRDLFDRAVVLSHYIH DLSSEMFSEFDKRYTHGRGFITKAINSCHTSSLATPEDKEQAQQMNQKDFLSL IVSILRSWNEPLYHLVTEVRGMQEAPEAILSKAVEIEEQTKRLLEGMELIVSQV HPETKENEIYPVWSGLPSLQMADEESRLSAYYNLLHCLRRDSHKIDNYLKLL KCRHHNNNC (SEQ ID NO: 118);EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITREPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGaLPICPGGAARCQVTLRDLFDRAVVLSHYIH DLSSEMFSEFDKRYTHGRGFITKAINSCHTSSLATPEDKEQAQQMNQKDFLSL IVSILRSWNEPLYHLVTEVRGMQEAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMADEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRHHNNNC (SEQ ID NO: 119);EPKSsDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGaLPICPGGAARCQVTLRDLFDRAVVLSHYIHDLSSEMFSEFDKRYTHGRGFITKAINSCHTSSLATPEDKEQAQQMNQKDFLSL IVSILRSWNEPLYHLVTEVRGMQEAPEAILSKAVEIEEQTKRLLEGMELIVSQV HPETKENEIYPVWSGLPSLQMADEESRLSAYYNLLHCLRRDSHKIDNYLKLL KCRIIHNNNCEQKLISEEDLNSAVDHHHHHH (SEQ ID NO: 120);EPKSsDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLwCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGaGGsGGLPICPGGAARCQVTLRDLFDRAWLSHYIHDLSSEMFSEFDKRYTHGRGFITKAINSCHTSSLATPEDKEQAQQMNQ KDFLSLIVSILRSWNEPLYHLVTEVRGMQEAPEAILSKAVEIEEQTKRLLEGME LIVSQVHPETKENEIYPVWSGLPSLQMADEESRLSAYYNLLHCLRRDSHKIDN YLKLLKCRIIHNNNC (SEQ ID NO: 121);EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVDHHDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHSHYTQKSLSLSPGaGGsGGLPICPGGAARCQVTLRDLFDRAWL SHYIHDL SSEMFSEFDKRYTHGRGFITKAINSCHTS SLATPED KE QAQQMNQK DFLSLIVSILRSWNEPLYHLVTEVRGMQEAPEAILSKAVEIEEQTKRLLEGMEL IVSQVHPETKENEIYPVWSGLPSLQMADEESRLSAYYNLLHCLRRDSHKIDNY LKLLKCRIIHNNNC (SEQ ID NO: 122);EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVDHHDWLNGKEY KCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKG FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVF SCSVMHEALHSHYTQKSLSLSPGaGGsGGLPICPGGAARCQVTLRDLFDRAVV LSHYIHDLSSEMFSEFDKRYTHGRGFITKAINSCHTSSLATPEDKEQAQQMNQ KDFLSLIVSILRSWNEPLYHLVTEVRGMQEAPEAILSKAVEIEEQTKRLLEGME LIVSQVHPETKENEIYPVWSGLPSLQMADEESRLSAYYNLLHCLRRDSHKIDN YLKLLKCRIIHNNNC (SEQ ID NO: 123);EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITREPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGaGGsGGLPICPGGAARCQVTLRDLFDRAW LSHYIHDLSSEMFSEFDKRYTHGRGFITKAINSCHTSSLATPEDKEQAQQMNQ KDFLSLIVSILRSWNEPLYHLVTEVRGMQEAPEAILSKAVEIEEQTKRLLEGME LIVSQVHPETKENEIYPVWSGLPSLQMADEESRLSAYYNLLHCLRRDSHKIDN YLKLLKCRIIHNNNC (SEQ ID NO: 124);EPKSsDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYVYPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFALVSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGaGGsGGLPICPGGAARCQVTLRDLFDRAW LSHYIHDLSSEMFSEFDKRYTHGRGFITKAINSCHTSSLATPEDKEQAQQMNQ KDFLSLIVSILRSWNEPLYHLVTEVRGMQEAPEAILSKAVEIEEQTKRLLEGME LIVSQVHPETKENEIYPVWSGLPSLQMADEESRLSAYYNLLHCLRRDSHKIDN YLKLLKCRIIHNNNC (SEQ ID NO: 125);EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVDHHDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYVYPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFALVSKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGaGGsGGLPICPGGAARCQVTLRDLFDRAWL SHYIHDLSSEMFSEFDKRYTHGRGFITKAINSCHTS SLATPED KE QAQQMNQK DFLSLIVSILRSWNEPLYHLVTEVRGMQEAPEAILSKAVEIEEQTKRLLEGMEL IVSQVHPETKENEIYPVWSGLPSLQMADEESRLSAYYNLLHCLRRDSHKIDNY LKLLKCRIIHNNNC (SEQ ID NO: 126);EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVDHHDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYVYPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFALVSKLTVDKSRWQQGNVFS CSVMHEALHSHYTQKSLSLSPGaGGsGGLPICPGGAARCQVTLRDLFDRAWL SHYIHDLSSEMFSEFDKRYTHGRGFITKAINSCHTS SLATPED KE QAQQMNQK DFLSLIVSILRSWNEPLYHLVTEVRGMQEAPEAILSKAVEIEEQTKRLLEGMEL IVSQVHPETKENEIYPVWSGLPSLQMADEESRLSAYYNLLHCLRRDSHKIDNY LKLLKCRIIHNNNC (SEQ ID NO: 127);EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVDHHDWLNGKEY KCKVSNKALGAPIEKTISKAKGQPREPQVYVYPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFALVSKLTVDKSRWQQGNVFS CSVMHEALHSHYTQKSLSLSPGaGGsGGLPICPGGAARCQVTLRDLFDRAWL SHYIHDLSSEMFSEFDKRYTHGRGFITKAINSCHTS SLATPED KE QAQQMNQK DFLSLIVSILRSWNEPLYHLVTEVRGMQEAPEAILSKAVEIEEQTKRLLEGMEL IVSQVHPETKENEIYPVWSGLPSLQMADEESRLSAYYNLLHCLRRDSHKIDNY LKLLKCRIIHNNNC (SEQ ID NO: 128);EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITREPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYVYPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFALVSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGaGGsGGLPICPGGAARCQVTLRDLFDRAW LSHYIHDLSSEMFSEFDKRYTHGRGFITKAINSCHTSSLATPEDKEQAQQMNQ KDFLSLIVSILRSWNEPLYHLVTEVRGMQEAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMADEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRIIHNNNC (SEQ ID NO: 129);LPICPGGAARCQVTLRDLFDRAVVLSHYIHDLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRIIHNNNCEPKSsDKTHTCPPC PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGFYPSDIAVEWESN GQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVF SCSVMHEALHNH YTQKSLSLSPGaEQKLISEEDLNSAVDHHHHHH (SEQ ID NO: 130);LPICPGGAARCQVTLRDLFDRAVVLSHYIHDLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRIIHNNNCGGsGGEPKSsDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYdSTYR VVSVLTVLHQDWLNGI<EYI<CI<VSNI< ALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDK SRWQQGNVF SC S VMHE A LHNHYTQKSLSLSPGa (SEQ ID NO: 131);LPICPGGAARCQVTLRDLFDRAVVLSHYIHDLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHKIDNYLKLLKsRIIHNNNSEPKSsDKTHTCPPC PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGFYPSDIAVEWESN GQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVF SCSVMHEALHNH YTQKSLSLSPGaEQKLISEEDLNSAVDHHHHHH (SEQ ID NO: 132);LPICPGGAARCQVTLRDLFDRAVVLSHYIHDLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHKIDNYLKLLKsRIIHNNNSEPKSsDKTHTSPPSP APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGFYPSDIAVEWESNG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY TQKSLSLSPGaEQKLISEEDLNSAVDHHHHHH (SEQ ID NO: 133);LPICPGGAARCQVTLRDLFDRAVVLSHYIHDLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRIIHNNNCGGsGGEPKSsDKT HTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYdSTYR VVSVLTVDHHDWLNGI<EYI<CI<VSNI< ALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDK SRWQQGNVF SC S VMHE A LHSHYTQKSLSLSPGa (SEQ ID NO: 134);LPICPGGAARCQVTLRDLFDRAVVLSHYIHDLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRIIHNNNCGGsGGEPKSsDKT HTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYdSTYR VVSVLTVDHHDWLNGI<EYI<CI<VSNI< ALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHSHYTQKSLSLSPGa (SEQ ID NO: 135);LPICPGGAARCQVTLRDLFDRAVVLSHYIHDLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRIIHNNNCGGsGGEPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITREPEVTCWVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYdSTYR VVSVLTVLHQDWLNGI<EYI<CI<VSNI< ALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDK SRWQQGNVF SC S VMHE A LHNHYTQKSLSLSPGa (SEQ ID NO: 136);LPICPGGAARCQVTLRDLFDRAVVLSHYIHDLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRIIHNNNCGGsGGEPKSsDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYdSTYR VVSVLTVLHQDWLNGI<EYI<CI<VSNI< ALPAPIEKTISKAKGQPREPQVYVYPPSRDELTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFALVSKLTVDKSRWQQGNVFSCSVMHEA LHNHYTQKSLSLSPGa (SEQ ID NO: 137);LPICPGGAARCQVTLRDLFDRAVVLSHYIHDLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRIIHNNNCGGsGGEPKSsDKT HTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYdSTYR VVSVLTVDHHDWLNGI<EYI<CI<VSNI< ALPAPIEKTISKAKGQPREPQVYVYPPSRDELTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFALVSKLTVDKSRWQQGNVFSCSVMHEA LHSHYTQKSLSLSPGa (SEQ ID NO: 138);LPICPGGAARCQVTLRDLFDRAVVLSHYIHDLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRIIHNNNCGGsGGEPKSsDKT HTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYdSTYR VVSVLTVDHHDWLNGI<EYI<CI<VSNI< ALPAPIEKTISKAKGQPREPQVYVYPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFALVSKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGa (SEQ ID NO: 139);LPICPGGAARCQVTLRDLFDRAVVLSHYIHDLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRIIHNNNCGGsGGEPKSsDKT HTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYdSTYR VVSVLTVDHHDWLNGI<EYI<CI<VSNI< ALGAPIEKTISKAKGQPREPQVYVYPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFALVSKLTVDKSRWQQGNVFSCSVMHE ALHSHYTQKSLSLSPGa (SEQ ID NO: 140); andLPICPGGAARCQVTLRDLFDRAVVLSHYIHDLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRIIHNNNCGGsGGEPKSsDKT HTCPPCPAPEAAGGPSVFLFPPKPKDTLYITREPEVTCWVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYdSTYR VVSVLTVLHQDWLNGI<EYI<CI<VSNI< ALPAPIEKTISKAKGQPREPQVYVYPPSRDELTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFALVSKLTVDKSRWQQGNVFSCSVMHEA LHNHYTQKSLSLSPGa (SEQ ID NO: 141).

[0278] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 113-141. In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 113-141. In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 113-141.

[0279] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 115, 119, 125, 129 and 141. In some embodiments, theFc-PRL fusion protein comprises an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 115, 119, 125, 129 and 141. In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 115, 119, 125, 129 and 141. In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 115, 119, 125, 129 and 141.

[0280] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 125. In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 125. In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 97%, 98% or 99% sequence identity to SEQ ID NO: 125. In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having 100% sequence identity to SEQ ID NO: 125.

[0281] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 125, provided that the sequence comprises a S at a position corresponding to position 5, a D at a position corresponding to position 82, an A at a position corresponding to position 232, a V at a position corresponding to position 135, a Y at a position corresponding to position 136, an A at a position corresponding to position 190, a V at a position corresponding to position 192, and / or a S at a position corresponding to position 268 of SEQ ID NO: 125.

[0282] Insome embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 113, provided that the sequence comprises a S at a position corresponding to position 263 SEQ ID NO: 113.

[0283] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 114, provided that the sequence comprises a S at aposition corresponding to position 5, a D at a position corresponding to position 82, and / or an A at a position corresponding to position 232 of SEQ ID NO: 114.

[0284] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 115, provided that the sequence comprises a S at a position corresponding to position 5, a D at a position corresponding to position 82, an A at a position corresponding to position 232, and / or a S at a position corresponding to position 263 of SEQ ID NO: 115.

[0285] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 116, provided that the sequence comprises a S at a position corresponding to position 5, a D at a position corresponding to position 82, an A at a position corresponding to position 232, and / or a S at a position corresponding to position 268 of SEQ ID NO: 116.

[0286] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 117, provided that the sequence comprises a S at a position corresponding to position 5, a D at a position corresponding to position 82, an A at a position corresponding to position 232, an A at a position corresponding to position 19, an A at a position corresponding to position 20, an E at a position corresponding to position 49, a D at a position corresponding to position 94, an H at a position corresponding to position 96, a S at a position corresponding to position 219, and / or a S at a position corresponding to position 263 of SEQ ID NO: 117.

[0287] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 118, provided that the sequence comprises a S at a position corresponding to position 5, a D at a position corresponding to position 82, an A at a position corresponding to position 232, an A at a position corresponding to position 19, an A at a position corresponding to position 20, a G at a position corresponding to position 114, an E at a position corresponding to position 49, a D at a position corresponding to position 94, anH at a position corresponding to position 96, a S at a position corresponding to position 219, and / or a S at a position corresponding to position 263 of SEQ ID NO: 118.

[0288] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 119, provided that the sequence comprises a S at a position corresponding to position 5, a D at a position corresponding to position 82, an A at a position corresponding to position 232, an A at a position corresponding to position 19, an A at a position corresponding to position 20, a Y at a position corresponding to position 37, a T at a position corresponding to position 39, an E at a position corresponding to position 41, and / or a S at a position corresponding to position 263 of SEQ ID NO: 119.

[0289] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 120, provided that the sequence comprises a S at a position corresponding to position 5, a D at a position corresponding to position 82, an A at a position corresponding to position 232, a W at a position corresponding to position 151, and / or a S at a position corresponding to position 263 of SEQ ID NO: 120.

[0290] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 121, provided that the sequence comprises a S at a position corresponding to position 5, a D at a position corresponding to position 82, an A at a position corresponding to position 232, a W at a position corresponding to position 151, and / or a S at a position corresponding to position 268 of SEQ ID NO: 121.

[0291] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 122, provided that the sequence comprises a S at a position corresponding to position 5, a D at a position corresponding to position 82, an A at a position corresponding to position 232, a W at a position corresponding to position 151, an A at a position corresponding to position 19, an A at a position corresponding to position 20, an E at a position corresponding to position 49, a D at a position corresponding to position 94, anH at a position corresponding to position 96, a S at a position corresponding to position 219, and / or a S at a position corresponding to position 268 of SEQ ID NO: 122.

[0292] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 123, provided that the sequence comprises a S at a position corresponding to position 5, a D at a position corresponding to position 82, an A at a position corresponding to position 232, a W at a position corresponding to position 151, an A at a position corresponding to position 19, an A at a position corresponding to position 20, a G at a position corresponding to position 114, an E at a position corresponding to position 49, a D at a position corresponding to position 94, an H at a position corresponding to position 96, a S at a position corresponding to position 219, and / or a S at a position corresponding to position 268 of SEQ ID NO: 123.

[0293] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 124, provided that the sequence comprises a S at a position corresponding to position 5, a D at a position corresponding to position 82, an A at a position corresponding to position 232, a W at a position corresponding to position 151, an A at a position corresponding to position 19, an A at a position corresponding to position 20, a Y at a position corresponding to position 37, a T at a position corresponding to position 39, an E at a position corresponding to position 41, and / or a S at a position corresponding to position 268 of SEQ ID NO: 124.

[0294] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 126, provided that the sequence comprises a S at a position corresponding to position 5, a D at a position corresponding to position 82, an A at a position corresponding to position 232, a V at a position corresponding to position 135, a Y at a position corresponding to position 136, an A at a position corresponding to position 190, a V at a position corresponding to position 192, an A at a position corresponding to position 19, an A at a position corresponding to position 20, an E at a position corresponding to position 49, a D at a position corresponding to position 94, an H at a position corresponding to position96, a S at a position corresponding to position 219, and / or a S at a position corresponding to position 268 of SEQ ID NO: 126.

[0295] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 127, provided that the sequence comprises a S at a position corresponding to position 5, a D at a position corresponding to position 82, an A at a position corresponding to position 232, a V at a position corresponding to position 135, a Y at a position corresponding to position 136, an A at a position corresponding to position 190, a V at a position corresponding to position 192, an A at a position corresponding to position 19, an A at a position corresponding to position 20, an E at a position corresponding to position 49, a D at a position corresponding to position 94, an H at a position corresponding to position 96, a S at a position corresponding to position 219, and / or a S at a position corresponding to position 268 of SEQ ID NO: 127.

[0296] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 128, provided that the sequence comprises a S at a position corresponding to position 5, a D at a position corresponding to position 82, an A at a position corresponding to position 232, a V at a position corresponding to position 135, a Y at a position corresponding to position 136, an A at a position corresponding to position 190, a V at a position corresponding to position 192, an A at a position corresponding to position 19, an A at a position corresponding to position 20, a G at a position corresponding to position 114, an E at a position corresponding to position 49, a D at a position corresponding to position 94, an H at a position corresponding to position 96, a S at a position corresponding to position 219, and / or a S at a position corresponding to position 268 of SEQ ID NO: 128.

[0297] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 129, provided that the sequence comprises a S at a position corresponding to position 5, a D at a position corresponding to position 82, an A at a position corresponding to position 232, a V at a position corresponding to position 135, a Y at a position corresponding to position 136, an A at a position corresponding to position 190, a V at a position corresponding to position 192, an A at a position corresponding to position 19,an A at a position corresponding to position 20, a Y at ap position corresponding to position 37, a T at a position corresponding to position 39, an E at a position corresponding to position 41, and / or a S at a position corresponding to position 268 of SEQ ID NO: 129.

[0298] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 130, provided that the sequence comprises a S at a position corresponding to position 5, a S at a position corresponding to position 204, a D at a position corresponding to position 281, an A at a position corresponding to position 431, and / or a W at a position corresponding to position 350 of SEQ ID NO: 130.

[0299] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 130, provided that the sequence comprises a S at a position corresponding to position 5, a S at a position corresponding to position 209, a D at a position corresponding to position 286, an A at a position corresponding to position 436, and / or a W at a position corresponding to position 355 of SEQ ID NO: 130.

[0300] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 131, provided that the sequence comprises a S at a position corresponding to position 5, a S at a position corresponding to position 191, a S at a position corresponding to position 199, a S at a position corresponding to position 204, a D at a position corresponding to position 281, an A at a position corresponding to position 431, and / or a W at a position corresponding to position 350 of SEQ ID NO: 131.

[0301] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 132, provided that the sequence comprises a S at a position corresponding to position 5, a S at a position corresponding to position 191, a S at a position corresponding to position 199, a S at a position corresponding to position 204, a S at a position corresponding to position 210, a S at a position corresponding to position 213, a D at a position corresponding to position 281, an A at a position corresponding to position 431, and / or a W at a position corresponding to position 350 of SEQ ID NO: 132.

[0302] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 134, provided that the sequence comprises a S at a position corresponding to position 5, a S at a position corresponding to position 209, a D at a position corresponding to position 286, an A at a position corresponding to position 436, a W at a position corresponding to position 355, an A at a position corresponding to position 223, an A at a position corresponding to position 224, an E at a position corresponding to position 253, a D at a position corresponding to position 298, an H at a position corresponding to position 300, and / or a S at a position corresponding to position 423 of SEQ ID NO: 134.

[0303] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 135, provided that the sequence comprises a S at a position corresponding to position 5, a S at a position corresponding to position 209, a D at a position corresponding to position 286, an A at a position corresponding to position 436, a W at a position corresponding to position 355, an A at a position corresponding to position 223, an A at a position corresponding to position 224, a G at a position corresponding to position 318, an E at a position corresponding to position 253, a D at a position corresponding to position 298, an H at a position corresponding to position 300, and / or a S at a position corresponding to position 423 of SEQ ID NO: 135.

[0304] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 136, provided that the sequence comprises a S at a position corresponding to position 5, a S at a position corresponding to position 209, a D at a position corresponding to position 286, an A at a position corresponding to position 436, a W at a position corresponding to position 355, an A at a position corresponding to position 223, an A at a position corresponding to position 224, a Y at a position corresponding to position 241, at a position corresponding to position 243, and / or an E at a position corresponding to position 245 of SEQ ID NO: 136.

[0305] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected fromthe group consisting of SEQ ID NO: 137, provided that the sequence comprises a S at a position corresponding to position 5, a S at a position corresponding to position 209, a D at a position corresponding to position 286, a V at a position corresponding to position 339, a Y at a position corresponding to position 340, an A at a position corresponding to position 394, and / or a Y at a position corresponding to position 396 of SEQ ID NO: 137.

[0306] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 138, provided that the sequence comprises a S at a position corresponding to position 5, a S at a position corresponding to position 209, a D at a position corresponding to position 286, a V at a position corresponding to position 339, a Y at a position corresponding to position 340, an A at a position corresponding to position 394, and / or a Y at a position corresponding to position 396, an A at a position corresponding to position 223, an A at a position corresponding to position 224, an E at a position corresponding to position 253, a D at a position corresponding to position 298, an H at a position corresponding to position 300, and / or a S at a position corresponding to position 423 of SEQ ID NO: 138

[0307] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 139, provided that the sequence comprises a S at a position corresponding to position 5, a S at a position corresponding to position 209, a D at a position corresponding to position 286, a V at a position corresponding to position 339, a Y at a position corresponding to position 340, an A at a position corresponding to position 394, and / or a Y at a position corresponding to position 396, an A at a position corresponding to position 223, an A at a position corresponding to position 224, an E at a position corresponding to position 253, a D at a position corresponding to position 298, an H at a position corresponding to position 300, and / or a S at a position corresponding to position 423 of SEQ ID NO: 139

[0308] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 140, provided that the sequence comprises a S at a position corresponding to position 5, a S at a position corresponding to position 209, a D at aposition corresponding to position 286, a V at a position corresponding to position 339, a Y at a position corresponding to position 340, an A at a position corresponding to position 394, and / or a Y at a position corresponding to position 396, an A at a position corresponding to position 223, an A at a position corresponding to position 224, a G at a position corresponding to position 318, an E at a position corresponding to position 253, a D at a position corresponding to position 298, an H at a position corresponding to position 300, and / or a S at a position corresponding to position 423 of SEQ ID NO: 140.

[0309] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 141, provided that the sequence comprises a S at a position corresponding to position 5, a S at a position corresponding to position 209, a D at a position corresponding to position 286, a V at a position corresponding to position 339, a Y at a position corresponding to position 340, an A at a position corresponding to position 394, and / or a Y at a position corresponding to position 396, an A at a position corresponding to position 223, an A at a position corresponding to position 224, a Y at a position corresponding to position 241, a T at a position corresponding to position 243, and / or an E at a position corresponding to position 245 of SEQ ID NO: 141.

[0310] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 125, provided that the sequence does not comprise a S at a position corresponding to position 5, a D at a position corresponding to position 82, an A at a position corresponding to position 232, a V at a position corresponding to position 135, a Y at a position corresponding to position 136, an A at a position corresponding to position 190, a V at a position corresponding to position 192, and / or a S at a position corresponding to position 268 of SEQ ID NO: 125.

[0311] Insome embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 113, provided that the sequence does not comprise a S at a position corresponding to position 263 SEQ ID NO: 113.

[0312] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 114, provided that the sequence does not comprise a S at a position corresponding to position 5, a D at a position corresponding to position 82, and / or an A at a position corresponding to position 232 of SEQ ID NO: 114.

[0313] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 115, provided that the sequence does not comprise a S at a position corresponding to position 5, a D at a position corresponding to position 82, an A at a position corresponding to position 232, and / or a S at a position corresponding to position 263 of SEQ ID NO: 115.

[0314] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 116, provided that the sequence does not comprise a S at a position corresponding to position 5, a D at a position corresponding to position 82, an A at a position corresponding to position 232, and / or a S at a position corresponding to position 268 of SEQ ID NO: 116.

[0315] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 117, provided that the sequence does not comprise a S at a position corresponding to position 5, a D at a position corresponding to position 82, an A at a position corresponding to position 232, an A at a position corresponding to position 19, an A at a position corresponding to position 20, an E at a position corresponding to position 49, a D at a position corresponding to position 94, an H at a position corresponding to position 96, a S at a position corresponding to position 219, and / or a S at a position corresponding to position 263 of SEQ ID NO: 117.

[0316] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 118, provided that the sequence does not comprise a S at a position corresponding to position 5, a D at a position corresponding to position 82, an A at a position corresponding to position 232, an A at a position corresponding to position 19, anA at a position corresponding to position 20, a G at a position corresponding to position 114, an E at a position corresponding to position 49, a D at a position corresponding to position 94, an H at a position corresponding to position 96, a S at a position corresponding to position 219, and / or a S at a position corresponding to position 263 of SEQ ID NO: 118.

[0317] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 119, provided that the sequence does not comprise a S at a position corresponding to position 5, a D at a position corresponding to position 82, an A at a position corresponding to position 232, an A at a position corresponding to position 19, an A at a position corresponding to position 20, a Y at a position corresponding to position 37, a T at a position corresponding to position 39, an E at a position corresponding to position 41, and / or a S at a position corresponding to position 263 of SEQ ID NO: 119.

[0318] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 120, provided that the sequence does not comprise a S at a position corresponding to position 5, a D at a position corresponding to position 82, an A at a position corresponding to position 232, a W at a position corresponding to position 151, and / or a S at a position corresponding to position 263 of SEQ ID NO: 120.

[0319] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 121, provided that the sequence does not comprise a S at a position corresponding to position 5, a D at a position corresponding to position 82, an A at a position corresponding to position 232, a W at a position corresponding to position 151, and / or a S at a position corresponding to position 268 of SEQ ID NO: 121.

[0320] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 122, provided that the sequence does not comprise a S at a position corresponding to position 5, a D at a position corresponding to position 82, an A at a position corresponding to position 232, a W at a position corresponding to position 151, an A at a position corresponding to position 19, an A at a position corresponding to position20, an E at a position corresponding to position 49, a D at a position corresponding to position 94, an H at a position corresponding to position 96, a S at a position corresponding to position 219, and / or a S at a position corresponding to position 268 of SEQ ID NO: 122.

[0321] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 123, provided that the sequence does not comprise a S at a position corresponding to position 5, a D at a position corresponding to position 82, an A at a position corresponding to position 232, a W at a position corresponding to position 151, an A at a position corresponding to position 19, an A at a position corresponding to position 20, a G at a position corresponding to position 114, an E at a position corresponding to position 49, a D at a position corresponding to position 94, an H at a position corresponding to position 96, a S at a position corresponding to position 219, and / or a S at a position corresponding to position 268 of SEQ ID NO: 123.

[0322] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 124, provided that the sequence does not comprise a S at a position corresponding to position 5, a D at a position corresponding to position 82, an A at a position corresponding to position 232, a W at a position corresponding to position 151, an A at a position corresponding to position 19, an A at a position corresponding to position 20, a Y at a position corresponding to position 37, a T at a position corresponding to position 39, an E at a position corresponding to position 41, and / or a S at a position corresponding to position 268 of SEQ ID NO: 124.

[0323] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 126, provided that the sequence does not comprise a S at a position corresponding to position 5, a D at a position corresponding to position 82, an A at a position corresponding to position 232, a V at a position corresponding to position 135, a Y at a position corresponding to position 136, an A at a position corresponding to position 190, a V at a position corresponding to position 192, an A at a position corresponding to position 19, an A at a position corresponding to position 20, an E at a position corresponding to position 49, a D at a position corresponding to position 94, an H at a position corresponding to position96, a S at a position corresponding to position 219, and / or a S at a position corresponding to position 268 of SEQ ID NO: 126.

[0324] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 127, provided that the sequence does not comprise a S at a position corresponding to position 5, a D at a position corresponding to position 82, an A at a position corresponding to position 232, a V at a position corresponding to position 135, aY at a position corresponding to position 136, an A at a position corresponding to position 190, a V at a position corresponding to position 192, an A at a position corresponding to position 19, an A at a position corresponding to position 20, an E at a position corresponding to position 49, a D at a position corresponding to position 94, an H at a position corresponding to position 96, a S at a position corresponding to position 219, and / or a S at a position corresponding to position 268 of SEQ ID NO: 127.

[0325] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 128, provided that the sequence does not comprise a S at a position corresponding to position 5, a D at a position corresponding to position 82, an A at a position corresponding to position 232, a V at a position corresponding to position 135, aY at a position corresponding to position 136, an A at a position corresponding to position 190, a V at a position corresponding to position 192, an A at a position corresponding to position 19, an A at a position corresponding to position 20, a G at a position corresponding to position 114, an E at a position corresponding to position 49, a D at a position corresponding to position 94, an H at a position corresponding to position 96, a S at a position corresponding to position 219, and / or a S at a position corresponding to position 268 of SEQ ID NO: 128.

[0326] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 129, provided that the sequence does not comprise a S at a position corresponding to position 5, a D at a position corresponding to position 82, an A at a position corresponding to position 232, a V at a position corresponding to position 135, aY at a position corresponding to position 136, an A at a position corresponding to position 190, a V at a position corresponding to position 192, an A at a position corresponding to position19, an A at a position corresponding to position 20, a Y at ap position corresponding to position 37, a T at a position corresponding to position 39, an E at a position corresponding to position 41, and / or a S at a position corresponding to position 268 of SEQ ID NO: 129.

[0327] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 130, provided that the sequence does not comprise a S at a position corresponding to position 5, a S at a position corresponding to position 204, a D at a position corresponding to position 281, an A at a position corresponding to position 431, and / or a W at a position corresponding to position 350 of SEQ ID NO: 130.

[0328] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 130, provided that the sequence does not comprise a S at a position corresponding to position 5, a S at a position corresponding to position 209, a D at a position corresponding to position 286, an A at a position corresponding to position 436, and / or a W at a position corresponding to position 355 of SEQ ID NO: 130.

[0329] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 131, provided that the sequence does not comprise a S at a position corresponding to position 5, a S at a position corresponding to position 191, a S at a position corresponding to position 199, a S at a position corresponding to position 204, a D at a position corresponding to position 281, an A at a position corresponding to position 431, and / or a W at a position corresponding to position 350 of SEQ ID NO: 131.

[0330] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 132, provided that the sequence does not comprise a S at a position corresponding to position 5, a S at a position corresponding to position 191, a S at a position corresponding to position 199, a S at a position corresponding to position 204, a S at a position corresponding to position 210, a S at a position corresponding to position 213, a D at a position corresponding to position 281, an A at a position corresponding to position 431, and / or a W at a position corresponding to position 350 of SEQ ID NO: 132.

[0331] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 134, provided that the sequence does not comprise a S at a position corresponding to position 5, a S at a position corresponding to position 209, a D at a position corresponding to position 286, an A at a position corresponding to position 436, a W at a position corresponding to position 355, an A at a position corresponding to position 223, an A at a position corresponding to position 224, an E at a position corresponding to position 253, a D at a position corresponding to position 298, an H at a position corresponding to position 300, and / or a S at a position corresponding to position 423 of SEQ ID NO: 134.

[0332] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 135, provided that the sequence does not comprise a S at a position corresponding to position 5, a S at a position corresponding to position 209, a D at a position corresponding to position 286, an A at a position corresponding to position 436, a W at a position corresponding to position 355, an A at a position corresponding to position 223, an A at a position corresponding to position 224, a G at a position corresponding to position 318, an E at a position corresponding to position 253, a D at a position corresponding to position 298, an H at a position corresponding to position 300, and / or a S at a position corresponding to position 423 of SEQ ID NO: 135.

[0333] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 136, provided that the sequence does not comprise a S at a position corresponding to position 5, a S at a position corresponding to position 209, a D at a position corresponding to position 286, an A at a position corresponding to position 436, a W at a position corresponding to position 355, an A at a position corresponding to position 223, an A at a position corresponding to position 224, a Y at a position corresponding to position 241, at a position corresponding to position 243, and / or an E at a position corresponding to position 245 of SEQ ID NO: 136.

[0334] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected fromthe group consisting of SEQ ID NO: 137, provided that the sequence does not comprise a S at a position corresponding to position 5, a S at a position corresponding to position 209, a D at a position corresponding to position 286, a V at a position corresponding to position 339, aY at a position corresponding to position 340, an A at a position corresponding to position 394, and / or a Y at a position corresponding to position 396 of SEQ ID NO: 137.

[0335] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 138, provided that the sequence does not comprise a S at a position corresponding to position 5, a S at a position corresponding to position 209, a D at a position corresponding to position 286, a V at a position corresponding to position 339, aY at a position corresponding to position 340, an A at a position corresponding to position 394, and / or a Y at a position corresponding to position 396, an A at a position corresponding to position 223, an A at a position corresponding to position 224, an E at a position corresponding to position 253, a D at a position corresponding to position 298, an H at a position corresponding to position 300, and / or a S at a position corresponding to position 423 of SEQ ID NO: 138

[0336] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 139, provided that the sequence does not comprise a S at a position corresponding to position 5, a S at a position corresponding to position 209, a D at a position corresponding to position 286, a V at a position corresponding to position 339, aY at a position corresponding to position 340, an A at a position corresponding to position 394, and / or a Y at a position corresponding to position 396, an A at a position corresponding to position 223, an A at a position corresponding to position 224, an E at a position corresponding to position 253, a D at a position corresponding to position 298, an H at a position corresponding to position 300, and / or a S at a position corresponding to position 423 of SEQ ID NO: 139

[0337] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 140, provided that the sequence does not comprise a S at a position corresponding to position 5, a S at a position corresponding to position 209, a Dat a position corresponding to position 286, a V at a position corresponding to position 339, aY at a position corresponding to position 340, an A at a position corresponding to position 394, and / or a Y at a position corresponding to position 396, an A at a position corresponding to position 223, an A at a position corresponding to position 224, a G at a position corresponding to position 318, an E at a position corresponding to position 253, a D at a position corresponding to position 298, an H at a position corresponding to position 300, and / or a S at a position corresponding to position 423 of SEQ ID NO: 140.

[0338] In some embodiments, the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 141, provided that the sequence does not comprise a S at a position corresponding to position 5, a S at a position corresponding to position 209, a D at a position corresponding to position 286, a V at a position corresponding to position 339, aY at a position corresponding to position 340, an A at a position corresponding to position 394, and / or a Y at a position corresponding to position 396, an A at a position corresponding to position 223, an A at a position corresponding to position 224, a Y at a position corresponding to position 241, a T at a position corresponding to position 243, and / or an E at a position corresponding to position 245 of SEQ ID NO: 141.

[0339] In some embodiments of any one of the aspects described herein, an Fc-PRL fusion protein described herein is more susceptible to protease cleavage relative to an Fc-prolactin protein comprising a wild-type prolactin polypeptide and a wild-type Fc domain under the same conditions. For example, a Fc-PRL fusion protein described is cleaved at a rate at least 10% or more compared to cleavage of an Fc-prolactin protein comprising a wild-type prolactin polypeptide and a wild-type Fc domain under the same conditions. In some embodiments, a Fc-PRL fusion protein described is cleaved at a rate 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% or more compared to cleavage of an Fc-prolactin protein comprising a wild-type prolactin polypeptide and a wild-type Fc domain under the same conditions.

[0340] In some embodiments of any one of the aspects described herein, an Fc-PRL fusion protein described herein has increased in vivo half-life compared to an Fc-prolactin protein comprising a wild-type prolactin polypeptide and a wild-type Fc domain under the same conditions. The term;"in vivo half-life’7as used herein refers to a biological half-life of a Fc- PRL fusion protein of interest in the circulation of a given animal, e.g., a mammal and isrepresented by a time required for half the quantity administered in the animal to be cleared from the circulation and / or other tissues in the animal . In vivo half-life is also referred to “serum half-life'’, “plasma half-life”, ortj-2. Half-life can be expressed as the time required to eliminate fifty percent (50%) of a known quantity of the Fc-PRI.. fusion protein from a subject's body (e g., a human patient or other mammal) or a specific compartment thereof, for example, as measured in serum (i.e., “in vivo circulating half-life”), or in other tissues. In general, an increase in half-life results in an increase in mean residence time (MRT) in circulation for the Fc-PRL fusion protein administered. In some embodiments of any one of the aspects described herein, an Fc-PRL fusion protein described herein has an in vivo half-life at least 5% longer than an Fc-prolactin protein comprising a wild-type prolactin polypeptide and a wildtype Fc domain. For example, an Fc-PRL fusion protein described herein has an in vivo halflife that 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% or more longer compared to an Fc-prolactin protein comprising a wild-type prolactin polypeptide and a wild-type Fc domain under the same conditions.Methods of use

[0341] The Fc-PRL fusion protein described herein can be used for treating a condition, disease or disorder characterized by a decreased PRL activity or level and / or decreased breast milk production in a subj ect. Generally, the method comprises administering a therapeutically effective amount of a Fc-PRL fusion protein described herein or a polynucleotide encoding the Fc-PRL fusion protein to a subject in need thereof.

[0342] As used herein terms “condition,” “disorder,” and “disease” relate to any unhealthy or abnormal state. The term “condition characterized by a decreased PRL activity or level and / or decreased human breast milk production” includes conditions, disorders, and diseases in which elevating PRL, e.g., increasing human breast milk production provides a therapeutic benefit. Conditions characterized by a decreased PRL activity or levels include conditions characterized by hypoprolactinemia. In particular, the such conditions include hypopituitarism, Sheehan syndrome, and isolated prolactin deficiency.

[0343] In some embodiments, the condition characterized by a lower PRL activity or level is hypoprolactinemia. Hypoprolactinemia is characterized by deficiency in the serum levels of the hypothalamic-pituitary hormone prolactin. It can result from autoimmune disease, hypopituitarism, growth hormone deficiency, hypothyroidism, excessive dopamine action inthe tuberoinfundibular pathway and / or the anterior pituitary, and ingestion of drugs that activate the D2 receptor, such as direct D2 receptor agonists like bromocriptine and pergolide, and indirect D2 receptor activators like amphetamines (through the induction of dopamine release).

[0344] Hypoprolactinemia is associated with ovarian dysfunction and decreased milk production in women, and, in men, metabolic syndrome, anxiety symptoms, arteriogenic erectile dysfunction, premature ejaculation, oligozoospermia (low concentration of sperm in semen), asthenospermia (reduced sperm motility), hypofunction of seminal vesicles, and hypoandrogenism. In one study, normal sperm characteristics were restored when prolactin levels were brought up to normal values in men with hypoprolactinemia. Hypoprolactinemia can be a cause of lactation failure after childbirth.

[0345] In some embodiments, the condition characterized by a lower PRL activity or level is hypopituitarism. Hypopituitarism is the decreased secretion of one or more of the eight hormones normally produced by the pituitary gland at the base of the brain. If there is decreased secretion of one specific pituitary hormone, the condition is known as selective hypopituitarism. If there is decreased secretion of most or all pituitary hormones, the term panhypopituitarism (pan meaning “all”) is used.

[0346] In some embodiments of the various aspects described herein, hypopituitarism is selective hypopituitarism.

[0347] In some other embodiments of the various aspects described herein, hypopituitarism is panhypopituitarism.

[0348] In some embodiments, the condition characterized by a lower PRL activity or level is Sheehan syndrome. Sheehan syndrome is a condition that happens when the pituitary gland is damaged during childbirth. It’s caused by excess blood loss (hemorrhage) or extremely low blood pressure during or after labor. A lack of blood deprives the pituitary of the oxygen it needs to work properly. Sheehan syndrome leads to decreased production of these pituitary hormones: thyroid-stimulating hormone (TSH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), growth hormone (GH), adrenocorticotropic hormone (ACTH), and prolactin.

[0349] In some embodiments, the condition characterized by a lower PRL activity or level is isolated prolactin deficiency. Isolated prolactin deficiency is characterized by a reduced level of prolactin in the blood circulation. It is considered an autosomal recessive trait. The affected females are generally healthy but are unable to nurse following parturition and have no detectable prolactin secretion after stimulation with phenothiazine.

[0350] In some embodiments, the method of detecting prolactin can comprise a step ofassaying a sample from the subject for determining prolactin activity and / or level prior to onset of treatment. The activity or level can be compared to a reference, e.g., prolactin activity or level in a healthy subject. A subject having decreased prolactin activity or level can be selected for treatment. Methods for determining prolactin activity and level are well known in the art and available to one of skill in the art.

[0351] In some embodiments, the method can comprise a step of obtaining or receiving results of an assay determining prolactin activity or level in a subject prior to administration.

[0352] It is noted that the terms “administered” and “subjected” are used interchangeably in the context of treatment of a disease or disorder. In jurisdictions that forbid the patenting of methods that are practiced on the human body, the meaning of “administering” of a composition to a human subject shall be restricted to prescribing a controlled substance that a human subject will be administer to the subject by any technique (e.g., orally, inhalation, topical application, injection, insertion, etc.). The broadest reasonable interpretation that is consistent with laws or regulations defining patentable subject matter is intended. In jurisdictions that do not forbid the patenting of methods that are practiced on the human body, the “administering” of compositions includes both methods practiced on the human body and also the foregoing activities.

[0353] As used herein, the term “administer” refers to the placement of the Fc-PRL fusion protein or a composition comprising the same into a subject by a method or route which results in at least partial localization of the composition at a desired site such that desired effect is produced. A Fc-PRL fusion protein or a composition comprising the same can be administered by any appropriate route known in the art including, but not limited to, oral or parenteral routes, including intravenous, intramuscular, subcutaneous, transdermal, airway (aerosol), pulmonary, nasal, rectal, and topical (including buccal and sublingual) administration.

[0354] Exemplary modes of administration include, but are not limited to, injection, infusion, instillation, inhalation, or ingestion. “Injection” includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intraventricular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, sub capsular, subarachnoid, intraspinal, intracerebro spinal, and intrasternal injection and infusion. In some embodiments, administration will generally be local rather than systemic. In some embodiments, administering is intravenous (IV), intraperitoneal (IP) administration, subcutaneous (SC) administration, or intramuscular (IM) administration.

[0355] The phrase “therapeutically effective amount” as used herein means that amount ofa Fc-PRL fusion protein described herein which is effective for producing some desired therapeutic effect in a subject at a reasonable benefit / risk ratio applicable to any medical treatment. Thus, “therapeutically effective amount” means that amount which, when administered to a subject for treating lactation insufficiency, is sufficient to affect such treatment for lactation insufficiency. IN the context of increasing milk production, “therapeutically effective amount” means that amount which, when administered to a subject, is sufficient to increase milk production by at least 10%, e.g. 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% or more compared to production when no Fc-PRL is administered.

[0356] Depending on the route of administration, effective doses can be calculated according to the body weight, body surface area, or organ size of the subject to be treated. Optimization of the appropriate dosages can readily be made by one skilled in the art in light of pharmacokinetic data observed in human clinical trials. Alternatively, or additionally, the dosage to be administered can be determined from studies using animal models for the particular type of condition to be treated, and / or from animal or human data obtained from agents which are known to exhibit similar pharmacological activities. The final dosage regimen will be determined by the attending surgeon or physician, considering various factors which modify the action of active agent, e.g., the agent’s specific activity, the agent’s specific half-life in vivo, the severity of the condition and the responsiveness of the patient, the age, condition, body weight, sex and diet of the patient, the severity of any present infection, time of administration, the use (or not) of other concomitant therapies, and other clinical factors.

[0357] Determination of an effective amount is well within the capability of those skilled in the art. Generally, the actual effective amount can vary with the specific compound, the use or application technique, the desired effect, the duration of the effect and side effects, the subject’s history, age, condition, sex, as well as the severity and type of the medical condition in the subject, and administration of other pharmaceutically active agents. Accordingly, an effective dose of compound described herein is an amount sufficient to produce at least some desired therapeutic effect in a subject.

[0358] The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of use or administration utilized.

[0359] The effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the therapeutic which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Levels in plasma can be measured, for example, by high performance liquid chromatography. The effects of any particular dosage can be monitored by a suitable bioassay. The effective plasma concentration for Fc-PRL fusion protein or a fragment thereof can be about 0.01 pM to about 10 pM, about 0.2 pM to about 5 pM, or about 0.8 to about 3 pM in a subject, such as a rat, dog, or human.

[0360] Generally, the compositions are administered so that a Fc-PRL fusion protein described herein is used or given at a dose from 50 pg / kg to 1000 mg / kg; 1 pg / kg to 500 mg / kg; 1 pg / kg to 150 mg / kg, 1 pg / kg to 100 mg / kg, 1 pg / kg to 50 mg / kg, 1 pg / kg to 20 mg / kg, 1 pg / kg to 10 mg / kg, 1 pg / kg to 1 mg / kg, 100 pg / kg to 100 mg / kg, 100 pg / kg to 50 mg / kg, 100 pg / kg to 20 mg / kg, 100 pg / kg to 10 mg / kg, lOOpg / kg to Img / kg, 1 mg / kg to 100 mg / kg, 1 mg / kg to 50 mg / kg, 1 mg / kg to 20 mg / kg, 1 mg / kg to 10 mg / kg, 10 mg / kg to 100 mg / kg, 10 mg / kg to 50 mg / kg, or 10 mg / kg to 20 mg / kg. It is to be understood that ranges given here include all intermediate ranges, for example, the range 1 mg / kg to 10 mg / kg includes 1 mg / kg to 2 mg / kg, 1 mg / kg to 3 mg / kg, Img / kg to 4 mg / kg, Img / kg to 5 mg / kg, 1 mg / kg to 6 mg / kg, Img / kg to 7 mg / kg, Img / kg to 8 mg / kg, Img / kg to 9 mg / kg, 2mg / kg to lOmg / kg, 3mg / kg to lOmg / kg, 4mg / kg to lOmg / kg, 5mg / kg to lOmg / kg, 6mg / kg to lOmg / kg, 7mg / kg to lOmg / kg, 8mg / kg to lOmg / kg, 9mg / kg to lOmg / kg, and the like. Further contemplated is a dose (either as a bolus or continuous infusion) of about 0.1 mg / kg to about 10 mg / kg, about 0.3 mg / kg to about 5 mg / kg, or 0.5 mg / kg to about 3 mg / kg. It is to be further understood that the ranges intermediate to those given above are also within the scope of this disclosure, for example, in the range 1 mg / kg to 10 mg / kg, for example use or dose ranges such as 2mg / kg to 8 mg / kg, 3mg / kg to 7 mg / kg, 4mg / kg to 6mg / kg, and the like.

[0361] Typically, a dose of 500 mgs, 1 gram, 2.5 grams or more is used for a human subject. For example, about 200 mgs to about 3mgs, or more of the Fc-PRL fusion protein can be administered to the subject, e.g., a human patient per day. In some embodiments, a subject, e.g., a human patient is treated with an Fc-PRL fusion protein described herein at a dose of at least 500 mgs per day. For example, a subject, e.g., a human patient can be treated with an Fc- PRL fusion protein described herein at a dose of at least 1 gram per day. In some embodiments, a subject, e.g., a human patient can be treated with an Fc-PRL fusion protein described herein at a dose of at least 2.5 grams per day.

[0362] In some embodiments, about 200 to 500 milligrams and more preferably about 320milligrams of the Fc-PRL fusion protein can be administered to a 70 kg subject, e.g., a human patient.

[0363] The Fc-PRL fusion protein described herein can be administered at once, or can be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment will be a function of the location of where the Fc-PRL fusion protein is administered, the carrier and other variables that can be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values can also vary with the age of the individual treated. It is to be further understood that for any particular subject, specific dosage regimens can need to be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations. Hence, the concentration ranges set forth herein are intended to be exemplary and are not intended to limit the scope or practice of the claimed formulations.

[0364] The Fc-PRL fusion protein can be administered as a single bolus or multiple boluses, as a continuous infusion, or a combination thereof. For example, the Fc-PRL fusion protein can be administered as a single bolus initially, and then administered as a continuous infusion following the bolus. The rate of the infusion can be any rate sufficient to maintain effective concentration, for example, to maintain effective plasma concentration. Some contemplated infusion rates include from 1 pg / kg / min to 100 mg / kg / min, or from 1 pg / kg / hr to 1000 mg / kg / hr. Rates of infusion can include 0.2 to 1.5 mg / kg / min, or more specifically 0.25 to 1 mg / kg / min, or even more specifically 0.25 to 0.5 mg / kg / min. It will be appreciated that the rate of infusion can be determined based upon the dose necessary to maintain effective plasma concentration and the rate of elimination of the compound, such that the compound is administered via infusion at a rate sufficient to safely maintain a sufficient effective plasma concentration of compound in the bloodstream.

[0365] It will be appreciated that methods of treatment of the present invention can be employed in combination with additional therapies. For example, a treatment according to the present disclosure can be co-administered with one or more desired therapeutics or medical procedures for treating lactation insufficiency.

[0366] The terms “co-administration” or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time. The particular combination of therapies (therapeutics or procedures) to employ in such a combination regimen will take into accountcompatibility of the desired therapeutics and / or procedures and the desired therapeutic effect to be achieved.

[0367] In some embodiments of the various aspects described herein, the subject methods include monitoring the patient for efficacy of treatment. Monitoring may measure milk production and / or monitoring for the presence or absence (either quantitatively or qualitatively) of a biomarker associated with the disease being treated. For example, diagnosis as well as the assessment of treatment efficacy for lactation insufficiency using the subject methods can be determined by the presence or absence of biomarkers in a biological sample (e.g., blood, stool, etc.) from the patient.

[0368] Examples of biomarkers that can be used to diagnose and / or determine the severity of lactation insufficiency can be found, for example, in Neifert et al, 1987, and US patent application publication 201562238914, contents of all of which are hereby incorporated by reference in their entireties.Pharmaceutical compositions

[0369] For administration to a subject, the Fc-PRL fusion protein described herein can be formulated into pharmaceutically acceptable compositions / formulations.

[0370] These pharmaceutically acceptable compositions comprise a Fc-PRL fusion protein described herein, formulated together with one or more pharmaceutically acceptable carriers (additives) and / or diluents. As described in detail below, the pharmaceutical compositions described herein can be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), gavages, lozenges, dragees, capsules, pills, tablets (e.g., those targeted for buccal, sublingual, and systemic absorption), boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; (8) transmucosally; or (9) nasally. Additionally, compounds can be implanted into a patient or injected using a drug delivery system. See, for example, Urquhart, et al., Ann. Rev. Pharmacol. Toxicol. 24: 199-236 (1984); Lewis, ed. “Controlled Release of Pesticides and Pharmaceuticals” (Plenum Press, New York, 1981); U.S. Pat. No. 3,773,919; and U.S. Pat. No. 35 3,270,960, content of all of which is herein incorporated byreference.

[0371] As used here, the term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0372] As used here, the term “pharmaceutically acceptable carried’ means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, methylcellulose, ethyl cellulose, microcrystalline cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) lubricating agents, such as magnesium stearate, sodium lauryl sulfate and talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol (PEG); (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer1s solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and / or polyanhydrides; (22) bulking agents, such as polypeptides and amino acids (23) serum component, such as serum albumin, HDL and LDL; (22) C2-C12 alcohols, such as ethanol; and (23) other non-toxic compatible substances employed in pharmaceutical formulations. Wetting agents, coloring agents, release agents, coating agents, sweetening agents, flavoring agents, perfuming agents, preservative and antioxidants can also be present in the formulation. The terms such as “excipient”, “carrier”, “pharmaceutically acceptable carrier” or the like are used interchangeably herein.

[0373] Examples of solid carriers include starch, sugar, bentonite, silica, and other commonly used carriers. Further non-limiting examples of carriers and diluents which can be used in the formulations comprising a Fc-PRL fusion protein described herein include saline,syrup, dextrose, and water.

[0374] Pharmaceutically acceptable antioxidants include, but are not limited to, (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lectithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acids, and the like.

[0375] The Fc-PR: fusion protein described herein can be formulated in a gelatin capsule, in tablet form, dragee, syrup, suspension, topical cream, suppository, injectable solution, or kits for the preparation of syrups, suspension, topical cream, suppository or injectable solution just prior to use. Also, Fc-PRL fusion protein described herein can be included in composites, which facilitate its slow release into the blood stream, e.g., silicon disc, polymer beads.

[0376] The formulations can conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques, excipients and formulations generally are found in, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1985, 17th edition, Nema et al., PDA J. Pharm. Sci. Tech. 1997 51 : 166-171. Methods to make invention formulations include the step of bringing into association or contacting a Fc-PRL fusion protein described herein with one or more excipients or carriers. In general, the formulations are prepared by uniformly and intimately bringing into association a Fc-PRL fusion protein described herein with liquid excipients or finely divided solid excipients or both, and then, if appropriate, shaping the product.

[0377] The preparative procedure may include the sterilization of the pharmaceutical preparations. The Fc-PRL fusion protein described herein may be mixed with auxiliary agents such as lubricants, preservatives, stabilizers, salts for influencing osmotic pressure, etc., which do not react deleted ously with the compounds.

[0378] Examples of injectable form include solutions, suspensions and emulsions. Injectable forms also include sterile powders for extemporaneous preparation of injectable solutions, suspensions or emulsions. The Fc-PRL fusion protein described herein can be injected in association with a pharmaceutical carrier such as normal saline, physiological saline, bacteriostatic water, Cremophor™ EL (BASF, Parsippany, N.J.), phosphate buffered saline (PBS), Ringer's solution, dextrose solution, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof, and other aqueous carriers known in the art. Appropriate non-aqueous carriers may also be used and examples include fixed oils and ethyl oleate. In all cases, the composition must be sterile andshould be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin. A suitable carrier is 5% dextrose in saline. Frequently, it is desirable to include additives in the carrier such as buffers and preservatives or other substances to enhance isotonicity and chemical stability.

[0379] In some embodiments, Fc-PRL fusion protein described herein can be administrated encapsulated within liposomes. The manufacture of such liposomes and insertion of molecules into such liposomes being well known in the art, for example, as described in US Pat. No. 4,522,811. Liposomal suspensions (including liposomes targeted to particular cells, e.g., a pituitary cell) can also be used as pharmaceutically acceptable carriers.

[0380] Conventional dosage forms generally provide rapid or immediate drug release from the formulation. Depending on the pharmacology and pharmacokinetics of the drug, use of conventional dosage forms can lead to wide fluctuations in the concentrations of the drug in a patient's blood and other tissues. These fluctuations can impact a number of parameters, such as dose frequency, onset of action, duration of efficacy, maintenance of therapeutic blood levels, toxicity, side effects, and the like. Advantageously, controlled-release formulations can be used to control a drug's onset of action, duration of action, plasma levels within the therapeutic window, and peak blood levels. In particular, controlled- or extended-release dosage forms or formulations can be used to ensure that the maximum effectiveness of a drug is achieved while minimizing potential adverse effects and safety concerns, which can occur both from under-dosing a drug (i.e., going below the minimum therapeutic levels) as well as exceeding the toxicity level for the drug. In some embodiments, the composition can be administered in a sustained release formulation.

[0381] Controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled release counterparts. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by aminimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled-release formulations include: 1) extended activity of the drug; 2) reduced dosage frequency; 3) increased patient compliance; 4) usage of less total drug; 5) reduction in local or systemic side effects; 6) minimization of drug accumulation; 7) reduction in blood level fluctuations; 8) improvement in efficacy of treatment; 9) reduction of potentiation or loss of drug activity; and 10) improvement in speed of control of diseases or conditions. Kim, Chemg-ju, Controlled Release Dosage Form Design, 2 (Technomic Publishing, Lancaster, Pa.: 2000).

[0382] Most controlled-release formulations are designed to initially release an amount of drug (active ingredient, e.g., a Fc-PRL fusion protein described herein) that promptly produces the desired therapeutic effect, and gradually and continually release other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, ionic strength, osmotic pressure, temperature, enzymes, water, and other physiological conditions or compounds.

[0383] A variety of known controlled- or extended-release dosage forms, formulations, and devices can be adapted for use with the salts and compositions of the disclosure. Examples include, but are not limited to, those described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5674,533; 5,059,595; 5,591 ,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,733,566; and 6,365,185; content of each of which is incorporated herein by reference. These dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems (such as OROS® (Alza Corporation, Mountain View, Calif. USA)), or a combination thereof to provide the desired release profile in varying proportions.

[0384] In some embodiments, the Fc-PRL fusion protein described herein is prepared with carriers that will protect the Fc-PRL fusion protein against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.I l l

[0385] In the case of oral ingestion, excipients useful for solid preparations for oral administration are those generally used in the art, and the useful examples are excipients such as lactose, sucrose, sodium chloride, starches, calcium carbonate, kaolin, crystalline cellulose, methyl cellulose, glycerin, sodium alginate, gum arabic and the like, binders such as polyvinyl alcohol, polyvinyl ether, polyvinyl pyrrolidone, ethyl cellulose, gum arabic, shellac, sucrose, water, ethanol, propanol, carboxymethyl cellulose, potassium phosphate and the like, lubricants such as magnesium stearate, talc and the like, and further include additives such as usual known coloring agents, disintegrators such as alginic acid and Primogel™, and the like. The Fc-PRL fusion protein described herein can be orally administered, for example, with an inert diluent, or with an assimilable edible carrier, or they may be enclosed in hard or soft shell capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet. For oral therapeutic administration, the Fc-PRL fusion protein described herein may be incorporated with excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, and the like. Such compositions and preparations should contain at least 0.1% of compound. The percentage of the agent in these compositions may, of course, be varied and may conveniently be between about 2% to about 60% of the weight of the unit. The amount of the Fc-PRL fusion protein described herein in such therapeutically useful compositions is such that a suitable dosage will be obtained. Preferred compositions according to the present invention are prepared so that an oral dosage unit contains between about 100 and 2000 mg of the Fc-PRL fusion protein described herein. Examples of bases useful for formulation of suppositories are oleaginous bases such as cacao butter, polyethylene glycol, lanolin, fatty acid triglycerides, WITEPSOL (DYNAMITE NOBEL CO. LTD.) and the like. Liquid preparations may be in the form of aqueous or oleaginous suspension, solution, syrup, elixir and the like, which can be prepared by a conventional way using additives. The compositions can be given as a bolus dose, to maximize the circulating levels for the greatest length of time after the dose. Continuous infusion may also be used after the bolus dose.

[0386] The Fc-PRL fusion protein described herein can also be administered parenterally. Solutions or suspensions of the Fc-PRL fusion protein described herein can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil. In general, water, saline, aqueous dextrose and related sugar solution, and glycols such as, propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions. Under ordinary conditions of storage and use,these preparations contain a preservative to prevent the growth of microorganisms.

[0387] It may be advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. As used herein, “dosage unit” refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of the Fc-PRL fusion protein described herein calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

[0388] Administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

[0389] For oral or enteral formulations as disclosed herein for use with the present invention, tablets can be formulated in accordance with conventional procedures employing solid carriers well-known in the art. Capsules employed for oral formulations to be used with the methods of the present invention can be made from any pharmaceutically acceptable material, such as gelatin or cellulose derivatives. Sustained release oral delivery systems and / or enteric coatings for orally administered dosage forms are also contemplated, such as those described in U.S. Pat. No. 4,704,295, “Enteric Film-Coating Compositions,” issued Nov. 3, 1987; U.S. Pat. No. 4, 556,552, “Enteric Film- Coating Compositions,” issued Dec. 3, 1985; U.S. Pat. No. 4,309,404, “Sustained Release Pharmaceutical Compositions,” issued Jan. 5, 1982; and U.S. Pat. No. 4,309,406, “Sustained Release Pharmaceutical Compositions,” issued Jan. 5, 1982.

[0390] As regards to formulations for administering a Fc-PRL fusion protein described herein, one particularly useful embodiment is a tablet formulation comprising a compound of Fc-PRL fusion protein described herein with an enteric polymer casing. An example of such a preparation can be found in W02005 / 021002. The active material in the core can be present in a micronized or solubilized form. In addition to active materials the core can contain additives conventional to the art of compressed tablets. Appropriate additives in such a tablet can comprise diluents such as anhydrous lactose, lactose monohydrate, calcium carbonate, magnesium carbonate, dicalcium phosphate or mixtures thereof; binders such as microcrystalline cellulose, hydroxypropylmethylcellulose, hydroxypropyl-cellulose, polyvinylpyrrolidone, pre-gelatinized starch or gum acacia or mixtures thereof; disintegrantssuch as microcrystalline cellulose (fulfilling both binder and disintegrant functions) crosslinked polyvinylpyrrolidone, sodium starch glycollate, croscarmellose sodium or mixtures thereof; lubricants, such as magnesium stearate or stearic acid, glidants or flow aids, such as colloidal silica, talc or starch, and stabilizers such as desiccating amorphous silica, coloring agents, flavors etc. Preferably the tablet comprises lactose as diluent. When a binder is present, it is preferably hydroxypropylmethyl cellulose. Preferably, the tablet comprises magnesium stearate as lubricant. Preferably the tablet comprises croscarmellose sodium as disintegrant. Preferably, the tablet comprises microcrystalline cellulose.

[0391] The diluent can be present in a range of 10 - 80% by weight of the core. The lubricant can be present in a range of 0.25 - 2% by weight of the core. The disintegrant can be present in a range of 1 - 10% by weight of the core. Microcrystalline cellulose, if present, can be present in a range of 10 - 80% by weight of the core.

[0392] The active ingredient, e.g., a Fc-PRL fusion protein described herein preferably comprises between 10 and 50% of the weight of the core, more preferably between 15 and 35% of the weight of the core (calculated as free base equivalent). The core can contain any therapeutically suitable dosage level of the active ingredient, but preferably contains up to 150mg of the active ingredient. Particularly preferably, the core contains 20, 30, 40, 50, 60, 80 or lOOmg of the active ingredient. The active ingredient can be present as is or as any pharmaceutically acceptable salt. If the active ingredient is present as a salt, the weight is adjusted such that the tablet contains the desired amount of active ingredient, calculated as free base or free acid of the salt.

[0393] The core can be made from a compacted mixture of its components. The components can be directly compressed or can be granulated before compression. Such granules can be formed by a conventional granulating process as known in the art. In an alternative embodiment, the granules can be individually coated with an enteric casing, and then enclosed in a standard capsule casing.

[0394] The core is surrounded by a casing which comprises an enteric polymer. Examples of enteric polymers are cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate, polyvinylacetate pthalate, polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic mono-ester copolymer, methyl acrylate-methacrylic acid copolymer or methacrylate-methacrylic acid-octyl acrylate copolymer. These can be used either alone or in combination, or together with other polymers than those mentioned above. The casing can also include insoluble substances which are neither decomposed nor solubilized in living bodies, such as alkyl cellulose derivatives suchas ethyl cellulose, cross-linked polymers such as styrene-divinylbenzene copolymer, polysaccharides having hydroxyl groups such as dextran, cellulose derivatives which are treated with bifunctional crosslinking agents such as epichlorohydrin, di chlorohydrin or 1, 2-, 3, 4-di epoxybutane. The casing can also include starch and / or dextrin.

[0395] In some embodiments, an enteric coating materials are the commercially available Eudragit® enteric polymers such as Eudragit® L, Eudragit® S and Eudragit® NE used alone or with a plasticizer. Such coatings are normally applied using a liquid medium, and the nature of the plasticizer depends upon whether the medium is aqueous or non-aqueous. Plasticizers for use with aqueous medium include propylene glycol, triethyl citrate, acetyl triethyl citrate or Citroflex® or Citroflex® A2. Non-aqueous plasticizers include these, and also diethyl and dibutyl phthalate and dibutyl sebacate. A preferred plasticizer is Triethyl citrate. The quantity of plasticizer included will be apparent to those skilled in the art.

[0396] The casing can also include an anti-tack agent such as talc, silica or glyceryl monostearate. Preferably the anti-tack agent is glyceryl monostearate. Typically, the casing can include around 5 - 25 wt% Plasticizers and up to around 50 wt % of anti-tack agent, preferably 1-10 wt % of anti -tack agent.

[0397] If desired, a surfactant can be included to aid with forming an aqueous suspension of the polymer. Many examples of possible surfactants are known to the person skilled in the art. Preferred examples of surfactants are polysorbate 80, polysorbate 20, or sodium lauryl sulphate. If present, a surfactant can form 0.1 - 10% of the casing, preferably 0.2 - 5% and particularly preferably 0.5 - 2%.

[0398] A seal coat can also be included between the core and the enteric coating. A seal coat is a coating material which can be used to protect the enteric casing from possible chemical attack by any alkaline ingredients in the core. The seal coat can also provide a smoother surface, thereby allowing easier attachment of the enteric casing. A person skilled in the art would be aware of suitable coatings. Preferably the seal coat is made of an OPADRY coating, and particularly preferably it is OPADRY WHITE OY-S-28876. Other enteric-coated preparations of this sort can be prepared by one skilled in the art, using these materials or their equivalents.Nucleic acids

[0399] The disclosure also provides a polynucleotide encoding a Fc-PRL fusion protein described herein. The skilled person will understand that, due to the degeneracy of the geneticcode, a given polypeptide can be encoded by different polynucleotides. These “variants” are encompassed herein.

[0400] It is noted that when the Fc-PRL protein is comprised in a multimeric molecule (e.g., Fc-PRL:Fc dimer or Fc-PRL:Fc-PRL dimer), all parts of the multimeric molecule can be encoded in a single nucleic acid. Alternatively, when the Fc-PRL protein is comprised in a multimeric molecule (e.g., Fc-PRL:Fc dimer or Fc-PRL:Fc-PRL dimer), different parts of the multimeric molecule can be encoded in separate nucleic acids. For example, when the multimeric molecule is a dimer (e.g., Fc-PRL:Fc dimer or Fc-PRL:Fc-PRL dimer), both components can be encoded in the same nucleic acid, or each component can be encoded in different nucleic acids.Nucleic acids encoding Fc-PRL fusion proteins

[0401] The present disclosure also a nucleic acid encoding the Fc-PRL fusion proteins described herein. In some embodiments, the nucleic acid encodes a Fc-PRL fusion protein with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 100% sequence identity to a Fc-PRL fusion protein described herein.

[0402] In some embodiments, the nucleic acid encodes a Fc-PRL fusion protein that is or includes an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 100% sequence identity to a human prolactin. For example, the nucleic acid encodes a Fc-PRL fusion protein that is or includes an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 100% sequence identity to one of SEQ ID NO: 12-18

[0403] In some embodiments, the nucleic acid encodes a Fc-PRL fusion protein that is or includes an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 100% sequence identity to any one of SEQ ID NOs: 113-141. In some embodiments, the nucleic acid encodes a Fc-PRL fusion protein that is or includes an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% sequence identity to SEQ ID NO: 115, 119, 125, 129 or 141 In some embodiments, the nucleic acid encodes a Fc-PRL fusion protein that is or includes an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% sequence identity to SEQ ID NO: 125.

[0404] The nucleic acid encoding the Fc-PRL fusion protein composition may comprise, for example, an origin of replication, and / or a promoter that drives expression of one or more nucleic acids encoding one or more Fc-PRL fusion proteins of SEQ ID NOs: 113-141.

[0405] The nucleic acid can be comprised in a bacterial plasmid vector into which isinserted a promoter (sometimes a strong viral promoter), one or more nucleic acids encoding one or more Fc-PRL fusion proteins of SEQ ID NOs: 113-141, and a polyadenylation / transcriptional termination sequence.

[0406] In some instances, the nucleic acid is DNA. In some other embodiments, the nucleic acid is RNA.

[0407] In all cases, due to degeneracy in the genetic code, other DNA sequences (including multiple codon-optimized sequences) could encode such Fc-PRL fusion proteins. In some embodiments, these nucleic acids are expressed in the individual, resulting in increased production of milk.

[0408] Exemplary plant systems for expression of the Fc-PRL fusion protein described herein include tobacco, potato, rice, maize, soybean, alfalfa, tomato, lettuce and legum...

Claims

CLAIMSWhat is claimed is:

1. An Fc fusion protein comprising a prolactin (PRL) polypeptide linked to an antibody Fc region, wherein the prolactin polypeptide comprises at least one mutation that eliminates a glycosylation site present in a wild-type prolactin polypeptide.

2. The Fc fusion protein of claim 1, wherein the PRL polypeptide comprises an amino acid sequence having at least 85% sequence identity to a human prolactin polypeptide, a mouse prolactin polypeptide, a cow prolactin polypeptide, a goat prolactin polypeptide, or a sheep prolactin polypeptide.

3. The Fc fusion protein of claim 1 or 2, wherein the PRL polypeptide comprises an amino acid sequence having a mutation at position 59 of a human prolactin polypeptide.

4. The Fc fusion protein of any one of claims 1-3, wherein the PRL polypeptide comprises an amino acid sequence having a N to D mutation at position 59 of a human prolactin polypeptide.

5. The Fc fusion protein of any one of claims 1-4, wherein the PRL polypeptide comprises an amino acid sequence having a mutation at position 219 of a human prolactin polypeptide.

6. The Fc fusion protein of any one of claims 1-5, wherein the PRL polypeptide comprises an amino acid sequence having a C to S mutation at position 219 of a human prolactin polypeptide.

7. The Fc fusion protein of any one of claims 1-6, wherein the PRL polypeptide comprises an amino acid sequence having a mutation at position 227 of a human prolactin polypeptide.

8. The Fc fusion protein of any one of claims 1-7, wherein the PRL polypeptide comprises an amino acid sequence having a C to S mutation at position 227 of a human prolactin polypeptide.

9. The Fc fusion protein of any one of claims 1-8, wherein the PRL polypeptide comprises an amino acid sequence having a mutation at positions 59, 219 and 227 of a human prolactin polypeptide.

10. The Fc fusion protein of any one of claims 1-8, wherein the PRL polypeptide comprises an amino acid sequence having a N to D mutation at position 59, a C to Smutation at position 219, and a C to S mutation at position 227 of a human prolactin polypeptide.

11. The Fc fusion protein of any one of claims 1-10, wherein the PRL polypeptide comprises an amino acid sequence having at least 85% sequence identity to the amino acid sequence LPICPGGAARCQVTLRDLFDRAVVLSHYIHNLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRIIHNNNC (SEQ ID NO: 12).

12. The Fc fusion protein of any one of claims 1-11, wherein the prolactin polypeptide comprises an amino acid sequence having a mutation at position 59 of SEQ ID NO:1213. The Fc fusion protein of any one of claims 1-12, wherein the prolactin polypeptide comprises an amino acid sequence having a N to D mutation at position 59 of SEQ ID NO: 1214. The Fc fusion protein of any one of claims 1-13, wherein the prolactin polypeptide comprises an amino acid sequence having a mutation at position 219 of SEQ ID NO: 1215. The Fc fusion protein of any one of claims 1-14, wherein the prolactin polypeptide comprises an amino acid sequence having a C to S mutation at position 219 of SEQ ID NO: 1216. The Fc fusion protein of any one of claims 1-15, wherein the prolactin polypeptide comprises an amino acid sequence having a mutation at position 227 of SEQ ID NO: 1217. The Fc fusion protein of any one of claims 1-16, wherein the prolactin polypeptide comprises an amino acid sequence having a C to S mutation at position 227 of SEQ ID NO: 1218. The Fc fusion protein of any one of claims 1-17, wherein the prolactin polypeptide comprises an amino acid sequence having a mutation at positions 59, 219 and 227 of SEQ ID NO: 1219. The Fc fusion protein of any one of claims 1-18, wherein the prolactin polypeptide comprises an amino acid sequence having a N to D mutation at position 59, a C to S mutation at position 219, and a C to S mutation at position 227 of SEQ ID NO: 12.

0. The Fc fusion protein of any one of claims 1-19, wherein the prolactin polypeptide comprises an amino acid sequence having at least 85% sequence identity to an amnio acid sequence selected from the group consisting ofLPICPGGAARCQVTLRDLFDRAVVLSHYIHDLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRIIHNNNC (SEQ ID NO: 13 (human PRL, N59D));LPICPGGAARCQVTLRDLFDRAVVLSHYIHNLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHI<IDNYLI<LLI<SRIIHNNNC (SEQ ID NO: 14 (human PRL, C219S));LPICPGGAARCQVTLRDLFDRAVVLSHYIHNLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRIIHNNNS (SEQ ID NO: 15 (human PRL, C227S));LPICPGGAARCQVTLRDLFDRAVVLSHYIHDLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHI<IDNYLI<LLI<SRIIHNNNC (SEQ ID NO: 16 (human PRL, N59D, C219S));LPICPGGAARCQVTLRDLFDRAVVLSHYIHDLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRIIHNNNS (SEQ ID NO: 17 (human PRL, N59D, C227S));LPICPGGAARCQVTLRDLFDRAVVLSHYIHDLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHKIDNYLKLLKSRIIHNNNS (SEQ ID NO: 18 (human PRL, N59D, C219S, C227S));TPVCPNGPGNCQVSLRDLFDRAVMVSHYIHDLSSEMFNEFDKRYAQGKGFIT MALNSCHTSSLPTPEDKEQAQQTHHEVLMSLILGLLRSWNDPLYHLVTEVRG MKGAPDAILSRAIEIEEENKRLLEGMEMIFGQVIPGAKETEPYPVWSGLPSLQT KDEDARYSAFYNLLHCLRRDSSKIDTYLKLLNCRIIYNNNC (SEQ ID NO: 19 (Cow PRL WT));TPVCPNGPGNCQVSLRDLFDRAVMVSHYIHNLSSEMFNEFDKRYAQGKGYIT MALNSCHTSSLPTPEDKEQAQQTHHEVLMSLILGLLRSWNDPLYHLVTEVRG MKGVPDAILSRAIEIEEENKRLLEGMEMILGQVIPGAKETEPYPVWSGLPSLQT KDEEARHSAFYNLLHCLRRDSSKIDTYLKLLNCRIIYNNNC (SEQ ID NO: 20 (Goat PRL WT));TPVCPNGPGNCQVSLRDLFDRAVMVSHYIHDLSSEMFNEFDKRYAQGKGYIT MALNSCHTSSLPTPEDKEQAQQTHHEVLMSLILGLLRSWNDPLYHLVTEVRG MKGVPDAILSRAIEIEEENKRLLEGMEMILGQVIPGAKETEPYPVWSGLPSLQT KDEEARHSAFYNLLHCLRRDSSKIDTYLKLLNCRIIYNNNC (SEQ ID NO: 21 (Goat PRL, N62D));TPVCPNGPGNCQVSLRDLFDRAVMVSHYIHNLSSEMFNEFDKRYAQGKGFIT MALNSCHTSSLPTPEDKEQAQQTHHEVLMSLILGLLRSWNDPLYHLVTEVRG MKGVPDAILSRAIEIEEENKRLLEGMEMIFGQVIPGAKETEPYPVWSGLPSLQT KDEDARHSAFYNLLHCLRRDSSKIDTYLKLLNCRIIYNNNC (SEQ ID NO: 22 (Sheep PRLWT)); orTPVCPNGPGNCQVSLRDLFDRAVMVSHYIHDLSSEMFNEFDKRYAQGKGFITMALNSCHTSSLPTPEDKEQAQQTHHEVLMSLILGLLRSWNDPLYHLVTEVRGMKGVPDAILSRAIEIEEENKRLLEGMEMIFGQVIPGAKETEPYPVWSGLPSLQTKDEDARHSAFYNLLHCLRRDSSKIDTYLKLLNCRIIYNNNC (SEQ ID NO: 23 (Sheep PRL, N61D));LPICSAGDCQTSLRELFDRWILSHYIHTLYTDMFIEFDKQYVQDREFMVKVIN DCPTSSLATPEDKEQALKVPPEVLLNLILSLVQSSSDPLFQLITGVGGIQEAPEY ILSRAKEIEEQNKQLLEGVEKIISQAYPEAKGNGIYFVWSQLPSLQGVDEESKI LSLRNTIRCLRRDSHKVDNFLKVLRCQIAHQNNC (SEQ ID NO: 24 (mouse PRL, N61D)); orSEQ ID NO: 12 (human PRL 29-227), and optionally, the prolactin polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 13-18, and preferably the prolactin polypeptide comprises the amino acid sequence SEQ ID NO: 13, 17 or 18, and even more preferably the prolactin polypeptide comprises the amino acid sequence of SEQ ID NO: 1321. The Fc fusion protein of any one of claims 1-20, wherein the antibody Fc region comprises at least one mutation that inhibits / reduces binding of the Fc region to an FcR.

22. The Fc fusion protein of any one of claims 1-21, wherein the antibody Fc region comprises at least one mutation that inhibits / reduces binding of the Fc region to FcgRI.

23. The Fc fusion protein of any one of claims 1-22, wherein the antibody Fc region comprises at least one mutation selected from the group consisting of LALA, PG, VE, YTE, LS, DHS, and negative charge modifications.

24. The Fc fusion protein of any one of claims 1-23, wherein the Fc region is an IgG Fc region.

25. The Fc fusion protein of any one of claims 1-24, wherein the Fc region is a human IgG Fc region.

26. The Fc fusion protein of any one of claims 1-25, wherein the Fc region is a IgGl Fc region.

27. The Fc fusion protein of any one of claims 1-26, wherein the antibody Fc region comprises an amino acid sequence having at least 85% sequence identity to an amino acid sequence selected from the group consisting ofEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 25);KTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRWSVLTVVHQDWLNGKEY KCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 26);ELKTPLGDTTHTCPRCPEPKSCDTPPPCPRCPEPKSCDTPPPCPRCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFKWYVDGVEVHNAKTK PWEEQYNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKTKGQ PREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAMEWESSGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNIFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 27);KVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLN GKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 28);GEKMGDGCVREPSVFIFPPKPKDTLMITGTPEVTCWVNVGHDNPEVQFSWFVDDVEVHTARTKPREEQFNSTYRVVSALPIQHQDWTGGKEFKCKVNNKGLS APIVRIISRSKGPAREPQVYVLDPPKEELSKSTLSVTCMVTGFYPEDVAVEWQ RNRQTESEDKYRTTPPQLDTDRSYFLYSKLRVDRNSWQEGDTYTCVVMHEA LHNHYTQKSTSKSAGK (SEQ ID NO: 29);TCPKCPGKSAEPLGGLSVFIFPPKPKDTLTISGTPEVTCVVVDVGQDDPEVQFSWFMDNVEVHTARTTPREEQFNSTFRVVSALPIQHKDWLQGKEFKCKVHNEGLPAPIIRTISRAKGQAREPQVYVLAPPREELSKSTLSVTCLITGFYPEEVDVEWQRDGQPESEDKYHTAPPQLDADGSYFLYSRLRVNKSSWQEGDTYTCAVMHEALRNHYKEKSISKSPGK (SEQ ID NO: 30);EPGCPDPCKHCRCPPPELPGGPSVFIFPPKPKDTLTISGTPEVTCVVVDVGQDD PEVQFSWFVDNVEVRTARTKPREEQFNSTFRVVSALPIQHQDWTGGKEFKCK VHNEALPAPIVRTISRTKGQAREPQVYVLAPPQEELSKSTLSVTCLVTGFYPD YIAVEWQKNGQPESEDKYGTTTSQLDADGSYFLYSRLRVDKNSWQEGDTYA CVVMHEALHNHYTQKSISKPPGK (SEQ ID NO: 31);EPRVPITQNPCPPLKECPPCAAPDLLGGPSVFIFPPKIKDVLMISLSPMVTCVVV DVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMS GKEFKCKVNNRALPSPIEKTISKPRGPVRAPQVYVLPPPAEEMTKKEFSLTCMI TGFLPAEIAVDWTSNGRTEQNYKNTATVLDSDGSYFMYSKLRVQKSTWERG SLFACSVVHEGLHNHLTTKTISRSLGK (SEQ ID NO: 32).

28. The Fc fusion protein of any one of claims 1-27, wherein the antibody Fc region comprises: a. an amino acid sequence having a mutation at positions 220, 297 and 447 (Eu numb eri ng of Kab at) ; b. an amino acid sequence having a mutation at positions 220, 297, 447, 234, 235, 264, 309, 311, and 434 (EU numbering of Kabat); c. an amino acid sequence having a mutation at positions 220, 297, 447, 234, 235, 329, 264, 309, 311, and 434 (EU numbering of Kabat); or d. an amino acid sequence having a mutation at positions 220, 297, 447, 234, 235, 252, 254 and 256 (EU numbering of Kabat), of an Fc domain of human IgG (e.g., human IgGl).

29. The Fc fusion protein claim 28, wherein the antibody Fc region comprises: a. an amino acid sequence having mutations C220S, N297D, and K447A (EU numbering of Kabat); b. an amino acid sequence having mutations C220S, N297D, K447A, L234A, L235A, V264E, L309D, Q311H, and N434S (EU numbering of Kabat);c. an amino acid sequence having mutations C220S, N297D, K447A, L234A, L235A, P329G, V264E, L309D, Q311H, and N434S (EU numbering of Kabat); or d. an amino acid sequence having mutations C220S, N297D, K447A, L234A, L235A, M252Y, S254T and T256E (EU numbering of Kabat), of an Fc domain of human IgG (e.g., human IgGl).

30. The Fc fusion protein of any one of claims 1-27, wherein the antibody Fc region comprises an amino acid sequence having at least 85% sequence identity to a sequence selected from the group consisting ofEPKSsDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVEDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGa (SEQ ID NO: 74, Fc 220S, N297D andK447A);EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVDHHDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHSHYTQKSLSLSPGa (SEQ ID NO: 75, Fc C220S, N297D, K447A, L234A, L235A, V264E, L309D, Q311H, N434S);EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVDHHDWLNGKEY KCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHSHYTQKSLSLSPGa (SEQ ID NO: 76, Fc C220S, N297D, K447A, L234A, L235A, P329G, V264E, L309D, Q311H, N434S); andEPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITREPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGa (SEQ ID NO: 77, C220S, N297D, K447A, L234A, L235A, M252Y, S254T, T256E).

31. The Fc fusion protein of any one of claims 1-27, wherein the antibody Fc region comprises: a. an amino acid sequence having a mutation at positions 220, 297, 447, 350, 351, 405 and 407 (EU numbering of Kabat); b. an amino acid sequence having a mutation at positions 220, 297, 447, 350, 351, 405, 407, 234, 235, 264, 309, 311 and 434 (EU numbering of Kabat); c. an amino acid sequence having a mutation at positions 220, 297, 447, 350, 351, 405, 407, 234, 235, 264, 309, 311, 434, 435 and 436 (EU numbering of Kabat); d. an amino acid sequence having a mutation at positions 220, 297, 447, 350, 351, 405, 407, 234, 235, 329, 264, 309, 311 and 434 (EU numbering of Kabat); e. an amino acid sequence having a mutation at positions 220, 297, 447, 350, 351, 405, 407, 234, 235, 252, 254 and 256 (EU numbering of Kabat), of an Fc domain of human IgG (e.g., human IgGl).

32. The Fc fusion protein of claim 31, wherein the antibody Fc region comprises: a. an amino acid sequence having mutations C220S, N297D, K447A, T350V, L351Y, F405A, and Y407V (EU numbering of Kabat); b. an amino acid sequence having mutations C220S, N297D, K447A, T350V, L351Y, F405A, Y407V, L234A, L235A, V264E, L309D, Q311H, and N434S (EU numbering of Kabat); c. an amino acid sequence having mutations C220S, N297D, K447A, T350V, L351Y, F405A, Y407V, L234A, L235A, P329G, V264E, L309D, Q311H, N434S, H435R, and Y436F (EU numbering of Kabat); d. an amino acid sequence having mutations C220S, N297D, K447A, T350V, L351Y, F405A, Y407V, L234A, L235A, P329G, V264E, L309D, Q311H, and N434S (EU numbering of Kabat); or e. an amino acid sequence having mutations C220S, N297D, K447A, T350V, L351Y, F405A, Y407V, L234A, L235A, M252Y, S254T, and T256E (EU numbering of Kabat), of an Fc domain of human IgG (e.g., human IgGl).

33. The Fc-PRL fusion protein of any one of claims 1-27, wherein the antibody Fc region comprises an amino acid sequence having at least 85% sequence identity to an amino acid sequence selected from the group consisting ofEPKSsDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYVYPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFALVSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGa (SEQ ID NO: 78, C220S, N297D, K447A, T350V, L351Y, F405A, Y407V); EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVDHHDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYVYPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFALVSKLTVDKSRWQQGNVFS CSVMHEALHSHYTQKSLSLSPGa (SEQ ID NO: 79, C220S, N297D, K447A, T350V, L351Y, F405A, Y407V, L234A, L235A, V264E, L309D, Q311H, N434S); PKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVEDVSHED PEVKFNWYVDGVEVHNAKTKPREEQYdSTYRWSVLTVDHHDWLNGKEYK CKVSNKALGAPIEKTISKAKGQPREPQVYVYPPSRDELTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFALVSKLTVDKSRWQQGNVFSC SVMHEALHSHYTQKSLSLSPGa (SEQ ID NO: 80, C220S, N297D, K447A, T350V, L351Y, F405A, Y407V, L234A, L235A, P329G, V264E, L309D, Q311H, N434S); and EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITREPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYVYPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFALVSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGa (SEQ ID NO: 81, (C220S, N297D, K447A, T350V, L351Y, F405A, Y407V, L234A, L235A, M252Y, S254T, T256E).

34. The Fc fusion protein of any one of claims 1-27, wherein the antibody Fc region comprises: a. an amino acid sequence having a mutation at positions 220, 297, 447, 350, 366, 392, and 394 (EU numbering of Kabat);b. an amino acid sequence having a mutation at positions 220, 297, 447, 350, 366, 392, 394, 435, and 436 (EU numbering of Kabat); c. an amino acid sequence having a mutation at positions 220, 297, 447, 350, 366, 392, 394, 234, 235, 264, 309, 311, and 434 (EU numbering of Kabat); d. an amino acid sequence having a mutation at positions 220, 297, 447, 350, 366, 392, 394, 234, 235, 264, 309, 311, 434, 435, and 436 (EU numbering of Kabat); e. an amino acid sequence having a mutation at positions 220, 297, 447, 350, 366, 392, 394, 234, 235, 329, 264, 309, 311, 434, 435, and 436 (EU numbering of Kabat); or f. an amino acid sequence having a mutation at positions 220, 297, 447, 350, 366, 392, 394, 435, 436, 234, 235, 252, 254, and 256 (EU numbering of Kabat), of an Fc domain of human IgG (e.g., human IgGl).

35. The Fc fusion protein of claim 34, wherein the antibody Fc region comprises: a. an amino acid sequence having mutations C220S, N297D, K447A, T350V, T366L, K392L, and T394W (EU numbering of Kabat); b. an amino acid sequence having mutations C220S, N297D, K447A, T350V, T366L, K392L, T394W, H435R, and Y436F (EU numbering of Kabat); c. an amino acid sequence having mutations C220S, N297D, K447A, T350V, T366L, K392L, T394W, L234A, L235A, V264E, L309D, Q311H, and N434S (EU numbering of Kabat); d. an amino acid sequence having mutations C220S, N297D, K447A, T350V, T366L, K392L, T394W, L234A, L235A, V264E, L309D, Q311H, N434S, H435R, and Y436F (EU numbering of Kabat); e. an amino acid sequence having mutations C220S, N297D, K447A, T350V, T366L, K392L, T394W, L234A, L235A, P329G, V264E, L309D, Q311H, N434S, H435R, and Y436F (EU numbering of Kabat); or f. an amino acid sequence having mutations C220S, N297D, K447A, T350V, T366L, K392L, T394W, H435R, Y436F, L234A, L235A, M252Y, S254T, and T256E (EU numbering of Kabat), of an Fc domain of human IgG (e.g., human IgGl).

6. The Fc-PRL fusion protein of any one of claims 1-27, wherein the antibody Fc region comprises an amino acid sequence having at least 85% sequence identity to an amino acid sequence selected from the group consisting ofEPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVDHHDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYVLPPSRDELTKNQVSLLCLVKGF YPSDI AVEWESNGQPENNYLTWPPVLD SDGSFFLYSKLTVDKSRWQQGNVF S CSVMHEALHSHYTQKSLSLSPGa (SEQ ID NO: 82, C220S, N297D, K447A, T350V, T366L, K392L, T394W, L234A, L235A, V264E, L309D, Q311H, N434S);EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVDHHDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYVLPPSRDELTKNQVSLLCLVKGF YPSDI AVEWESNGQPENNYLTWPPVLD SDGSFFLYSKLTVDKSRWQQGNVF S CSVMHEALHSRFTQKSLSLSPGa (SEQ ID NO: 83, C220S, N297D, K447A, T350V, T366L, K392L, T394W, L234A, L235A, V264E, L309D, Q311H, N434S, H435R, Y436F);EPKSsDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYVLPPSRDELTKNQVSLLCLVKGF YPSDI AVEWESNGQPENNYLTWPPVLD SDGSFFLYSKLTVDKSRWQQGNVF S CSVMHEALHNHYTQKSLSLSPGa (SEQ ID NO: 84, C220S, N297D, K447A, T350V, T366L, K392L, and T394W);EPKSsDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYVLPPSRDELTKNQVSLLCLVKGF YPSDI AVEWESNGQPENNYLTWPPVLD SDGSFFLYSKLTVDKSRWQQGNVF S CSVMHEALHNRFTQKSLSLSPGa (SEQ ID NO: 85, C220S, N297D, K447A, T350V, T366L, K392L, T394W, H435R, and Y436F);EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVDHHDWLNGKEY KCKVSNKALGAPIEKTISKAKGQPREPQVYVLPPSRDELTKNQVSLLCLVKGF YPSDI AVEWESNGQPENNYLTWPPVLD SDGSFFLYSKLTVDKSRWQQGNVF S CSVMHEALHSRFTQKSLSLSPGa (SEQ ID NO: 86, C220S, N297D, K447A, T350V, T366L, K392L, T394W, L234A, L235A, P329G, V264E, L309D, Q311H, N434S, H435R, Y436F); andEPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITREPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYVLPPSRDELTKNQVSLLCLVKGF YPSDI AVEWESNGQPENNYLTWPPVLD SDGSFFLYSKLTVDKSRWQQGNVF S CSVMHEALHNRFTQKSLSLSPGa (SEQ ID NO: 87, C220S, N297D, K447A, T350V, T366L, K392L, T394W, H435R, Y436F, L234A, L235A, M252Y, S254T, T256E).

37. The Fc fusion protein of any one of claims 1-27, wherein the antibody Fc region comprises: a. an amino acid sequence having a mutation at positions 220, 297, 447, and 366 (EU numbering of Kabat); b. an amino acid sequence having a mutation at positions 220, 447, 297, 366, 234, 235, 264, 309, 311, and 434 (EU numbering of Kabat); c. an amino acid sequence having a mutation at positions 220, 447, 297, 366, 234, 235, 329, 264, 309, 311, and 434 (EU numbering of Kabat); d. an amino acid sequence having a mutation at positions 220, 447, 297, 366, 234, 235, 252, 254, and 256 (EU numbering of Kabat); or e. an amino acid sequence having a mutation at positions 220, 226, 229, 297, 447, and 366 (EU numbering of Kabat), of an Fc domain of human IgG (e.g., human IgGl).

38. The Fc fusion protein of claim 37, wherein the antibody Fc region comprises: a. an amino acid sequence having mutations C220S, N297D, K447A, andT366W (EU numbering of Kabat);b. an amino acid sequence having mutations C220S, K447A, N297D, T366W, L234A, L235A, V264E, L309D, Q311H, and N434S (EU numbering of Kabat); c. an amino acid sequence having mutations C220S, K447A, N297D, T366W, L234A, L235A, P329G, V264E, L309D, Q311H, and N434S (EU numbering of Kabat); d. an amino acid sequence having mutations C220S, K447A, N297D, L234A, L235A, M252Y, S254T, and T256E (EU numbering of Kabat); or e. an amino acid sequence having mutations C220S, C226S, C229S, N297D, K447A, and T366W (EU numbering of Kabat), of an Fc domain of human IgG (e.g., human IgGl).

39. The Fc-PRL fusion protein of any one of claims 1-27, wherein the antibody Fc region comprises an amino acid sequence having at least 85% sequence identity to an amino acid sequence selected from the group consisting ofEPKSsDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGa (SEQ ID NO: 88, C220S, N297D, K447A, and T366W)EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVDHHDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHSHYTQKSLSLSPGa (SEQ ID NO: 89, C220S, K447A, N297D, T366W, L234A, L235A, V264E, L309D, Q311H, andN434S)EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVDHHDWLNGKEY KCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKG FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGa (SEQ ID NO: 90, C220S, K447A, N297D, T366W, L234A, L235A, P329G, V264E, L309D, Q311H, andN434S)EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITREPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGa (SEQ ID NO: 91, C220S, K447A, N297D, L234A, L235A, M252Y, S254T, and T256E);EPKSsDKTHTSPPSPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGa (SEQ ID NO: 92, C220S, C226S, C229S, N297D, K447A, and T366W); and40. The Fc fusion protein of any one of claims 1-27, wherein the antibody Fc region comprises: a. an amino acid sequence having a mutation at positions 220, 297, 447, 366, 368, and 407 (EU numbering of Kabat); b. an amino acid sequence having a mutation at positions 220, 297, 447, 366, 368, 407, 435, 436, 234, 235, 264, 309, 311, and 434 (EU numbering of Kabat); c. an amino acid sequence having a mutation at positions 220, 297, 447, 366, 368, 407, 435, 436, 234, 235, 329, 264, 309, 311, and 434 (EU numbering of Kabat); or d. an amino acid sequence having a mutation at positions 220, 297, 447, 366, 368, 407, 435, 436, 234, 235, 252, 254, 256 (EU numbering of Kabat), of an Fc domain of human IgG (e.g., human IgGl).

41. The Fc fusion protein of claim 40, wherein the antibody Fc region comprises: a. an amino acid sequence having mutations C220S, N297D, K447A, T366S,L368A, and Y407V (EU numbering of Kabat);b. an amino acid sequence having mutations C220S, N297D, K447A, T366S, L368A, Y407V, H435R, Y436F, L234A, L235A, V264E, L309D, Q311H, and N434S (EU numbering of Kabat); c. an amino acid sequence having mutations C220S, N297D, K447A, T366S, L368A, Y407V, H435R, Y436F, L234A, L235A, P329G, V264E, L309D, Q311H, and N434S (EU numbering of Kabat); or d. an amino acid sequence having mutations C220S, N297D, K447A, T366S, L368A, Y407V, H435R, Y436F, L234A, L235A, M252Y, S254T, and T256E (EU numbering of Kabat), of an Fc domain of human IgG (e.g., human IgGl).

42. The Fc-PRL fusion protein of any one of claims 1-27, wherein the antibody Fc region comprises an amino acid sequence having at least 85% sequence identity to an amino acid sequence selected from the group consisting ofEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYDSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLSCAVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGA (SEQ ID NO: 94, C220S, N297D, K447A, T366S, L368A, and Y407V);EPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYDSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLSCAVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFS CSVMHEALHNRFTQKSLSLSPGA (SEQ ID NO: 95, C220S, N297D, K447A, T366S, L368A, Y407V, H435R, Y436F);EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHE DPEVI<FNWYVDGVEVHNAI<TI<PREEQYDSTYRVVSVLTVDHHDWLNGI<EY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLSCAVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFS CSVMHEALHSRFTQKSLSLSPGA (SEQ ID NO: 96, C220S, N297D, K447A,T366S, L368A, Y407V, H435R, Y436F, L234A, L235A, V264E, L309D, Q311H, and N434S);EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYDSTYRVVSVLTVDHHDWLNGKEY KCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLSCAVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFS CSVMHEALHSRFTQKSLSLSPGA (SEQ ID NO: 97, C220S, N297D, K447A, T366S, L368A, Y407V, H435R, Y436F, L234A, L235A, P329G, V264E, L309D, Q311H, and N434S); andEPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITREPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYDSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLSCAVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFS CSVMHEALHNRFTQKSLSLSPGA (SEQ ID NO: 98, C220S, N297D, K447A, T366S, L368A, Y407V, H435R, Y436F, L234A, L235A, M252Y, S254T, and T256E).

43. The Fc fusion protein of any one of claims 1-42, wherein the C-terminus of the Fc region is linked to the N-terminus of the prolactin polypeptide.

44. The Fc fusion protein of any one of claims 1-42, wherein the N-terminus of the Fc region is linked to the C-terminus of the prolactin polypeptide.

45. The Fc fusion protein of any one of claims 1-44, wherein the prolactin polypeptide is linked directly (e.g., via a bond or an amide bond) to the antibody Fc region.

46. The Fc fusion protein of any one of claims 1-44, wherein the prolactin polypeptide is linked to the antibody Fc region through a linker.

47. The Fc fusion protein of claim 46, wherein the linker is a peptide linker.

48. The Fc fusion protein of claim 46 or 47, wherein the linker comprises of the amino acid sequence GGsGG (SEQ ID NO: 103).

49. The Fc fusion protein of claim 1, wherein the fusion protein comprises an amino acid sequence having at least 85% sequence identity to an amino acid sequence selected from the group consisting of:EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKLPICPGGAARCQVTLRDLFDRAWLSHYIHDLSSEMFSEFDKRYTHGRGFITKAINSCHTSSLATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHLVTEVRGMQEAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMADEESRLSAYYNLLHCLRRDSHKIDNYLKL LKCRIIHNNNC (SEQ ID NO: 113);EPKSsDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGaLPICPGGAARCQVTLRDLFDRAVVLSHYIHNLSSEMFSEFDKRYTHGRGFITKAINSCHTSSLATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHLVTEVRGMQEAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMADEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRIIHNNNCEQKLISEEDLNSAVDHHHHHH (SEQ ID NO: 114);EPKSsDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGaLPICPGGAARCQVTLRDLFDRAVVLSHYIHDLSSEMFSEFDKRYTHGRGFITKAINSCHTSSLATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHLVTEVRGMQEAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMADEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRHHNNNC (SEQ ID NO: 115);EPKSsDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGaGGsGGLPICPGGAARCQVTLRDLFDRAW LSHYIHDLSSEMFSEFDKRYTHGRGFITKAINSCHTSSLATPEDKEQAQQMNQ KDFLSLIVSILRSWNEPLYHLVTEVRGMQEAPEAILSKAVEIEEQTKRLLEGME LIVSQVHPETKENEIYPVWSGLPSLQMADEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRIIHNNNCEQKLISEEDLNSAVDHHHHHH (SEQ ID NO: 116);EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVDHHDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGaLPICPGGAARCQVTLRDLFDRAVVLSHYIH DLSSEMFSEFDKRYTHGRGFITKAINSCHTSSLATPEDKEQAQQMNQKDFLSL IVSILRSWNEPLYHLVTEVRGMQEAPEAILSKAVEIEEQTKRLLEGMELIVSQV HPETKENEIYPVWSGLPSLQMADEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRHHNNNC (SEQ ID NO: 117);EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVDHHDWLNGKEY KCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGaLPICPGGAARCQVTLRDLFDRAVVLSHYIH DLSSEMFSEFDKRYTHGRGFITKAINSCHTSSLATPEDKEQAQQMNQKDFLSL IVSILRSWNEPLYHLVTEVRGMQEAPEAILSKAVEIEEQTKRLLEGMELIVSQV HPETKENEIYPVWSGLPSLQMADEESRLSAYYNLLHCLRRDSHKIDNYLKLL KCRHHNNNC (SEQ ID NO: 118);EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITREPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGaLPICPGGAARCQVTLRDLFDRAVVLSHYIH DLSSEMFSEFDKRYTHGRGFITKAINSCHTSSLATPEDKEQAQQMNQKDFLSL IVSILRSWNEPLYHLVTEVRGMQEAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMADEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRHHNNNC (SEQ ID NO: 119);EPKSsDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGaLPICPGGAARCQVTLRDLFDRAVVLSHYIHDLSSEMFSEFDKRYTHGRGFITKAINSCHTSSLATPEDKEQAQQMNQKDFLSL IVSILRSWNEPLYHLVTEVRGMQEAPEAILSKAVEIEEQTKRLLEGMELIVSQV HPETKENEIYPVWSGLPSLQMADEESRLSAYYNLLHCLRRDSHKIDNYLKLL KCRIIHNNNCEQKLISEEDLNSAVDHHHHHH (SEQ ID NO: 120);EPKSsDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGaGGsGGLPICPGGAARCQVTLRDLFDRAW LSHYIHDLSSEMFSEFDKRYTHGRGFITKAINSCHTSSLATPEDKEQAQQMNQ KDFLSLIVSILRSWNEPLYHLVTEVRGMQEAPEAILSKAVEIEEQTKRLLEGME LIVSQVHPETKENEIYPVWSGLPSLQMADEESRLSAYYNLLHCLRRDSHKIDN YLKLLKCRIIHNNNC (SEQ ID NO: 121);EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVDHHDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHSHYTQKSLSLSPGaGGsGGLPICPGGAARCQVTLRDLFDRAWL SHYIHDL SSEMFSEFDKRYTHGRGFITKAINSCHTS SLATPED KE QAQQMNQK DFLSLIVSILRSWNEPLYHLVTEVRGMQEAPEAILSKAVEIEEQTKRLLEGMEL IVSQVHPETKENEIYPVWSGLPSLQMADEESRLSAYYNLLHCLRRDSHKIDNY LKLLKCRIIHNNNC (SEQ ID NO: 122);EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVDHHDWLNGKEY KCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKG FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVF SCSVMHEALHSHYTQKSLSLSPGaGGsGGLPICPGGAARCQVTLRDLFDRAVV LSHYIHDLSSEMFSEFDKRYTHGRGFITKAINSCHTSSLATPEDKEQAQQMNQ KDFLSLIVSILRSWNEPLYHLVTEVRGMQEAPEAILSKAVEIEEQTKRLLEGME LIVSQVHPETKENEIYPVWSGLPSLQMADEESRLSAYYNLLHCLRRDSHKIDN YLKLLKCRIIHNNNC (SEQ ID NO: 123);EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITREPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGaGGsGGLPICPGGAARCQVTLRDLFDRAW LSHYIHDLSSEMFSEFDKRYTHGRGFITKAINSCHTSSLATPEDKEQAQQMNQ KDFLSLIVSILRSWNEPLYHLVTEVRGMQEAPEAILSKAVEIEEQTKRLLEGME LIVSQVHPETKENEIYPVWSGLPSLQMADEESRLSAYYNLLHCLRRDSHKIDN YLKLLKCRIIHNNNC (SEQ ID NO: 124);EPKSsDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYVYPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFALVSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGaGGsGGLPICPGGAARCQVTLRDLFDRAW LSHYIHDLSSEMFSEFDKRYTHGRGFITKAINSCHTSSLATPEDKEQAQQMNQ KDFLSLIVSILRSWNEPLYHLVTEVRGMQEAPEAILSKAVEIEEQTKRLLEGME LIVSQVHPETKENEIYPVWSGLPSLQMADEESRLSAYYNLLHCLRRDSHKIDN YLKLLKCRIIHNNNC (SEQ ID NO: 125);EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVDHHDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYVYPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFALVSKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGaGGsGGLPICPGGAARCQVTLRDLFDRAWL SHYIHDLSSEMFSEFDKRYTHGRGFITKAINSCHTS SLATPED KE QAQQMNQK DFLSLIVSILRSWNEPLYHLVTEVRGMQEAPEAILSKAVEIEEQTKRLLEGMEL IVSQVHPETKENEIYPVWSGLPSLQMADEESRLSAYYNLLHCLRRDSHKIDNY LKLLKCRIIHNNNC (SEQ ID NO: 126);EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVDHHDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYVYPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFALVSKLTVDKSRWQQGNVFS CSVMHEALHSHYTQKSLSLSPGaGGsGGLPICPGGAARCQVTLRDLFDRAWL SHYIHDLSSEMFSEFDKRYTHGRGFITKAINSCHTS SLATPED KE QAQQMNQK DFLSLIVSILRSWNEPLYHLVTEVRGMQEAPEAILSKAVEIEEQTKRLLEGMEL IVSQVHPETKENEIYPVWSGLPSLQMADEESRLSAYYNLLHCLRRDSHKIDNY LKLLKCRIIHNNNC (SEQ ID NO: 127);EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVDHHDWLNGKEY KCKVSNKALGAPIEKTISKAKGQPREPQVYVYPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFALVSKLTVDKSRWQQGNVFS CSVMHEALHSHYTQKSLSLSPGaGGsGGLPICPGGAARCQVTLRDLFDRAWL SHYIHDLSSEMFSEFDKRYTHGRGFITKAINSCHTS SLATPED KE QAQQMNQK DFLSLIVSILRSWNEPLYHLVTEVRGMQEAPEAILSKAVEIEEQTKRLLEGMEL IVSQVHPETKENEIYPVWSGLPSLQMADEESRLSAYYNLLHCLRRDSHKIDNY LKLLKCRIIHNNNC (SEQ ID NO: 128);EPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITREPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYVYPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFALVSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGaGGsGGLPICPGGAARCQVTLRDLFDRAW LSHYIHDLSSEMFSEFDKRYTHGRGFITKAINSCHTSSLATPEDKEQAQQMNQ KDFLSLIVSILRSWNEPLYHLVTEVRGMQEAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMADEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRIIHNNNC (SEQ ID NO: 129);LPICPGGAARCQVTLRDLFDRAVVLSHYIHDLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRIIHNNNCEPKSsDKTHTCPPC PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGFYPSDIAVEWESN GQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVF SCSVMHEALHNH YTQKSLSLSPGaEQKLISEEDLNSAVDHHHHHH (SEQ ID NO: 130);LPICPGGAARCQVTLRDLFDRAVVLSHYIHDLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRIIHNNNCGGsGGEPKSsDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYdSTYR VVSVLTVLHQDWLNGI<EYI<CI<VSNI< ALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDK SRWQQGNVF SC S VMHE A LHNHYTQKSLSLSPGa (SEQ ID NO: 131);LPICPGGAARCQVTLRDLFDRAVVLSHYIHDLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHKIDNYLKLLKsRIIHNNNSEPKSsDKTHTCPPC PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGFYPSDIAVEWESN GQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVF SCSVMHEALHNH YTQKSLSLSPGaEQKLISEEDLNSAVDHHHHHH (SEQ ID NO: 132);LPICPGGAARCQVTLRDLFDRAVVLSHYIHDLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHKIDNYLKLLKsRIIHNNNSEPKSsDKTHTSPPSP APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYdSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGFYPSDIAVEWESNG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY TQKSLSLSPGaEQKLISEEDLNSAVDHHHHHH (SEQ ID NO: 133);LPICPGGAARCQVTLRDLFDRAVVLSHYIHDLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRIIHNNNCGGsGGEPKSsDKT HTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYdSTYR VVSVLTVDHHDWLNGI<EYI<CI<VSNI< ALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDK SRWQQGNVF SC S VMHE A LHSHYTQKSLSLSPGa (SEQ ID NO: 134);LPICPGGAARCQVTLRDLFDRAVVLSHYIHDLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRIIHNNNCGGsGGEPKSsDKT HTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYdSTYR VVSVLTVDHHDWLNGI<EYI<CI<VSNI< ALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHSHYTQKSLSLSPGa (SEQ ID NO: 135);LPICPGGAARCQVTLRDLFDRAVVLSHYIHDLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRIIHNNNCGGsGGEPKSsDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYItREPEVTCWVDVSHEDPEVKFNW YVDGVEVHNAKTKPREEQYdSTYRWSVLTVLHQDWLNGKEYKCKVSNKA LPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDK SRWQQGNVF SC S VMHE A LHNHYTQKSLSLSPGa (SEQ ID NO: 136);LPICPGGAARCQVTLRDLFDRAVVLSHYIHDLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRIIHNNNCGGsGGEPKSsDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYdSTYR VVSVLTVLHQDWLNGI<EYI<CI<VSNI< ALPAPIEKTISKAKGQPREPQVYVYPPSRDELTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFALVSKLTVDKSRWQQGNVFSCSVMHEA LHNHYTQKSLSLSPGa (SEQ ID NO: 137);LPICPGGAARCQVTLRDLFDRAVVLSHYIHDLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRIIHNNNCGGsGGEPKSsDKT HTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYdSTYR VVSVLTVDHHDWLNGI<EYI<CI<VSNI< ALPAPIEKTISKAKGQPREPQVYVYPPSRDELTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFALVSKLTVDKSRWQQGNVFSCSVMHEA LHSHYTQKSLSLSPGa (SEQ ID NO: 138);LPICPGGAARCQVTLRDLFDRAVVLSHYIHDLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRIIHNNNCGGsGGEPKSsDKT HTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYdSTYR VVSVLTVDHHDWLNGI<EYI<CI<VSNI< ALPAPIEKTISKAKGQPREPQVYVYPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFALVSKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGa (SEQ ID NO: 139);LPICPGGAARCQVTLRDLFDRAVVLSHYIHDLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRIIHNNNCGGsGGEPKSsDKT HTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWEDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYdSTYR VVSVLTVDHHDWLNGI<EYI<CI<VSNI< ALGAPIEKTISKAKGQPREPQVYVYPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFALVSKLTVDKSRWQQGNVFSCSVMHE ALHSHYTQKSLSLSPGa (SEQ ID NO: 140); andLPICPGGAARCQVTLRDLFDRAVVLSHYIHDLSSEMFSEFDKRYTHGRGFITK AINSCHT S SL ATPEDKEQAQQMNQKDFLSLIVSILRSWNEPLYHL VTEVRGMQ EAPEAILSKAVEIEEQTKRLLEGMELIVSQVHPETKENEIYPVWSGLPSLQMA DEESRLSAYYNLLHCLRRDSHKIDNYLKLLKCRIIHNNNCGGsGGEPKSsDKT HTCPPCPAPEAAGGPSVFLFPPKPKDTLYITREPEVTCWVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYdSTYR VVSVLTVLHQDWLNGI<EYI<CI<VSNI< ALPAPIEKTISKAKGQPREPQVYVYPPSRDELTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFALVSKLTVDKSRWQQGNVFSCSVMHEA LHNHYTQKSLSLSPGa (SEQ ID NO: 141).

50. The Fc fusion protein of claim 49, wherein the Fusion protein comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 115, 119, 125, 129 and 141.

51. The Fc fusion protein of any one of claims 1-50, wherein the Fc fusion protein has an increased in vivo half-life relative to a wild-type prolactin polypeptide.

52. The Fc fusion protein of any one of claims 1-51, wherein the Fc fusion protein has an in vivo half-life of at least 10 hours.

53. The Fc fusion protein of any one of claims 1-52, wherein the Fc fusion protein is more susceptible to protease cleavage relative to an Fc-prolactin protein comprising a wild-type prolactin polypeptide and a wild-type Fc domain.

54. A multimeric molecule comprising: a. a first Fc fusion protein of any one of claims 1-53; andb. a second polypeptide comprising an antibody Fc region, and wherein the Fc region of the Fc fusion protein and the Fc region of the polypeptide pair to form a dimer.

55. The multimeric molecule of claim 54, wherein the Fc region of the Fc fusion protein and the Fc region of the second polypeptide have asymmetric complementary structures (e.g., knobs-into-holes or Zwl mutations).

56. The multimeric molecule of claim 54 or 55, wherein the antibody Fc region of the polypeptide comprises: (a) an amino acid sequence having a mutation at positions 220, 297, 447, 350, 351, 405 and 407; (b) an amino acid sequence having a mutation at positions 220, 297, 447, 350, 351, 405, 407, 234, 235, 264, 309, 311 and 434; (c) an amino acid sequence having a mutation at positions 220, 297, 447, 350, 351, 405, 407, 234, 235, 264, 309, 311, 434, 435 and 436; (d) an amino acid sequence having a mutation at positions 220, 297, 447, 350, 351, 405, 407, 234, 235, 329, 264, 309, 311 and 434; or (e) an amino acid sequence having a mutation at positions 220, 297, 447, 350, 351, 405, 407, 234, 235, 252, 254 and 256 of an Fc domain of human IgG (e.g., human IgGl) (EU numbering of Kabat).

57. The multimeric molecule of claim 56, wherein the antibody Fc region of the polypeptide comprises: (a) an amino acid sequence having mutations C220S, N297D, K447A, T350V, L351 Y, F405A, and Y407V; (b) an amino acid sequence having mutations C220S, N297D, K447A, T350V, L351Y, F405A, Y407V, L234A, L235A, V264E, L309D, Q311H, and N434S; (c) an amino acid sequence having mutations C220S, N297D, K447A, T350V, L351 Y, F405A, Y407V, L234A, L235A, P329G, V264E, L309D, Q311H, N434S, H435R, and Y436F; (d) an amino acid sequence having mutations C220S, N297D, K447A, T350V, L351 Y, F405A, Y407V, L234A, L235A, P329G, V264E, L309D, Q311H, and N434S; or (e) an amino acid sequence having mutations C220S, N297D, K447A, T350V, L351 Y, F405A, Y407V, L234A, L235A, M252Y, S254T, and T256E of an Fc domain of human IgG (e.g., human IgGl) (EU numbering of Kabat).

58. The multimeric molecule of claim 54 or 55, wherein the antibody Fc region of the polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 78-8159. The multimeric molecule of claim 54 or 55, wherein the antibody Fc region of the polypeptide comprises: (a) an amino acid sequence having a mutation at positions 220, 297, 447, 350, 366, 392, and 394; (b) an amino acid sequence having a mutationat positions 220, 297, 447, 350, 366, 392, 394, 435, and 436; (c) an amino acid sequence having a mutation at positions 220, 297, 447, 350, 366, 392, 394, 234, 235, 264, 309, 311, and 434 (EU numbering of Kabat); (d) an amino acid sequence having a mutation at positions 220, 297, 447, 350, 366, 392, 394, 234, 235, 264, 309, 311, 434, 435, and 436 (EU numbering of Kabat); (e) an amino acid sequence having a mutation at positions 220, 297, 447, 350, 366, 392, 394, 234, 235, 329, 264, 309, 311, 434, 435, and 436; or (f) an amino acid sequence having a mutation at positions 220, 297, 447, 350, 366, 392, 394, 435, 436, 234, 235, 252, 254, and 256 of an Fc domain of human IgG (e.g., human IgGl) (EU numbering of Kabat).

60. The multimeric molecule of claim 59, wherein the antibody Fc region of the polypeptide comprises: (a) an amino acid sequence having mutations C220S, N297D, K447A, T350V, T366L, K392L, and T394W; (b) an amino acid sequence having mutations C220S, N297D, K447A, T350V, T366L, K392L, T394W, H435R, and Y436F; (c) an amino acid sequence having mutations C220S, N297D, K447A, T350V, T366L, K392L, T394W, L234A, L235A, V264E, L309D, Q311H, and N434S (EU numbering of Kabat); (d) an amino acid sequence having mutations C220S, N297D, K447A, T350V, T366L, K392L, T394W, L234A, L235A, V264E, L309D, Q311H, N434S, H435R, and Y436F (EU numbering of Kabat); (e) an amino acid sequence having mutations C220S, N297D, K447A, T350V, T366L, K392L, T394W, L234A, L235A, P329G, V264E, L309D, Q311H, N434S, H435R, and Y436F; or (f) an amino acid sequence having mutations C220S, N297D, K447A, T350V, T366L, K392L, T394W, H435R, Y436F, L234A, L235A, M252Y, S254T, and T256E of an Fc domain of human IgG (e.g., human IgGl) (EU numbering of Kabat).

61. The multimeric molecule of claim 54 or 55, wherein the antibody Fc region of the polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 82-8762. The multimeric molecule of claim 54 or 55, wherein the antibody Fc region of the polypeptide comprises: (a) an amino acid sequence having a mutation at positions 220, 297, 447, and 366; (b) an amino acid sequence having a mutation at positions 220, 447, 297, 366, 234, 235, 264, 309, 311, and 434; (c) an amino acid sequence having a mutation at positions 220, 447, 297, 366, 234, 235, 329, 264, 309, 311, and 434 (d) an amino acid sequence having a mutation at positions 220, 447, 297, 366, 234, 235, 252, 254, and 256; or (e) an amino acid sequence having a mutation atpositions 220, 226, 229, 297, 447, and 366 of an Fc domain of human IgG (e.g., human IgGl) (EU numbering of Kabat).

63. The Fc fusion protein of claim 62, wherein the antibody Fc region of the polypeptide comprises: (a) an amino acid sequence having mutations C220S, N297D, K447A, and T366W; (b) an amino acid sequence having mutations C220S, K447A, N297D, T366W, L234A, L235A, V264E, L309D, Q311H, and N434S; (c) an amino acid sequence having mutations C220S, K447A, N297D, T366W, L234A, L235A, P329G, V264E, L309D, Q311H, and N434S; (d) an amino acid sequence having mutations C220S, K447A, N297D, L234A, L235A, M252Y, S254T, and T256E; or (e) an amino acid sequence having mutations C220S, C226S, C229S, N297D, K447A, and T366W of an Fc domain of human IgG (e.g., human IgGl) (EU numbering of Kabat).

64. The multimeric molecule of claim 54 or 55, wherein the antibody Fc region of the polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 88-9265. The multimeric molecule of claim 54 or 55, wherein the antibody Fc region of the polypeptide comprises: (a) an amino acid sequence having a mutation at positions 220, 297, 447, 366, 368, and 407; (b) an amino acid sequence having a mutation at positions 220, 297, 447, 366, 368, 407, 435, 436, 234, 235, 264, 309, 311, and 434; (c) an amino acid sequence having a mutation at positions 220, 297, 447, 366, 368, 407, 435, 436, 234, 235, 329, 264, 309, 311, and 434; or (d) an amino acid sequence having a mutation at positions 220, 297, 447, 366, 368, 407, 435, 436, 234, 235, 252, 254, 256 of an Fc domain of human IgG (e.g., human IgGl) (EU numbering of Kabat).

66. The Fc fusion protein of claim 65, wherein the antibody Fc region of the polypeptide comprises: (a) an amino acid sequence having mutations C220S, N297D, K447A, T366S, L368A, and Y407V; (b) an amino acid sequence having mutations C220S, N297D, K447A, T366S, L368A, Y407V, H435R, Y436F, L234A, L235A, V264E, L309D, Q311H, and N434S; (c) an amino acid sequence having mutations C220S, N297D, K447A, T366S, L368A, Y407V, H435R, Y436F, L234A, L235A, P329G, V264E, L309D, Q311H, and N434S; or (d) an amino acid sequence having mutations C220S, N297D, K447A, T366S, L368A, Y407V, H435R, Y436F, L234A, L235A, M252Y, S254T, and T256E of an Fc domain of human IgG (e.g., human IgGl) (EU numb eri ng of Kab at) .

67. The multimeric molecule of claim 54 or 55, wherein the antibody Fc region of the polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 94-9868. The multimeric molecule of any one of claims 54-67, wherein the second polypeptide does not comprise a prolactin polypeptide linked to the antibody Fc region.

69. The multimeric molecule of any one of claims 54-68, wherein the second polypeptide comprising an antibody Fc region further comprises prolactin polypeptide linked to the Fc region.

70. The multimeric molecule of claim 69, wherein the second polypeptide comprising an antibody Fc region is a second Fc fusion protein of any one of claims 1-53.

71. The multimeric molecule of claim 70, wherein the first and second Fc fusion proteins are same.

72. The multimeric molecule of claim 70, wherein the first and second Fc fusion proteins are different.

73. The multimeric molecule of any one of claims 54-72, wherein one of the Fc regions (e.g., Fc region of the Fc fusion protein and the Fc region of the second polypeptide) comprises: (a) an amino acid sequence having a mutation at positions 220, 297, 447, 350, 351, 405 and 407; (b) an amino acid sequence having a mutation at positions 220, 297, 447, 350, 351, 405, 407, 234, 235, 264, 309, 311 and 434; (c) an amino acid sequence having a mutation at positions 220, 297, 447, 350, 351, 405, 407, 234, 235, 264, 309, 311, 434, 435 and 436; (d) an amino acid sequence having a mutation at positions 220, 297, 447, 350, 351, 405, 407, 234, 235, 329, 264, 309, 311 and 434; or (e) an amino acid sequence having a mutation at positions 220, 297, 447, 350, 351, 405, 407, 234, 235, 252, 254 and 256, of an Fc domain of human IgG (e.g., human IgGl) (EU numbering of Kabat), and the other Fc region comprises: (a) an amino acid sequence having a mutation at positions 220, 297, 447, 350, 366, 392, and 394; (b) an amino acid sequence having a mutation at positions 220, 297, 447, 350, 366, 392, 394, 435, and 436; (c) an amino acid sequence having a mutation at positions 220, 297, 447, 350, 366, 392, 394, 234, 235, 264, 309, 311, and 434; (d) an amino acid sequence having a mutation at positions 220, 297, 447, 350, 366, 392, 394, 234, 235, 264, 309, 311, 434, 435, and 436; (e) an amino acid sequence having a mutation at positions 220, 297, 447, 350, 366, 392, 394, 234, 235, 329, 264, 309, 311, 434, 435, and 436; or (f) an amino acidsequence having a mutation at positions 220, 297, 447, 350, 366, 392, 394, 435, 436, 234, 235, 252, 254, and 256 of an Fc domain of human IgG (e.g., human IgGl) (EU numb eri ng of Kab at) .

74. The multimeric molecule of any one of claims 54-73 wherein one of the Fc regions (e.g., Fc region of the Fc fusion protein and the Fc region of the second polypeptide) comprises: comprises: (a) an amino acid sequence having mutations C220S, N297D, K447A, T350V, L351 Y, F405A, and Y407V; (b) an amino acid sequence having mutations C220S, N297D, K447A, T350V, L351Y, F405A, Y407V, L234A, L235A, V264E, L309D, Q311H, and N434S; (c) an amino acid sequence having mutations C220S, N297D, K447A, T350V, L351 Y, F405A, Y407V, L234A, L235A, P329G, V264E, L309D, Q311H, N434S, H435R, and Y436F; (d) an amino acid sequence having mutations C220S, N297D, K447A, T350V, L351 Y, F405A, Y407V, L234A, L235A, P329G, V264E, L309D, Q311H, and N434S; or (e) an amino acid sequence having mutations C220S, N297D, K447A, T350V, L351 Y, F405A, Y407V, L234A, L235A, M252Y, S254T, and T256E of an Fc domain of human IgG (e.g., human IgGl) (EU numbering of Kabat), and the other Fc region comprises: (a) an amino acid sequence having mutations C220S, N297D, K447A, T350V, T366L, K392L, and T394W; (b) an amino acid sequence having mutations C220S, N297D, K447A, T350V, T366L, K392L, T394W, H435R, and Y436F; (c) an amino acid sequence having mutations C220S, N297D, K447A, T350V, T366L, K392L, T394W, L234A, L235A, V264E, L309D, Q311H, and N434S; (d) an amino acid sequence having mutations C220S, N297D, K447A, T350V, T366L, K392L, T394W, L234A, L235A, V264E, L309D, Q311H, N434S, H435R, and Y436F; (e) an amino acid sequence having mutations C220S, N297D, K447A, T350V, T366L, K392L, T394W, L234A, L235A, P329G, V264E, L309D, Q311H, N434S, H435R, and Y436F; or (f) an amino acid sequence having mutations C220S, N297D, K447A, T350V, T366L, K392L, T394W, H435R, Y436F, L234A, L235A, M252Y, S254T, and T256E of an Fc domain of human IgG (e.g., human IgGl) (EU numbering of Kabat).

75. The multimeric molecule of any one of claims 54-72, wherein one of the Fc regions (e.g., Fc region of the Fc fusion protein and the Fc region of the second polypeptide) comprises: (a) an amino acid sequence having a mutation at positions 220, 297, 447, and 366; (b) an amino acid sequence having a mutation at positions 220, 297, 447,366, 234, 235, 264, 309, 311, and 434; (c) an amino acid sequence having a mutation at positions 220, 297, 447, 366, 234, 235, 329, 264, 309, 311, and 434 (d) an amino acid sequence having a mutation at positions 220, 297, 447, 366, 234, 235, 252, 254, and 256; or (e) an amino acid sequence having a mutation at positions 220, 226, 229, 297, 447, and 366 of an Fc domain of human IgG (e.g., human IgGl) (EU numbering ofKabat), and the other Fc region comprises: (a) an amino acid sequence having a mutation at positions 220, 297, 447, 366, 368, and 407; (b) an amino acid sequence having a mutation at positions 220, 297, 447, 366, 368, 407, 435, 436, 234, 235, 264, 309, 311, and 434; (c) an amino acid sequence having a mutation at positions 220, 297, 447, 366, 368, 407, 435, 436, 234, 235, 329, 264, 309, 311, and 434; or (d) an amino acid sequence having a mutation at positions 220, 297, 447, 366, 368, 407, 435, 436, 234, 235, 252, 254, 256 of an Fc domain of human IgG (e.g., human IgGl) (EU numbering ofKabat).

76. The multimeric molecule of any one of claims 54-72, wherein one of the Fc regions (e.g., Fc region of the Fc fusion protein and the Fc region of the second polypeptide) comprises: (a) an amino acid sequence having mutations C220S, N297D, K447A, and T366W; (b) an amino acid sequence having mutations C220S, K447A, N297D, T366W, L234A, L235A, V264E, L309D, Q311H, and N434S; (c) an amino acid sequence having mutations C220S, K447A, N297D, T366W, L234A, L235A, P329G, V264E, L309D, Q311H, and N434S; (d) an amino acid sequence having mutations C220S, K447A, N297D, L234A, L235A, M252Y, S254T, and T256E; or (e) an amino acid sequence having mutations C220S, C226S, C229S, N297D, K447A, and T366W of an Fc domain of human IgG (e.g., human IgGl) (EU numbering ofKabat), and the other Fc region comprises: (a) an amino acid sequence having mutations C220S, N297D, K447A, T366S, L368A, and Y407V; (b) an amino acid sequence having mutations C220S, N297D, K447A, T366S, L368A, Y407V, H435R, Y436F, L234A, L235A, V264E, L309D, Q311H, and N434S; (c) an amino acid sequence having mutations C220S, N297D, K447A, T366S, L368A, Y407V, H435R, Y436F, L234A, L235A, P329G, V264E, L309D, Q311H, and N434S; or (d) an amino acid sequence having mutations C220S, N297D, K447A, T366S, L368A, Y407V, H435R, Y436F,L234A, L235A, M252Y, S254T, and T256E of an Fc domain of human IgG (e.g., human IgGl) (EU numbering of Kabat).

77. The multimeric molecule of any one of claims 54-72, wherein one of the Fc regions (e.g., Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide) comprises an amino acid sequence having at least 85% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 78-81 and the other Fc region comprises an amino acid sequence having at least 85% sequence identity to an amino acid sequence selected from the group consisting of: SEQ ID NO: 82-8778. The multimeric molecule of claim 77, wherein: a. one of the Fc regions (e.g., Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide) comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 78 and the and the other Fc region comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 85; b. one of the Fc regions (e.g., Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide) comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 79 and the and the other Fc region comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 82; c. one of the Fc regions (e.g., Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide) comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 79 and the and the other Fc region comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 83; d. one of the Fc regions (e.g., Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide) comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 80 and the and the other Fc region comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 86; or e. one of the Fc regions (e.g., Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide) comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 81 and the and the other Fcregion comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 87.

79. The multimeric molecule of claim 78, wherein the Fc region of the Fc-PRL fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 78-8180. The multimeric molecule of any one of claims 54-72, wherein one of the Fc regions (e.g., Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide) comprises an amino acid sequence having at least 85% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 88-92 and the other Fc region comprises an amino acid sequence having at least 85% sequence identity to an amino acid sequence selected from the group consisting of: SEQ ID NO: 94-9881. The multimeric molecule of claim 80 wherein: a. one of the Fc regions (e.g., Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide) comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 88 and the and the other Fc region comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 94; b. one of the Fc regions (e.g., Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide) comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 88 and the and the other Fc region comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 95; c. one of the Fc regions (e.g., Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide) comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 89 and the and the other Fc region comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 96; d. one of the Fc regions (e.g., Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide) comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 90 and the and the other Fc region comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 97;e. one of the Fc regions (e.g., Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide) comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 91 and the and the other Fc region comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 98; f. one of the Fc regions (e.g., Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide) comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 92 and the and the other Fc region comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 95; g. one of the Fc regions (e.g., Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide) comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 89 and the and the other Fc region comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 96; h. one of the Fc regions (e.g., Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide) comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 80 and the and the other Fc region comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 97; or i. one of the Fc regions (e.g., Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide) comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 92 and the and the other Fc region comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 98.

82. The multimeric molecule of claim 81, wherein the Fc region of the Fc-PRL fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 88-9283. The multimeric molecule of any one of claims 54-72, wherein: a. the Fc fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 120 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 94;b. the Fc fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 121 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 95; c. the Fc fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 122 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 95; d. the Fc fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 123 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 97; e. the Fc fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 124 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 98; f. the Fc fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 125 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 85; g. the Fc fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 126 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 82; h. the Fc fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 127 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 83; i. the Fc fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 128 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 86; j . the Fc fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 129 and the second polypeptide comprisesan amino acid sequence having at least 85% sequence identity to SEQ ID NO: 87; k. the Fc fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 130 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 95; l. the Fc fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 131 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 95; m. the Fc fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 132 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 95; n. the Fc fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 133 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 95; o. the Fc fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 134 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 96; p. the Fc fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 135 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 97; q. the Fc fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 136 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 98; r. the Fc fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 137 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 85;s. the Fc fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 138 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 82; t. the Fc fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 139 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 83; u. the Fc fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 140 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 86; or v. the Fc fusion protein comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 141 and the second polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO:87.

84. A pharmaceutical composition comprising: (i) a Fc fusion protein of any one of claims 1-53 or a multimeric molecule of any one of claims 54-83; and (ii) a pharmaceutically acceptable carrier or excipient.

85. A cell comprising a Fc fusion protein of any one of claims 1-53 or a multimeric molecule of any one of claims 54-83.

86. A nucleic acid encoding a Fc fusion protein of any one of claims 1-53 or a multimeric molecule of any one of claims 54-83.

87. A cell comprising a nucleic acid of claim 86.

88. A kit comprising: (i) an Fc fusion protein or a polynucleotide encoding a Fc fusion protein of any one of claims 1-53; or (ii) a multimeric molecule or a polynucleotide encoding a multimeric molecule of any one of claims 54-83.

89. A method for treating lactation insufficiency in a subj ect, the method comprising administering an effective amount of a Fc fusion protein of any one of claims 1-53, a multimeric molecule of any one of claims 54-83, a polynucleotide encoding a Fc fusion protein of any one of claims 1-53, or a polynucleotide encoding a multimeric molecule of any one of claims 54-83 to a subject in need thereof.

90. A method for increasing milk production in a subject, the method comprising administering an effective amount of a Fc fusion protein of any one of claims 1-53, amultimeric molecule of any one of claims 54-83, a polynucleotide encoding a Fc fusion protein of any one of claims 1-53, or a polynucleotide encoding a multimeric molecule of any one of claims 54-83 to a subject in need thereof.

91. The method of claim 89 or 90, wherein the subject is a mammal.

92. The method of any one of claims 89-91, wherein the subject is human.

93. The method of any one of claims 89-92, wherein the subject is a non-human.

94. The method of claim 93, wherein the subject is a livestock animal.

95. The method of any one of claims 89-94, wherein said administering is by injection, infusion, instillation, inhalation, or ingestion.

96. The method of any one of claims 87-95, wherein said administering is intravenous (IV), intraperitoneal (IP), subcutaneous (SC) or intramuscular (IM) administration.

97. A method for preparing an Fc-PRL fusion protein, the method comprising:(a) culturing a host cell comprising a nucleic acid encoding an Fc-PRL fusion protein; and(b) recovering the Fc-PRL fusion protein from the host cell culture.

98. A method for preparing a multimeric molecule comprising an Fc-PRL fusion protein and a second polypeptide comprising an antibody Fc region, the method comprising:(a) culturing a host cell comprising a nucleic acid encoding the Fc-PRL fusion protein and a nucleic acid encoding the second polypeptide comprising an antibody Fc region; and(b) recovering the Fc-PRL fusion protein and the second polypeptide from the host cell culture, wherein the Fc region of the Fc-PRL fusion protein and the Fc region of the polypeptide pair to form a dimer.

99. The method of claim 98, wherein the method further comprises forming the multimeric molecule after recovering the Fc-PRL fusion protein and the second polypeptide from the host cell culture.

100. The method of any one of claims 98, wherein the method comprises forming the multimeric molecule prior to recovering the Fc-PRL fusion protein and the second polypeptide from the host cell culture.

101. The method of any one of claims 98-100, wherein the Fc region of the second polypeptide comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%or 99% sequence identity to an amino acid sequence selected from the group consisting of: SEQ ID NO: 78-92 and 94-98.

102. The method of any one of claims 98-101, wherein one of the Fc regions (e.g., Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide) comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence selected from the group consisting of: SEQ ID NO: 78-81 and the other Fc region comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence selected from the group consisting of: SEQ ID NO: 82-87.

103. The method of any one of claims 98-101, wherein one of the Fc regions (e.g., Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide) comprises an amino acid sequence having at least 85% sequence identity to an amino acid sequence selected from the group consisting of: SEQ ID NO: 88-92 and the other Fc region comprises an amino acid sequence having at least 85% sequence identity to an amino acid sequence selected from the group consisting of: SEQ ID NO: 94-98104. The method of any one of claims 97-103, wherein the second polypeptide is a second Fc-PRL fusion protein.

105. The method of any one of claims 97-104, wherein the Fc-PRL fusion protein is an Fc- PRL of any one of claims 1-53.

106. The method of any one of claims 97-105, wherein the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to any one of SEQ ID NO: 113-141.

107. The method of any one of claims 97-106, wherein the nucleic acid encoding the Fc- PRL fusion protein comprises a nucleotide sequence encoding an FC-PRL fusion protein comprising an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 125108. The method of any one of claims 97-107, wherein the nucleic acid encoding the Fc- PRL fusion protein comprises a nucleotide sequence encoding an FC-PRL fusionprotein comprising an amino acid sequence having 100% sequence identity to SEQ ID NO: 125109. The method of any one of claims 97-108, wherein the host cell is a eukaryotic cell.

110. The method of any one of claims 97-109, wherein the host cell is selected from the group consisting of monkey COS-cells, mouse L-cells, mouse C127-cells, hamster BHK-21 cells, human embryonic kidney 293 cells, and hamster CHO-cells.

111. The method of claim 110, wherein the host cell is a hamster CHO-cell.

112. The method of any one of claims 97-109, wherein the host cell is a yeast cell.

113. The method of claim 112, wherein the yeast cell is from the genera Pichia, Saccharomyces, Kluyveromyces, Aspergillus, Candida, Torulopsis, Torulaspora, Schizosaccharomyces, Citeromyces, Pachysolen, Zygosaccharomyces, Debaromyces, Trichoderma, Cephalosporium, Humicola, Mucor, Neurospora, Yarrowia, Metschunikowia, Rhodosporidium, Leucosporidium, Botryoascus, Sporidiobolus, or Endomycopsis.

114. The method of claim 113, wherein the yeast cell is from the genera Pichia.

115. The method of any one of claims 97-114, wherein the host cell is a prokaryotic cell.

116. A method for preparing a multimeric molecule comprising an Fc-PRL fusion protein and a second polypeptide comprising an antibody Fc region, the method comprising:(a) culturing a first host cell comprising a nucleic acid encoding the Fc-PRL fusion protein;(b) culturing a second host cell comprising a nucleic acid encoding the second polypeptide comprising an antibody Fc region;(c) recovering the Fc-PRL fusion protein and the second polypeptide from the host cell cultures; and(d) forming the multimeric molecule with the recovered Fc-PRL fusion protein and the second polypeptide, wherein the Fc region of the Fc-PRL fusion protein and the Fc region of the polypeptide pair to form a dimer.

117. The method of claim 116, wherein the Fc region of the second polypeptide comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence selected from the group consisting of: SEQ ID NO: 78-92 and 94-98118. The method of any one of claims 116-117, wherein one of the Fc regions (e.g., Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide) comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence selected from the group consisting of: SEQ ID NO: 78-81 and the other Fc region comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 82-87.

119. The method of any one of claims 116-118, wherein one of the Fc regions (e.g., Fc region of the Fc-PRL fusion protein and the Fc region of the second polypeptide) comprises an amino acid sequence having at least 85% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 88-92 and the other Fc region comprises an amino acid sequence having at least 85% sequence identity to an amino acid sequence selected from the group consisting of: SEQ ID NO: 94-98120. The method of any one of claims 116-119, wherein the second polypeptide is a second Fc-PRL fusion protein.

121. The method of any one of claims 116-120, wherein the Fc-PRL fusion protein is an Fc-PRL of any one of claims 1-53.

122. The method of any one of claims 116-121, wherein the Fc-PRL fusion protein comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to any one of SEQ ID NO: 113-141.

123. The method of any one of claims 116-122, wherein the nucleic acid encoding the Fc- PRL fusion protein comprises a nucleotide sequence encoding an FC-PRL fusion protein comprising an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 125124. The method of any one of claims 116-123, wherein the nucleic acid encoding the Fc- PRL fusion protein comprises a nucleotide sequence encoding an FC-PRL fusion protein comprising an amino acid sequence having 100% sequence identity to SEQ ID NO: 125125. The method of any one of claims 116-124, wherein are least one of the first and second host cell is a eukaryotic cell.

126. The method of any one of claims 116-125, wherein at least one of the first and second host cell is selected from the group consisting of monkey COS-cells, mouse L-cells, mouse C127-cells, hamster BHK-21 cells, human embryonic kidney 293 cells, and hamster CHO-cells.

127. The method of claim 126, wherein the host cell is a hamster CHO-cell.

128. The method of any one of claims 116-125, wherein at least one of the first and the second host cell is a yeast cell.

129. The method of claim 128, wherein the yeast cell is from the genera Pichia, Saccharomyces, Kluyveromyces, Aspergillus, Candida, Torulopsis, Torulaspora, Schizosaccharomyces, Citeromyces, Pachysolen, Zygosaccharomyces, Debaromyces, Trichoderma, Cephalosporium, Humicola, Mucor, Neurospora, Yarrowia, Metschunikowia, Rhodosporidium, Leucosporidium, Botryoascus, Sporidiobolus, or Endomycopsis.

130. The method of claim 129, wherein the yeast cell is from the genera Pichia.

131. The method of any one of claims 116-130, wherein at least one of the first and second host cell is a prokaryotic cell.

132. The method of any one of claims 116-131, wherein the first and second host cells are different.

133. The method of any one of claims 116-131, wherein the first and second host cells are same.

Images