Veterinary IgG Fc variants

Abstract

The present invention relates to a veterinary IgG Fc variant, and provides various embodiments involving a variant IgG Fc polypeptide in a companion animal, the variant IgG Fc polypeptide having increased protein A binding for ease of purification, reduced C1q binding for reduction of complement-mediated immune response, reduced CD16 binding, enhanced stability, and / or the ability to form heterodimeric proteins. In addition, various embodiments relating to antibodies and fusion proteins comprising such variant IgG Fc polypeptides are provided. Also provided are various embodiments relating to contiguous polypeptides comprising one or more variant GLP1 polypeptides. In addition, various embodiments are provided that relate to a contiguous polypeptide or a heterodimeric polypeptide that is a dual GLP1 receptor and glucagon receptor agonist. In various embodiments, such polypeptides may be used to treat, for example, diabetes, obesity, or related indications in companion animals such as dogs, cats, and horses.

Description

This invention application is a divisional application based on an invention patent application with an application date of August 15, 2018, application number 201880064650.9 (international application number PCT / IB2018 / 056142) and name “IgG Fc variant for veterinary medicine”. CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 62 / 545,858 (filed on August 15, 2017), which is incorporated herein by reference in its entirety for any purpose. Technical Field

[0002] The present specification relates to variant IgG Fc polypeptides for companion animals having enhanced characteristics, including increased protein A binding (e.g., to facilitate purification), reduced C1q binding (e.g., to reduce complement-mediated immune responses), reduced CD16 binding (e.g., reduced antibody-dependent cellular cytotoxicity (ADCC) induction), enhanced stability, and / or the ability to form heterodimeric proteins. The variant IgG Fc polypeptides described herein may have a wide range of applications in the treatment of companion animals. For example, the variant IgG Fc polypeptides may be used to design and produce long-acting GLP1 polypeptides to treat, for example, diabetes, obesity, or related indications in companion animals, such as canines, cats, and horses. In addition, the variant IgG Fc polypeptides may be used to design and produce antibodies or fusion proteins to treat a variety of conditions in companion animals. Background Art

[0003] IgG Fc plays an important role in Fc-mediated functions through interactions with FcRn, Fc receptors, and C1q. In companion animals, various IgG subtypes have different functions that are often considered when selecting a particular IgG antibody or IgG Fc fusion protein for therapeutic or diagnostic applications. For example, the ability of an IgG subtype to have weak or unmeasurable binding affinity for C1q or CD16 may be advantageous. In addition, the ability of IgG Fc to bind Protein A may facilitate purification using a Protein A affinity purification platform.

[0004] However, most IgG Fc subtypes of canine, feline, and equine do not have protein A binding, and have weak or unmeasurable binding affinity to CD16, and weak or unmeasurable binding affinity to C1q. For example, of the four canine IgG Fc subtypes (IgG-A, IgG-B, IgG-C, and IgG-D), only canine IgG-B Fc has an evaluable affinity for protein A. Meanwhile, only canine IgG-A Fc and IgG-D Fc have no or only weak C1q binding or CD16 binding. Antibodies and Fc fusion proteins comprising variant IgG Fc polypeptides that have reduced binding to C1q and / or CD16 and / or are capable of binding to protein A are needed.

[0005] Glucagon-like peptide-1 (GLP1) is a potent anti-hyperglycemic hormone that plays an important role in regulating blood glucose. The half-life of native GLP1 in vivo is about 2 minutes. Long-acting GLP1 polypeptides can be used to treat diabetes and obesity, prevent diabetes, control hyperglycemic conditions, lower blood lipids, treat conditions that benefit from lowered blood glucose levels, inhibit gastric or intestinal motility, slow gastric emptying and / or reduce food intake. There is still a need for long-acting GLP1 polypeptides to treat hyperglycemia or uncontrollable blood glucose-induced conditions in companion animals such as dogs, cats, and horses. Summary of the invention Embodiment 1. A polypeptide comprising a variant IgG Fc polypeptide comprising at least one amino acid modification relative to a wild-type IgG Fc polypeptide of a companion animal species, wherein the variant IgG Fc polypeptide has an enhanced binding affinity for protein A relative to the wild-type IgG Fc polypeptide. Embodiment 2. A polypeptide comprising a variant IgG Fc polypeptide comprising at least one amino acid modification relative to a wild-type IgG Fc polypeptide of a companion animal species, wherein the variant IgG Fc polypeptide has reduced binding affinity for C1q and / or CD16 relative to the wild-type IgG Fc polypeptide. Embodiment 3. The polypeptide of embodiment 1 or embodiment 2, wherein the variant IgG Fc polypeptide binds to C1q and / or CD16 with a dissociation constant (K d ) is greater than 5x 10 -6 M, greater than 1x 10 -5 M, greater than 5x 10 -5 M, greater than 1x 10 -4 M, greater than 5x 10 -4 M or greater than 1x 10 -3 M, as determined by biofilm interferometry. Embodiment 4. A polypeptide according to any of the preceding embodiments, wherein the variant IgG Fc polypeptide has an enhanced binding affinity for Protein A relative to the wild-type IgG Fc polypeptide. Embodiment 5. The polypeptide according to any one of the preceding embodiments, wherein the variant IgG Fc polypeptide binds to protein A with a dissociation constant (K d ) is less than 5x 10 -6 M, less than 1x10 -6 M, less than 5x 10 -7 M, less than 1x10 -7 M, less than 5x 10 -8 M, less than 1x 10 -8 M, less than 5x 10 -9 M, less than 1x 10 -9 M, less than 5x 10 -10 M, less than 1x 10 -10 M, less than 5x 10 -11 M, less than 1x 10 -11 M, less than 5x 10 -12 M or less than 1x 10 -12 M, as determined by biofilm interferometry. Embodiment 6. The polypeptide of any of the preceding embodiments, wherein the companion animal species is canine, feline, or equine. Embodiment 7. A polypeptide according to any one of the preceding embodiments, wherein the wild-type IgG Fc polypeptide is a) canine IgG-AFc, IgG-B Fc, IgG-C Fc or IgG-D Fc; b) equine IgG1 Fc, IgG2 Fc, IgG3 Fc, IgG4 Fc, IgG5 Fc, IgG6 Fc or IgG7 Fc; or c) Feline IgG1a Fc, IgG1b Fc or IgG2 Fc. Embodiment 8. A polypeptide comprising a variant IgG Fc polypeptide comprising at least one amino acid modification to the hinge region relative to a wild-type feline or equine IgG Fc polypeptide, wherein the variant IgG Fc polypeptide has increased recombinant production and / or increased hinge disulfide bond formation relative to the wild-type IgG Fc polypeptide as determined by SDS-PAGE analysis under reducing and / or non-reducing conditions. Embodiment 9. A polypeptide according to any one of the preceding embodiments, wherein the variant IgG Fc polypeptide comprises: a) at least one amino acid substitution relative to a wild-type feline IgG Fc polypeptide, wherein the variant the IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to position 16 of SEQ ID NO: 16, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 117 or SEQ ID NO: 118; b) at least one amino acid substitution relative to a wild-type equine IgG Fc polypeptide, wherein the variant IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to position 3 of SEQ ID NO: 129; and / or c) at least one amino acid substitution relative to a wild-type equine IgG Fc polypeptide, wherein the variant IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to position 20 of SEQ ID NO:129. Embodiment 10. The polypeptide according to any one of the preceding embodiments, wherein the variant IgG Fc polypeptide comprises: a) at least one amino acid substitution relative to a wild-type feline IgG Fc polypeptide, wherein the variant IgG Fc polypeptide comprises an amino acid substitution at position 16 of SEQ ID NO: 16, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 117 or SEQ ID NO: 118; b) at least one amino acid substitution relative to a wild-type equine IgG Fc polypeptide, wherein the variant IgG Fc polypeptide comprises an amino acid substitution at position 3 of SEQ ID NO: 129; and / or c) at least one amino acid substitution relative to a wild-type equine IgG Fc polypeptide, wherein the variant IgG Fc polypeptide comprises an amino acid substitution at position 20 of SEQ ID NO: 129. Embodiment 11. A polypeptide according to any one of the preceding embodiments, wherein the variant IgG Fc polypeptide comprises: a) at least one amino acid substitution relative to a wild-type feline IgG Fc polypeptide, wherein the variant IgG Fc polypeptide comprises a proline at position 16 or a position corresponding to position 16 of SEQ ID NO: 16, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 117 or SEQ ID NO: 118; b) at least one amino acid substitution relative to a wild-type equine IgG Fc polypeptide, wherein the variant IgG Fc polypeptide comprises a serine at position 3 of SEQ ID NO: 129, or at a position corresponding to position 3 of SEQ ID NO: 129; and / or c) at least one amino acid substitution relative to a wild-type equine IgG Fc polypeptide, wherein the variant IgG Fc polypeptide comprises a proline at position 20 of SEQ ID NO: 129 or at a position corresponding to position 20 of SEQ ID NO: 129. Embodiment 12. A polypeptide according to any one of the preceding embodiments, wherein the variant IgG Fc polypeptide comprises a hinge region or a portion of a hinge region from an IgG Fc polypeptide of a different isotype. Embodiment 13. A polypeptide according to any of the preceding embodiments, wherein the variant IgG Fc polypeptide comprises a hinge region or a portion of a hinge region from a wild-type feline IgG-1a Fc polypeptide, from a wild-type feline IgG-1b Fc polypeptide, or from a wild-type equine IgG1 Fc polypeptide. Embodiment 14. A polypeptide according to any of the preceding embodiments, wherein the variant IgG Fc polypeptide comprises SEQ ID NO: 19, SEQ ID NO: 125 or SEQ ID NO: 126, SEQ ID NO: 127, SEQ ID NO: 128, SEQ ID NO: SEQ ID NO: 129, SEQ ID NO: 130, SEQ ID NO: 131, SEQ ID NO: 132, SEQ ID NO: 133, SEQ ID N: 134, SEQ ID NO: 135. Embodiment 15. A polypeptide comprising the amino acid sequence of SEQ ID NO:19, SEQ ID NO:125 or SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135. Embodiment 16. A polypeptide comprising a variant IgG2 Fc polypeptide comprising at least one amino acid substitution relative to a wild-type feline IgG2 Fc polypeptide, wherein the at least one amino acid substitution is cysteine, and wherein the variant IgG2 Fc polypeptide is capable of forming at least one additional interchain disulfide bond relative to the wild-type feline IgG2 Fc polypeptide. Embodiment 17. A polypeptide according to any of the preceding embodiments, wherein the variant IgG Fc polypeptide comprises at least one amino acid substitution relative to a wild-type feline IgG Fc polypeptide, wherein the at least one amino acid substitution is cysteine, and wherein the variant IgG Fc polypeptide is capable of forming at least one additional interchain disulfide bond relative to the wild-type feline IgG Fc polypeptide. Embodiment 18. A polypeptide according to any of the preceding embodiments, wherein the variant IgG Fc polypeptide comprises a cysteine ​​at a position corresponding to position 8, position 9, position 10, position 11, position 12, position 13, position 14, position 15 or position 16 of SEQ ID NO: 16. Embodiment 19. A polypeptide according to any of the preceding embodiments, wherein the variant IgG Fc polypeptide comprises a cysteine ​​at the position corresponding to position 14 of SEQ ID NO:16. Embodiment 20. A polypeptide according to any of the preceding embodiments, wherein the variant IgG Fc polypeptide comprises a cysteine ​​at position 14 of SEQ ID NO: 16. Embodiment 21. The polypeptide according to any one of the foregoing embodiments, wherein the variant IgG Fc polypeptide has an amino acid sequence SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:100, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO:120, SEQ ID NO:121, SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ IDNO:154, SEQ ID NO:155, SEQ ID NO:156 or SEQ ID NO:157 are at least 90% identical, at least 95% identical, at least 97% identical, or at least 99% identical. Embodiment 22. A polypeptide according to any of the preceding embodiments, wherein the variant IgG Fc polypeptide comprises SEQ ID NO:17. Embodiment 23. A polypeptide comprising the amino acid sequence of SEQ ID NO:17. Embodiment 24. A polypeptide according to any one of the preceding embodiments, wherein the variant IgG Fc polypeptide comprises: a) an amino acid substitution at the position corresponding to position 21 of SEQ ID NO: 1, an amino acid substitution at the position corresponding to position 23 of SEQ ID NO: 1, an amino acid substitution at the position corresponding to position 25 of SEQ ID NO: 1, an amino acid substitution at the position corresponding to position 80 of SEQ ID NO: 1, an amino acid substitution at the position corresponding to position 205 of SEQ ID NO: 1, and / or an amino acid substitution at the position corresponding to position 207 of SEQ ID NO: 1; b) an amino acid substitution at the position corresponding to position 21 of SEQ ID NO: 3, an amino acid substitution at the position corresponding to position 23 of SEQ ID NO: 3, and / or an amino acid substitution at the position corresponding to position 24 of SEQ ID NO: 3; c) an amino acid substitution at the position corresponding to position 21 of SEQ ID NO:4, an amino acid substitution at the position corresponding to position 23 of SEQ ID NO:4, an amino acid substitution at the position corresponding to position 25 of SEQ ID NO:4, an amino acid substitution at the position corresponding to position 80 of SEQ ID NO:4, and / or an amino acid substitution at the position corresponding to position 207 of SEQ ID NO:4; d) an amino acid substitution at the position corresponding to position 15 of SEQ ID NO: 64, and / or an amino acid substitution at the position corresponding to position 203 of SEQ ID NO: 64; e) an amino acid substitution at the position corresponding to position 199 of SEQ ID NO: 67, and / or an amino acid substitution at the position corresponding to position 200 of SEQ ID NO: 67; and / or f) an amino acid substitution at a position corresponding to position 199 of SEQ ID NO:68, an amino acid substitution at a position corresponding to position 200 of SEQ ID NO:68, an amino acid substitution at a position corresponding to position 201 of SEQ ID NO:68, and / or an amino acid substitution at a position corresponding to position 202 of SEQ ID NO:68. Embodiment 25. A polypeptide according to any one of the preceding embodiments, wherein the variant IgG Fc polypeptide comprises: a) an amino acid substitution at position 21 of SEQ ID NO: 1, an amino acid substitution at position 23 of SEQ ID NO: 1, an amino acid substitution at position 25 of SEQ ID NO: 1, an amino acid substitution at position 80 of SEQ ID NO: 1, an amino acid substitution at position 205 of SEQ ID NO: 1, and / or an amino acid substitution at position 207 of SEQ ID NO: 1; b) an amino acid substitution at position 21 of SEQ ID NO:3, an amino acid substitution at position 23 of SEQ ID NO:3, and / or an amino acid substitution at position 24 of SEQ ID NO:3; c) an amino acid substitution at position 21 of SEQ ID NO:4, an amino acid substitution at position 23 of SEQ ID NO:4, an amino acid substitution at position 25 of SEQ ID NO:4, an amino acid substitution at position 80 of SEQ ID NO:4, and / or an amino acid substitution at position 207 of SEQ ID NO:4; d) an amino acid substitution at position 15 of SEQ ID NO:64, and / or an amino acid substitution at position 203 of SEQ ID NO:64; e) an amino acid substitution at position 199 of SEQ ID NO:67, and / or an amino acid substitution at position 200 of SEQ ID NO:67; and / or f) an amino acid substitution at position 199 of SEQ ID NO:68, an amino acid substitution at position 200 of SEQ ID NO:68, an amino acid substitution at position 201 of SEQ ID NO:68, and / or an amino acid substitution at position 202 of SEQ ID NO:68. Embodiment 26. A polypeptide according to any one of the preceding embodiments, wherein the variant IgG Fc polypeptide comprises: a) a threonine at the position corresponding to position 21 of SEQ ID NO: 1, a leucine at the position corresponding to position 23 of SEQ ID NO: 1, an alanine at the position corresponding to position 25 of SEQ ID NO: 1, a glycine at the position corresponding to position 80 of SEQ ID NO: 1, an alanine at the position corresponding to position 205 of SEQ ID NO: 1, and / or a histidine at the position corresponding to position 207 of SEQ ID NO: 1; b) a threonine at the position corresponding to position 21 of SEQ ID NO:3, a leucine at the position corresponding to position 23 of SEQ ID NO:3, and / or an isoleucine at the position corresponding to position 24 of SEQ ID NO:3; c) a threonine at the position corresponding to position 21 of SEQ ID NO:4, a leucine at the position corresponding to position 23 of SEQ ID NO:4, an alanine at the position corresponding to position 25 of SEQ ID NO:4, a glycine at the position corresponding to position 80 of SEQ ID NO:4, and / or a histidine at the position corresponding to position 207 of SEQ ID NO:4; d) a threonine or valine at the position corresponding to position 15 of SEQ ID NO: 64, and / or a tyrosine or valine at the position corresponding to position 203 of SEQ ID NO: 64; e) a leucine at the position corresponding to position 199 of SEQ ID NO:67, and / or a histidine at the position corresponding to position 200 of SEQ ID NO:67; and / or f) a leucine at a position corresponding to position 199 of SEQ ID NO:68, a histidine at a position corresponding to position 200 of SEQ ID NO:68, an asparagine at a position corresponding to position 201 of SEQ ID NO:68, and / or a histidine at a position corresponding to position 202 of SEQ ID NO:68. Embodiment 27. A polypeptide according to any one of the preceding embodiments, wherein the variant IgG Fc polypeptide comprises: a) threonine at position 21 of SEQ ID NO: 1, leucine at position 23 of SEQ ID NO: 1, alanine at position 25 of SEQ ID NO: 1, glycine at position 80 of SEQ ID NO: 1, alanine at position 205 of SEQ ID NO: 1, and / or histidine at position 207 of SEQ ID NO: 1; b) threonine, which is at position 21 of SEQ ID NO:3, leucine, which is at position 23 of SEQ ID NO:3, and / or isoleucine, which is at position 24 of SEQ ID NO:3; c) threonine at position 21 of SEQ ID NO:4, leucine at position 23 of SEQ ID NO:4, alanine at position 25 of SEQ ID NO:4, glycine at position 80 of SEQ ID NO:4, and / or histidine at position 207 of SEQ ID NO:4; d) threonine or valine, which is at position 15 of SEQ ID NO: 64, and / or tyrosine or valine, which is at position 203 of SEQ ID NO: 64; e) leucine, which is at position 199 of SEQ ID NO:67, and / or histidine, which is at position 200 of SEQ ID NO:67; and / or f) leucine at position 199 of SEQ ID NO:68, histidine at position 200 of SEQ ID NO:68, asparagine at position 201 of SEQ ID NO:68, and / or histidine at position 202 of SEQ ID NO:68. Embodiment 28. A polypeptide according to any one of the preceding embodiments, wherein the variant IgG Fc polypeptide comprises the following amino acid sequence: a) SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62 or SEQ ID NO:84; or b) SEQ ID NO:19, SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:75 or SEQ ID NO:76. Embodiment 29. A polypeptide comprising the amino acid sequence of SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:84, SEQ ID NO:19, SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:75 or SEQ ID NO:76. Embodiment 30. A polypeptide according to any one of the preceding embodiments, wherein the variant IgG Fc polypeptide comprises: a) an amino acid substitution at the position corresponding to position 93 of SEQ ID NO: 2, or an amino acid substitution at the position corresponding to position 93 of SEQ ID NO: 3; b) an amino acid substitution at the position corresponding to position 87 of SEQ ID NO:63, an amino acid substitution at the position corresponding to position 87 of SEQ ID NO:65, an amino acid substitution at the position corresponding to position 87 of SEQ ID NO:66, or an amino acid substitution at the position corresponding to position 87 of SEQ ID NO:69; or c) an amino acid substitution at the position corresponding to position 198 of SEQ ID NO:80, or an amino acid substitution at the position corresponding to position 198 of SEQ ID NO:81. Embodiment 31. A polypeptide according to any one of the preceding embodiments, wherein the variant IgG Fc polypeptide comprises: a) an amino acid substitution at position 93 of SEQ ID NO:2, or an amino acid substitution at position 93 of SEQ ID NO:3; b) an amino acid substitution at position 87 of SEQ ID NO:63, an amino acid substitution at position 87 of SEQ ID NO:65, an amino acid substitution at position 87 of SEQ ID NO:66, or an amino acid substitution at position 87 of SEQ ID NO:69; or c) an amino acid substitution at position 198 of SEQ ID NO:80, or an amino acid substitution at position 198 of SEQ ID NO:81. Embodiment 32. A polypeptide according to any one of the preceding embodiments, wherein the variant IgG Fc polypeptide comprises: a) an arginine at a position corresponding to position 93 of SEQ ID NO: 2, or an arginine at a position corresponding to position 93 of SEQ ID NO: 3; b) a serine at a position corresponding to position 87 of SEQ ID NO:63, a serine at a position corresponding to position 87 of SEQ ID NO:65, a serine at a position corresponding to position 87 of SEQ ID NO:66, or a serine at a position corresponding to position 87 of SEQ ID NO:69; or c) an alanine at a position corresponding to position 198 of SEQ ID NO:80, or an alanine at a position corresponding to position 198 of SEQ ID NO:81. Embodiment 33. A polypeptide according to any one of the preceding embodiments, wherein the variant IgG Fc polypeptide comprises: a) arginine at position 93 of SEQ ID NO:2, or arginine at position 93 of SEQ ID NO:3; b) serine at position 87 of SEQ ID NO:63, serine at position 87 of SEQ ID NO:65, serine at position 87 of SEQ ID NO:66, or serine at position 87 of SEQ ID NO:69; or c) Alanine at position 198 of SEQ ID NO:80, or Alanine at position 198 of SEQ ID NO:81. Embodiment 34. A polypeptide according to any one of the preceding embodiments, wherein the variant IgG Fc polypeptide comprises the following amino acid sequence: a) SEQ ID NO:78, SEQ ID NO:79 or SEQ ID NO:84; or b) SEQ ID NO:70, SEQ ID NO:73, SEQ ID NO:74 or SEQ ID NO:77; or c) SEQ ID NO:82 or SEQ ID NO:83. Embodiment 35. A polypeptide comprising the amino acid sequence of SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:84, SEQ ID NO:70, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:77, SEQ ID NO:82, or SEQ ID NO:83. Embodiment 36. A polypeptide according to any one of the preceding embodiments, wherein the variant IgG Fc polypeptide comprises: a) an amino acid substitution at the position corresponding to position 5 of SEQ ID NO: 2, an amino acid substitution at the position corresponding to position 38 of SEQ ID NO: 2, an amino acid substitution at the position corresponding to position 39 of SEQ ID NO: 2, an amino acid substitution at the position corresponding to position 97 of SEQ ID NO: 2, and / or an amino acid substitution at the position corresponding to position 98 of SEQ ID NO: 2; or b) an amino acid substitution at the position corresponding to position 5 of SEQ ID NO:3, an amino acid substitution at the position corresponding to position 38 of SEQ ID NO:3, an amino acid substitution at the position corresponding to position 39 of SEQ ID NO:3, an amino acid substitution at the position corresponding to position 97 of SEQ ID NO:3, and / or an amino acid substitution at the position corresponding to position 98 of SEQ ID NO:3. Embodiment 37. A polypeptide according to any one of the preceding embodiments, wherein the variant IgG Fc polypeptide comprises: a) an amino acid substitution at position 5 of SEQ ID NO:2, an amino acid substitution at position 38 of SEQ ID NO:2, an amino acid substitution at position 39 of SEQ ID NO:2, an amino acid substitution at position 97 of SEQ ID NO:2, and / or an amino acid substitution at position 98 of SEQ ID NO:2; or b) an amino acid substitution at position 5 of SEQ ID NO:3, an amino acid substitution at position 38 of SEQ ID NO:3, an amino acid substitution at position 39 of SEQ ID NO:3, an amino acid substitution at position 97 of SEQ ID NO:3, and / or an amino acid substitution at position 98 of SEQ ID NO:3. Embodiment 38. A polypeptide according to any one of the preceding embodiments, wherein the variant IgG Fc polypeptide comprises: a) proline at the position corresponding to position 5 of SEQ ID NO:2, glycine at the position corresponding to position 38 of SEQ ID NO:2, arginine at the position corresponding to position 39 of SEQ ID NO:2, isoleucine at the position corresponding to position 97 of SEQ ID NO:2, and / or glycine at the position corresponding to position 98 of SEQ ID NO:2; or b) proline at the position corresponding to position 5 of SEQ ID NO:3, glycine at the position corresponding to position 38 of SEQ ID NO:3, arginine at the position corresponding to position 39 of SEQ ID NO:3, isoleucine at the position corresponding to position 97 of SEQ ID NO:3, and / or glycine at the position corresponding to position 98 of SEQ ID NO:3. Embodiment 39. A polypeptide according to any one of the preceding embodiments, wherein the variant IgG Fc polypeptide comprises: a) proline, which is at position 5 of SEQ ID NO:2, glycine, which is at position 38 of SEQ ID NO:2, arginine, which is at position 39 of SEQ ID NO:2, isoleucine, which is at position 97 of SEQ ID NO:2, and / or glycine, which is at position 98 of SEQ ID NO:2; or b) proline, which is at position 5 of SEQ ID NO:3, glycine, which is at position 38 of SEQ ID NO:3, arginine, which is at position 39 of SEQ ID NO:3, isoleucine, which is at position 97 of SEQ ID NO:3, and / or glycine, which is at position 98 of SEQ ID NO:3. Embodiment 40. A polypeptide according to any one of the preceding embodiments, wherein the variant IgG Fc polypeptide comprises the following amino acid sequence: a) SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146 or SEQ ID NO:147; or b) SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156 or SEQ ID NO:157. Embodiment 41. A polypeptide comprising the amino acid sequence of SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, or SEQ ID NO:157. Embodiment 42. A polypeptide comprising a variant IgG Fc polypeptide, wherein the variant IgG Fc polypeptide comprises: a) a tyrosine or tryptophan at the position corresponding to position 138 of SEQ ID NO: 1, a tyrosine or tryptophan at the position corresponding to position 137 of SEQ ID NO: 2, a tyrosine or tryptophan at the position corresponding to position 137 of SEQ ID NO: 3, or a tyrosine or tryptophan at the position corresponding to position 138 of SEQ ID NO: 4; or b) a tyrosine or tryptophan at a position corresponding to position 154 of SEQ ID NO:16, a tyrosine or tryptophan at a position corresponding to position 154 of SEQ ID NO:80 or SEQ ID NO:117, or a tyrosine or tryptophan at a position corresponding to position 154 of SEQ ID NO:81 or SEQ ID NO:118. Embodiment 43. A polypeptide according to any one of the preceding embodiments, wherein the variant IgG Fc polypeptide comprises: a) tyrosine or tryptophan at position 138 of SEQ ID NO: 1, tyrosine or tryptophan at position 137 of SEQ ID NO: 2, tyrosine or tryptophan at position 137 of SEQ ID NO: 3, or tyrosine or tryptophan at position 138 of SEQ ID NO: 4; or b) tyrosine or tryptophan at position 154 of SEQ ID NO:16, tyrosine or tryptophan at position 154 of SEQ ID NO:80 or SEQ ID NO:117, or tyrosine or tryptophan at a position corresponding to position 154 of SEQ ID NO:81 or SEQ ID NO:118. Embodiment 44. A polypeptide according to any of the preceding embodiments, wherein the variant IgG Fc polypeptide comprises the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:109, SEQ ID NO:111, SEQ ID NO:113, SEQ ID NO:115, SEQ ID NO:119, SEQ ID NO:121 or SEQ ID NO:123. Embodiment 45. A polypeptide comprising the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:109, SEQ ID NO:111, SEQ ID NO:113, SEQ ID NO:115, SEQ ID NO:119, SEQ ID NO:121 or SEQ ID NO:123. Embodiment 46. A contiguous polypeptide comprising a polypeptide according to any one of the preceding embodiments and a glucagon-like peptide-1 (GLP1) polypeptide. Embodiment 47. A contiguous polypeptide comprising a polypeptide according to any one of the preceding embodiments and a glucagon polypeptide. Embodiment 48. A polypeptide comprising a variant IgG Fc polypeptide, wherein the variant IgG Fc polypeptide comprises: a) a serine at a position corresponding to position 138 of SEQ ID NO: 1, a serine at a position corresponding to position 137 of SEQ ID NO: 2, a serine at a position corresponding to position 137 of SEQ ID NO: 3, a serine at a position corresponding to position 138 of SEQ ID NO: 4, a serine at a position corresponding to position 154 of SEQ ID NO: 16, a serine at a position corresponding to position 154 of SEQ ID NO: 80 or SEQ ID NO: 117, or a serine at a position corresponding to position 154 of SEQ ID NO: 81 or SEQ ID NO: 118; b) an alanine at a position corresponding to position 140 of SEQ ID NO: 1, an alanine at a position corresponding to position 139 of SEQ ID NO: 2, an alanine at a position corresponding to position 139 of SEQ ID NO: 3, an alanine at a position corresponding to position 140 of SEQ ID NO: 4, an alanine at a position corresponding to position 156 of SEQ ID NO: 16, an alanine at a position corresponding to position 156 of SEQ ID NO: 80 or SEQ ID NO: 117, or an alanine at a position corresponding to position 156 of SEQ ID NO: 81 or SEQ ID NO: 118; and / or c) a threonine at a position corresponding to position 181 of SEQ ID NO:1, a threonine at a position corresponding to position 180 of SEQ ID NO:2, a threonine at a position corresponding to position 180 of SEQ ID NO:3, a threonine at a position corresponding to position 181 of SEQ ID NO:4, a threonine at a position corresponding to position 197 of SEQ ID NO:16, a threonine at a position corresponding to position 197 of SEQ ID NO:80 or SEQ ID NO:117, or a threonine at a position corresponding to position 197 of SEQ ID NO:81 or SEQ ID NO:118. Embodiment 49. A polypeptide according to any one of the preceding embodiments, wherein the variant IgG Fc polypeptide comprises: a) serine at position 138 of SEQ ID NO: 1, serine at position 137 of SEQ ID NO: 2, serine at position 137 of SEQ ID NO: 3, serine at position 138 of SEQ ID NO: 4, serine at position 154 of SEQ ID NO: 16, serine at position 154 of SEQ ID NO: 80 or SEQ ID NO: 117, or serine at position 154 of SEQ ID NO: 81 or SEQ ID NO: 118; b) alanine at position 140 of SEQ ID NO: 1, alanine at position 139 of SEQ ID NO: 2, alanine at position 139 of SEQ ID NO: 3, alanine at position 140 of SEQ ID NO: 4, alanine at position 156 of SEQ ID NO: 16, alanine at position 156 of SEQ ID NO: 80 or SEQ ID NO: 117, or alanine at position 156 of SEQ ID NO: 81 or SEQ ID NO: 118; and / or; c) threonine at position 181 of SEQ ID NO:1, threonine at position 181 of SEQ ID NO:2, threonine at position 181 of SEQ ID NO:3, threonine at position 181 of SEQ ID NO:4, threonine at position 197 of SEQ ID NO:16, threonine at position 197 of SEQ ID NO:80 or SEQ ID NO:117, or threonine at position 197 of SEQ ID NO:81 or SEQ ID NO:118. Embodiment 50. A polypeptide according to any of the preceding embodiments, wherein the variant IgG Fc polypeptide comprises the amino acid sequence of SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:110, SEQ ID NO:112, SEQ ID NO:114, SEQ ID NO:116, SEQ ID NO:120, SEQ ID NO:122 or SEQ ID NO:124. Embodiment 51. A polypeptide comprising the amino acid sequence of SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:110, SEQ ID NO:112, SEQ ID NO:114, SEQ ID NO:116, SEQ ID NO:120, SEQ ID NO:122, or SEQ ID NO:124. Embodiment 52. A polypeptide according to any of the preceding embodiments, wherein the polypeptide is glycosylated. Embodiment 53. A polypeptide according to any one of embodiments 1 to 51, wherein the polypeptide is not glycosylated. Embodiment 54. A contiguous polypeptide comprising a polypeptide according to any one of embodiments 48 to 53 and a glucagon-like peptide-1 (GLP1) polypeptide. Embodiment 55. A contiguous polypeptide comprising a polypeptide according to any one of embodiments 48 to 53 and a glucagon polypeptide. Embodiment 56. A heterodimeric protein comprising a contiguous polypeptide according to embodiment 46 and a contiguous polypeptide according to embodiment 54. Embodiment 57. A heterodimeric protein comprising a contiguous polypeptide according to embodiment 47 and a contiguous polypeptide according to embodiment 55. Embodiment 58. A contiguous polypeptide or heterodimeric protein according to any one of embodiments 46, 47 or 54 to 57, wherein the GLP1 polypeptide is a wild-type GLP1 polypeptide, which optionally comprises the amino acid sequence SEQ ID NO:85. Embodiment 59. The contiguous polypeptide or heterodimeric protein according to any one of embodiments 46, 47 or 54 to 58, wherein the GLP1 polypeptide is a variant GLP1 polypeptide. Embodiment 60. A contiguous polypeptide or heterodimeric protein according to any one of embodiments 46, 47, or 54 to 59, wherein the GLP1 polypeptide comprises the amino acid sequence of SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:98 or SEQ ID NO:99. Embodiment 61. A contiguous polypeptide or heterodimeric protein according to any one of embodiments 46, 47 or 54 to 60, wherein the glucagon polypeptide is a wild-type glucagon polypeptide, which optionally comprises the amino acid sequence SEQ ID NO:21. Embodiment 62. The contiguous polypeptide or heterodimeric protein of any one of Embodiments 46, 47, or 54 to 61, wherein the glucagon polypeptide is a variant glucagon polypeptide. Embodiment 63. A heterodimeric protein comprising: i) a first variant canine IgG Fc polypeptide comprising at least one amino acid modification relative to a first wild-type canine IgG Fc polypeptide, and a second variant canine IgG Fc polypeptide comprising at least one amino acid modification relative to a second wild-type canine IgG Fc polypeptide; or ii) a first variant feline IgG Fc polypeptide comprising at least one amino acid modification relative to a first wild-type feline IgG Fc polypeptide, and a second variant feline IgG Fc polypeptide comprising at least one amino acid modification relative to a second wild-type feline IgG Fc polypeptide, wherein: a) the first variant canine IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to position 138 of SEQ ID NO:1, position 137 of SEQ ID NO:2, position 137 of SEQ ID NO:3, or position 138 of SEQ ID NO:4; b) the second variant canine IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to position 138, position 140, and / or position 181 of SEQ ID NO: 1, position 137, position 139, and / or position 180 of SEQ ID NO: 2, position 137, position 139, and / or position 180 of SEQ ID NO: 3, or position 138, position 140, and / or position 181 of SEQ ID NO: 4; c) the first variant feline IgG Fc polypeptide comprises an amino acid substitution at position 154, position 156 and / or position 197 corresponding to SEQ ID NO:6, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:117 or SEQ ID NO:118; and / or d) the second variant feline IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to position 154, position 156, and / or position 197 of SEQ ID NO:6, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:117, or SEQ ID NO:118. Embodiment 64. A heterodimeric protein according to Embodiment 63, wherein the first wild-type canine IgG Fc polypeptide and the second wild-type canine IgG Fc polypeptide are from the same IgG subtype and / or the first wild-type feline IgG Fc polypeptide and the second wild-type feline IgG Fc polypeptide are from the same IgG subtype. Embodiment 65. A heterodimeric protein according to Embodiment 63, wherein the first wild-type canine IgG Fc polypeptide and the second wild-type canine IgG Fc polypeptide are from different IgG subtypes and / or the first wild-type feline IgG Fc polypeptide and the second wild-type feline IgG Fc polypeptide are from the same IgG subtype. Embodiment 66. The heterodimeric protein of any one of Embodiments 63 to 65, wherein: a) said first variant canine IgG Fc polypeptide comprises a tyrosine or tryptophan at the position corresponding to position 138 of SEQ ID NO: 1, position 137 of SEQ ID NO: 2, position 137 of SEQ ID NO: 3, or position 138 of SEQ ID NO: 4; and / or b) said first variant feline IgG Fc polypeptide comprises a tryptophan at the position corresponding to position 154 of SEQ ID NO:6, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:117 or SEQ ID NO:118. Embodiment 67. The heterodimeric protein of any one of Embodiments 63 to 66, wherein: a) said second variant canine IgG Fc polypeptide comprises a serine at a position corresponding to position 138 of SEQ ID NO: 1, an alanine at a position corresponding to position 140 of SEQ ID NO: 1, and / or a threonine at a position corresponding to position 181 of SEQ ID NO: 1, a serine at a position corresponding to position 137 of SEQ ID NO: 2, an alanine at a position corresponding to position 139 of SEQ ID NO: 2, and / or a threonine at a position corresponding to position 180 of SEQ ID NO: 2, a serine at a position corresponding to position 137 of SEQ ID NO: 3, an alanine at a position corresponding to position 139 of SEQ ID NO: 3, and / or a threonine at a position corresponding to position 180 of SEQ ID NO: 3, and / or a serine at a position corresponding to position 138 of SEQ ID NO: 4, an alanine at a position corresponding to position 140 of SEQ ID NO: 4, and / or a threonine at a position corresponding to position 181 of SEQ ID NO: 4; and / or b) the second variant feline IgG Fc polypeptide comprises a serine at a position corresponding to position 154 of SEQ ID NO:6, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:117 or SEQ ID NO:118, an alanine at a position corresponding to position 156 thereof, and / or a threonine at a position corresponding to position 197 thereof. Embodiment 68. The heterodimeric protein of any one of Embodiments 63 to 67, wherein: a) said first variant canine IgG Fc polypeptide comprises the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:109, SEQ ID NO:111, SEQ ID NO:113 or SEQ ID NO:115; and / or b) said first variant feline IgG Fc polypeptide comprises the amino acid sequence of SEQ ID NO:119, SEQ ID NO:121 or SEQ ID NO:123. Embodiment 69. The heterodimeric protein of any one of Embodiments 63 to 68, wherein: a) said second variant canine IgG Fc polypeptide comprises the amino acid sequence of SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:110, SEQ ID NO:112, SEQ ID NO:114 or SEQ ID NO:116; and / or b) said second variant feline IgG Fc polypeptide comprises the amino acid sequence of SEQ ID NO:120, SEQ ID NO:122 or SEQ ID NO:123. Embodiment 70. A polypeptide, contiguous polypeptide or heterodimeric protein according to any one of embodiments 42 to 69, wherein the variant IgG Fc polypeptide, the first variant IgG Fc polypeptide, and / or the second variant IgG Fc polypeptide comprises at least one additional amino acid modification relative to a wild-type IgG Fc polypeptide and has an enhanced binding affinity for protein A relative to a wild-type IgG Fc polypeptide. Embodiment 71. The polypeptide, contiguous polypeptide or heterodimeric protein of any one of Embodiments 42 to 70, wherein the variant IgG Fc polypeptide, the first variant IgG Fc polypeptide, and / or the second variant IgG Fc polypeptide comprises: a) an amino acid substitution at the position corresponding to position 21 of SEQ ID NO: 1, an amino acid substitution at the position corresponding to position 23 of SEQ ID NO: 1, an amino acid substitution at the position corresponding to position 25 of SEQ ID NO: 1, an amino acid substitution at the position corresponding to position 80 of SEQ ID NO: 1, an amino acid substitution at the position corresponding to position 205 of SEQ ID NO: 1, and / or an amino acid substitution at the position corresponding to position 207 of SEQ ID NO: 1; b) an amino acid substitution at the position corresponding to position 21 of SEQ ID NO: 3, an amino acid substitution at the position corresponding to position 23 of SEQ ID NO: 3, and / or an amino acid substitution at the position corresponding to position 24 of SEQ ID NO: 3; or c) an amino acid substitution at the position corresponding to position 21 of SEQ ID NO:4, an amino acid substitution at the position corresponding to position 23 of SEQ ID NO:4, an amino acid substitution at the position corresponding to position 25 of SEQ ID NO:4, an amino acid substitution at the position corresponding to position 80 of SEQ ID NO:4, and / or an amino acid substitution at the position corresponding to position 207 of SEQ ID NO:4. Embodiment 72. The polypeptide, contiguous polypeptide or heterodimeric protein of any one of Embodiments 42 to 71, wherein the variant IgG Fc polypeptide, the first variant IgG Fc polypeptide and / or the second variant IgG Fc polypeptide comprises: a) an amino acid substitution at position 21 of SEQ ID NO: 1, an amino acid substitution at position 23 of SEQ ID NO: 1, an amino acid substitution at position 25 of SEQ ID NO: 1, an amino acid substitution at position 80 of SEQ ID NO: 1, an amino acid substitution at position 205 of SEQ ID NO: 1, and / or an amino acid substitution at position 207 of SEQ ID NO: 1; b) an amino acid substitution at position 21 of SEQ ID NO:3, an amino acid substitution at position 23 of SEQ ID NO:3, and / or an amino acid substitution at position 24 of SEQ ID NO:3; or c) an amino acid substitution at position 21 of SEQ ID NO:4, an amino acid substitution at position 23 of SEQ ID NO:4, an amino acid substitution at position 25 of SEQ ID NO:4, an amino acid substitution at position 80 of SEQ ID NO:4, and / or an amino acid substitution at position 207 of SEQ ID NO:4. Embodiment 73. The polypeptide, contiguous polypeptide or heterodimeric protein of any one of Embodiments 42 to 72, wherein the variant IgG Fc polypeptide, the first variant IgG Fc polypeptide and / or the second variant IgG Fc polypeptide comprises: a) a threonine at the position corresponding to position 21 of SEQ ID NO: 1, a leucine at the position corresponding to position 23 of SEQ ID NO: 1, an alanine at the position corresponding to position 25 of SEQ ID NO: 1, a glycine at the position corresponding to position 80 of SEQ ID NO: 1, an alanine at the position corresponding to position 205 of SEQ ID NO: 1, and / or a histidine at the position corresponding to position 207 of SEQ ID NO: 1; b) a threonine at the position corresponding to position 21 of SEQ ID NO: 3, a leucine at the position corresponding to position 23 of SEQ ID NO: 3, and / or an isoleucine at the position corresponding to position 24 of SEQ ID NO: 3; or c) a threonine at a position corresponding to position 21 of SEQ ID NO:4, a leucine at a position corresponding to position 23 of SEQ ID NO:4, an alanine at a position corresponding to position 25 of SEQ ID NO:4, a glycine at a position corresponding to position 80 of SEQ ID NO:4, and / or a histidine at a position corresponding to position 207 of SEQ ID NO:4. Embodiment 74. The polypeptide, contiguous polypeptide or heterodimeric protein of any one of Embodiments 42 to 73, wherein the variant IgG Fc polypeptide, the first variant IgG Fc polypeptide and / or the second variant IgG Fc polypeptide comprises: a) threonine at position 21 of SEQ ID NO: 1, leucine at position 23 of SEQ ID NO: 1, alanine at position 25 of SEQ ID NO: 1, glycine at position 80 of SEQ ID NO: 1, alanine at position 205 of SEQ ID NO: 1, and / or histidine at position 207 of SEQ ID NO: 1; b) threonine, which is at position 21 of SEQ ID NO:3, leucine, which is at position 23 of SEQ ID NO:3, and / or isoleucine, which is at position 24 of SEQ ID NO:3; or c) threonine at position 21 of SEQ ID NO:4, leucine at position 23 of SEQ ID NO:4, alanine at position 25 of SEQ ID NO:4, glycine at position 80 of SEQ ID NO:4, and / or histidine at position 207 of SEQ ID NO:4. Embodiment 75. A polypeptide, contiguous polypeptide or heterodimeric protein according to any one of embodiments 42 to 74, wherein the variant IgG Fc polypeptide, the first variant IgG Fc polypeptide, and / or the second variant IgG Fc polypeptide comprises at least one additional amino acid modification relative to the wild-type IgG Fc polypeptide and has a reduced binding affinity for CD16 relative to the wild-type IgG Fc polypeptide. Embodiment 76. The polypeptide, contiguous polypeptide or heterodimeric protein of any one of Embodiments 42 to 75, wherein the variant IgG Fc polypeptide, the first variant IgG Fc polypeptide and / or the second variant IgG Fc polypeptide comprises: a) an amino acid substitution at the position corresponding to position 5 of SEQ ID NO: 2, an amino acid substitution at the position corresponding to position 38 of SEQ ID NO: 2, an amino acid substitution at the position corresponding to position 39 of SEQ ID NO: 2, an amino acid substitution at the position corresponding to position 97 of SEQ ID NO: 2, and / or an amino acid substitution at the position corresponding to position 98 of SEQ ID NO: 2; or b) an amino acid substitution at the position corresponding to position 5 of SEQ ID NO:3, an amino acid substitution at the position corresponding to position 38 of SEQ ID NO:3, an amino acid substitution at the position corresponding to position 39 of SEQ ID NO:3, an amino acid substitution at the position corresponding to position 97 of SEQ ID NO:3, and / or an amino acid substitution at the position corresponding to position 98 of SEQ ID NO:3. Embodiment 77. The polypeptide, contiguous polypeptide or heterodimeric protein of any one of Embodiments 42 to 76, wherein the variant IgG Fc polypeptide, the first variant IgG Fc polypeptide and / or the second variant IgG Fc polypeptide comprises: a) an amino acid substitution at position 5 of SEQ ID NO:2, an amino acid substitution at position 38 of SEQ ID NO:2, an amino acid substitution at position 39 of SEQ ID NO:2, an amino acid substitution at position 97 of SEQ ID NO:2, and / or an amino acid substitution at position 98 of SEQ ID NO:2; or b) an amino acid substitution at position 5 of SEQ ID NO:3, an amino acid substitution at position 38 of SEQ ID NO:3, an amino acid substitution at position 39 of SEQ ID NO:3, an amino acid substitution at position 97 of SEQ ID NO:3, and / or an amino acid substitution at position 98 of SEQ ID NO:3. Embodiment 78. The polypeptide, contiguous polypeptide or heterodimeric protein of any one of Embodiments 42 to 77, wherein the variant IgG Fc polypeptide, the first variant IgG Fc polypeptide and / or the second variant IgG Fc polypeptide comprises: a) proline at the position corresponding to position 5 of SEQ ID NO:2, glycine at the position corresponding to position 38 of SEQ ID NO:2, arginine at the position corresponding to position 39 of SEQ ID NO:2, isoleucine at the position corresponding to position 97 of SEQ ID NO:2, and / or glycine at the position corresponding to position 98 of SEQ ID NO:2; or b) proline at the position corresponding to position 5 of SEQ ID NO:3, glycine at the position corresponding to position 38 of SEQ ID NO:3, arginine at the position corresponding to position 39 of SEQ ID NO:3, isoleucine at the position corresponding to position 97 of SEQ ID NO:3, and / or glycine at the position corresponding to position 98 of SEQ ID NO:3. Embodiment 79. The polypeptide, contiguous polypeptide or heterodimeric protein of any one of Embodiments 42 to 78, wherein the variant IgG Fc polypeptide, the first variant IgG Fc polypeptide and / or the second variant IgG Fc polypeptide comprises: a) proline, which is at position 5 of SEQ ID NO:2, glycine, which is at position 38 of SEQ ID NO:2, arginine, which is at position 39 of SEQ ID NO:2, isoleucine, which is at position 97 of SEQ ID NO:2, and / or glycine, which is at position 98 of SEQ ID NO:2; or b) proline, which is at position 5 of SEQ ID NO:3, glycine, which is at position 38 of SEQ ID NO:3, arginine, which is at position 39 of SEQ ID NO:3, isoleucine, which is at position 97 of SEQ ID NO:3, and / or glycine, which is at position 98 of SEQ ID NO:3. Embodiment 80. A polypeptide, contiguous polypeptide or heterodimeric protein according to any one of embodiments 42 to 79, wherein the variant IgG Fc polypeptide, the first variant IgG Fc polypeptide and / or the second variant IgG Fc polypeptide comprises at least one additional amino acid modification relative to a wild-type canine IgG Fc polypeptide and has a reduced binding affinity for C1q relative to a wild-type canine IgG Fc polypeptide. Embodiment 81. A polypeptide, contiguous polypeptide or heterodimeric protein according to any one of Embodiments 42 to 80, wherein the variant IgG Fc polypeptide, the first variant IgG Fc polypeptide and / or the second variant IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to position 93 of SEQ ID NO:2, or an amino acid substitution at a position corresponding to position 93 of SEQ ID NO:3. Embodiment 82. A polypeptide, a contiguous polypeptide or a heterodimeric protein according to any one of Embodiments 42 to 81, wherein the variant IgG Fc polypeptide, the first variant IgG Fc polypeptide and / or the second variant IgG Fc polypeptide comprises an amino acid substitution at position 93 of SEQ ID NO:2, or an amino acid substitution at position 93 of SEQ ID NO:3. Embodiment 83. A polypeptide, a contiguous polypeptide or a heterodimeric protein according to any one of Embodiments 42 to 82, wherein the variant IgG Fc polypeptide, the first variant IgG Fc polypeptide and / or the second variant IgG Fc polypeptide comprises an arginine at a position corresponding to position 93 of SEQ ID NO:2, or an arginine at a position corresponding to position 93 of SEQ ID NO:3. Embodiment 84. A polypeptide, a contiguous polypeptide or a heterodimeric protein according to any one of Embodiments 42 to 83, wherein the variant IgG Fc polypeptide, the first variant IgG Fc polypeptide and / or the second variant IgG Fc polypeptide comprises arginine at position 93 of SEQ ID NO:2, or arginine at position 93 of SEQ ID NO:3. Embodiment 85. A polypeptide, contiguous polypeptide or heterodimeric protein according to any one of embodiments 1 to 84, wherein the polypeptide is an antibody, antibody fusion or fusion polypeptide. Embodiment 86. A contiguous polypeptide comprising: a) a first glucagon-like peptide-1 (GLP1) polypeptide (GLP1A); b) a first connector (L1); c) Fc polypeptide (Fc) of a companion animal species; d) an optional second linker (L2); and e) optionally a second GLP1 polypeptide (GLP1B). Embodiment 87. The contiguous polypeptide of embodiment 65, comprising: Formula (I): GLP1A-L1-Fc; or Formula (II): Fc-L1-GLP1A. Embodiment 88. The contiguous polypeptide of embodiment 65, comprising: Formula (III): GLP1A—L1—Fc—L2—GLP1B. Embodiment 89. The contiguous polypeptide of any one of embodiments 86 to 88, wherein GLP1B, if present, comprises the same amino acid sequence as GLP1A. Embodiment 90. A contiguous polypeptide comprising: a) glucagon-like peptide-1 (GLP1) polypeptide; b) a first connector (L1); c) Fc polypeptide (Fc); d) a second connector (L2); and e) Glucagon polypeptide (Gluc). Embodiment 91. The contiguous polypeptide of embodiment 90, comprising: Formula (IV): GLP1-L1-Fc-L2-Gluc; or Formula (V): Gluc—L1—Fc—L2—GLP1. Embodiment 92. The contiguous polypeptide of any one of embodiments 86 to 91, wherein GLP1A, GLP1 and / or GLP1B, if present, comprise a wild-type GLP1 polypeptide. Embodiment 93. The contiguous polypeptide of any one of embodiments 86 to 92, wherein GLP1A, GLP1 and / or GLP1B, if present, comprise a variant GLP1 polypeptide. Embodiment 94. The contiguous polypeptide of any one of embodiments 86 to 93, wherein GLP1A, GLP1 and / or GLP1B, if present, comprises the amino acid sequence of SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:98 or SEQ ID NO:99. Embodiment 95. The contiguous polypeptide of any one of embodiments 86 to 94, wherein the glucagon polypeptide comprises a wild-type glucagon polypeptide, optionally comprising the amino acid sequence of SEQ ID NO:21. Embodiment 96. The contiguous polypeptide of any one of embodiments 86 to 95, wherein the glucagon polypeptide is a variant glucagon polypeptide. Embodiment 97. The contiguous polypeptide of any one of Embodiments 86 to 96, wherein the Fc polypeptide is human IgG Fc. Embodiment 98. The contiguous polypeptide of any one of embodiments 86 to 97, wherein the Fc polypeptide is human IgG1 Fc, IgG2 Fc, IgG3 Fc, or IgG4 Fc. Embodiment 99. The contiguous polypeptide of any one of Embodiments 86 to 98, wherein the Fc polypeptide is an Fc of a companion animal species. Embodiment 100. The contiguous polypeptide of any one of embodiments 86 to 97 or 99, wherein the Fc polypeptide comprises: a) canine IgG-A Fc, IgG-B Fc, IgG-C Fc or IgG-D Fc; b) equine IgG1 Fc, IgG2 Fc, IgG3 Fc, IgG4 Fc, IgG5 Fc, IgG6 Fc or IgG7 Fc; or c) Feline IgG1a Fc, IgG1b Fc or IgG2 Fc. Embodiment 101. The contiguous polypeptide of any one of Embodiments 86 to 100, wherein the Fc polypeptide is a wild-type IgG Fc polypeptide. Embodiment 102. The contiguous polypeptide of any one of Embodiments 86 to 100, wherein the Fc polypeptide is a variant IgG Fc polypeptide. Embodiment 103. The contiguous polypeptide of any one of embodiments 86 to 102, wherein the Fc polypeptide comprises a polypeptide, a contiguous polypeptide, or a heterodimeric protein of any one of embodiments 1 to 84. Embodiment 104. The contiguous polypeptide of any one of embodiments 85 to 102, wherein the contiguous polypeptide has a longer serum half-life than the wild-type GLP1 polypeptide. Embodiment 105. The contiguous polypeptide of any one of embodiments 86 to 104, wherein L1 and L2, if present, are each independently a flexible linker. Embodiment 106. A contiguous polypeptide according to any one of embodiments 86 to 105, wherein the amino acid sequences of L1 and L2, if present, each independently comprise 100%, at least 95%, at least 90%, at least 85% serine and / or glycine amino acid residues. Embodiment 107. The contiguous polypeptide of any one of Embodiments 86 to 106, wherein the contiguous polypeptide comprises an extension at its C-terminus. Embodiment 108. The contiguous polypeptide of any one of embodiments 86 to 107, wherein the contiguous polypeptide comprises one glycine residue, two glycine residues, three glycine residues, four glycine residues, five glycine residues, six glycine residues, seven glycine residues, eight glycine residues, or greater than eight glycine residues at its C-terminus. Embodiment 109. The contiguous polypeptide of any one of embodiments 86 to 108, wherein the contiguous polypeptide comprises at its C-terminus the amino acid sequence of SEQ ID NO:88, SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, or SEQ ID NO:95. Embodiment 110. The contiguous polypeptide of any one of embodiments 86 to 109, wherein the contiguous polypeptide comprises: a) The amino acid sequences SEQ ID NO:23; SEQ ID NO:24; SEQ ID NO:25; SEQ ID NO:26; SEQ ID NO:27; SEQ ID NO:28; SEQ ID NO:29; SEQ ID NO:30; SEQ ID NO:31; SEQ ID NO:32; SEQ ID NO:33; SEQ ID NO:34; SEQ ID NO:35; SEQ ID NO:36; SEQ ID NO:37; SEQ ID NO:38; SEQ ID NO:39; SEQ ID NO:40; SEQ ID NO:41; SEQ ID NO:42; SEQ ID NO:43; SEQ ID NO:44; SEQ ID NO:45; SEQ ID NO:46; SEQ ID NO:47, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105 or SEQ ID NO:106; or b) The amino acid sequences SEQ ID NO:52; SEQ ID NO:53; SEQ ID NO:54; SEQ ID NO:55; SEQ ID NO:56; SEQ ID NO:57; SEQ ID NO:58; or SEQ ID NO:59. Embodiment 111. A polypeptide comprising the amino acid sequence SEQ ID NO:23; SEQ ID NO:24; SEQ ID NO:25; SEQ ID NO:26; SEQ ID NO:27; SEQ ID NO:28; SEQ ID NO:29; SEQ ID NO:30; SEQ ID NO:31; SEQ ID NO:36; SEQ ID NO:37; SEQ ID NO:38; SEQ ID NO:39; SEQ ID NO:40; SEQ ID NO:41; SEQ ID NO:42; SEQ ID NO:43; SEQ ID NO:44; SEQ ID NO:45; SEQ ID NO:46; SEQ ID NO:47, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:52; SEQ ID NO:53; SEQ ID NO:54; SEQ ID NO:55; SEQ ID NO:56; SEQ ID NO:57; SEQ ID NO:58; SEQ ID NO:59; SEQ ID NO:103; SEQ ID NO:104, SEQ ID NO:105 or SEQ ID NO:106. Embodiment 112. A polypeptide, heterodimeric protein or contiguous polypeptide according to any of the preceding embodiments, wherein the at least one amino acid modification or substitution comprises an amino acid substitution with an amino acid derivative. Embodiment 113. An isolated nucleic acid encoding a polypeptide, heterodimeric protein or contiguous polypeptide according to any of the preceding embodiments. Embodiment 114. A host cell comprising the nucleic acid according to embodiment 113. Embodiment 115. A method of producing a polypeptide, comprising culturing the host cell according to embodiment 114 and isolating the polypeptide. Embodiment 116. A pharmaceutical composition comprising a polypeptide, a heterodimeric protein or a contiguous polypeptide according to any one of Embodiments 1 to 112, and a pharmaceutically acceptable carrier. Embodiment 117. A method of increasing cAMP production in a cell, the method comprising exposing the cell to a polypeptide, heterodimeric protein, adjacent polypeptide or pharmaceutical composition according to any one of embodiments 1 to 112 or 116 under conditions that allow the polypeptide, heterodimeric protein or adjacent polypeptide to bind to GLP1R. Embodiment 118. A method according to embodiment 117, wherein the cell is exposed to the polypeptide, heterodimeric protein, contiguous polypeptide or pharmaceutical composition ex vivo. Embodiment 119. The method of embodiment 117, wherein the cell is exposed to the polypeptide, heterodimeric protein, contiguous polypeptide or pharmaceutical composition in vivo. Embodiment 120. The method of any one of Embodiments 118 to 119, wherein the cell is a human cell, a canine cell, a feline cell, or an equine cell. Embodiment 121. A method of delivering a polypeptide to a subject, comprising parenterally administering the polypeptide, heterodimeric protein, contiguous polypeptide, or pharmaceutical composition of any one of Embodiments 1 to 112 or 116. Embodiment 122. A method of delivering a polypeptide to a subject, comprising administering the polypeptide, heterodimeric protein, contiguous polypeptide or pharmaceutical composition of any one of embodiments 1 to 112 or 116 via an intramuscular route, an intraperitoneal route, an intracerebrospinal route, a subcutaneous route, an intraarterial route, an intrasynovial route, an intrathecal route or an inhalation route. Embodiment 123. A method for treating a subject suffering from diabetes or obesity, the method comprising administering to the subject a therapeutically effective amount of a polypeptide, heterodimeric protein, contiguous polypeptide or pharmaceutical composition according to any one of Embodiments 1 to 112 or 116. Embodiment 124. The method according to embodiment 123, comprising administering insulin, a DPP4 inhibitor, a SGLT2 inhibitor, a biguanide, a sulfonylurea, a meglitinide derivative, an α-glucosidase inhibitor, a thiazolidinedione (TZD), an amylinomimetic, a bile acid sequestrant, or a dopamine agonist. Embodiment 125. A method according to any one of Embodiments 121 to 124, wherein the subject is a human subject. Embodiment 126. The method of any one of Embodiments 121 to 124, wherein the subject is a companion animal species. Embodiment 127. The method of claim 126, wherein the companion animal species is canine, equine, or feline. This application further includes the following: 1. A polypeptide comprising a variant IgG Fc polypeptide comprising at least one amino acid modification relative to a wild-type IgG Fc polypeptide of a companion animal species, wherein the variant IgG Fc polypeptide has an enhanced binding affinity for protein A relative to the wild-type IgG Fc polypeptide. 2. A polypeptide comprising a variant IgG Fc polypeptide comprising at least one amino acid modification relative to a wild-type IgG Fc polypeptide of a companion animal species, wherein the variant IgG Fc polypeptide has reduced binding affinity for C1q and / or CD16 relative to the wild-type IgG Fc polypeptide. 3. A polypeptide according to item 1 or 2, wherein the variant IgG Fc polypeptide binds to C1q and / or CD16 with a dissociation constant (K d ) is greater than 5x 10 -6 M, greater than 1x 10 -5 M, greater than 5x 10 -5 M, greater than 1x 10 -4 M, greater than 5x 10 - 4 M or greater than 1x 10 -3 M, as determined by biofilm interferometry. 4. The polypeptide according to any of the preceding items, wherein the variant IgG Fc polypeptide has an enhanced binding affinity to Protein A relative to the wild-type IgG Fc polypeptide. 5. A polypeptide according to any one of the preceding items, wherein the variant IgG Fc polypeptide binds to protein A with a dissociation constant (K d ) is less than 5x 10 -6 M, less than 1x 10 -6 M, less than 5x 10 -7 M, less than 1x 10 -7 M, less than 5x10 -8 M, less than 1x 10 -8 M, less than 5x 10 -9 M, less than 1x 10 -9 M, less than 5x 10 -10 M, less than 1x 10 -10 M, less than 5x10 -11 M, less than 1x 10 -11 M, less than 5x 10 -12 M or less than 1x 10 -12 M, as determined by biofilm interferometry. 6. The polypeptide according to any of the preceding items, wherein the companion animal species is canine, feline or equine. 7. A polypeptide according to any one of the preceding items, wherein the wild-type IgG Fc polypeptide is a) canine IgG-A Fc, IgG-B Fc, IgG-C Fc or IgG-D Fc; b) equine IgG1 Fc, IgG2 Fc, IgG3 Fc, IgG4 Fc, IgG5 Fc, IgG6 Fc or IgG7 Fc; or c) Feline IgG1a Fc, IgG1b Fc or IgG2 Fc. 8. A polypeptide comprising a variant IgG Fc polypeptide comprising at least one amino acid modification to the hinge region relative to a wild-type feline or equine IgG Fc polypeptide, wherein the variant IgG Fc polypeptide has increased recombinant production and / or increased hinge disulfide bond formation relative to the wild-type IgG Fc polypeptide as determined by SDS-PAGE analysis under reducing and / or non-reducing conditions. 9. The polypeptide according to any one of the preceding items, wherein the variant IgG Fc polypeptide comprises: a) at least one amino acid substitution relative to a wild-type feline IgG Fc polypeptide, wherein the variant IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to position 16 of SEQ ID NO: 16, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 117 or SEQ ID NO: 118; b) at least one amino acid substitution relative to a wild-type equine IgG Fc polypeptide, wherein the variant IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to position 3 of SEQ ID NO: 129; and / or c) at least one amino acid substitution relative to a wild-type equine IgG Fc polypeptide, wherein the variant IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to position 20 of SEQ ID NO:129. 10. The polypeptide according to any one of the preceding items, wherein the variant IgG Fc polypeptide comprises: a) at least one amino acid substitution relative to a wild-type feline IgG Fc polypeptide, wherein the variant IgG Fc polypeptide comprises an amino acid substitution at position 16 of SEQ ID NO: 16, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 117 or SEQ ID NO: 118; b) at least one amino acid substitution relative to a wild-type equine IgG Fc polypeptide, wherein the variant IgG Fc polypeptide comprises an amino acid substitution at position 3 of SEQ ID NO: 129; and / or c) at least one amino acid substitution relative to a wild-type equine IgG Fc polypeptide, wherein the variant IgG Fc polypeptide comprises an amino acid substitution at position 20 of SEQ ID NO: 129. 11. The polypeptide according to any of the preceding items, wherein the variant IgG Fc polypeptide comprises: a) at least one amino acid substitution relative to a wild-type feline IgG Fc polypeptide, wherein the variant IgG Fc polypeptide comprises a proline at or at a position corresponding to position 16 of SEQ ID NO: 16, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 117 or SEQ ID NO: 118; b) at least one amino acid substitution relative to a wild-type equine IgG Fc polypeptide, wherein the variant IgG Fc polypeptide comprises a serine at position 3 of SEQ ID NO: 129, or at a position corresponding to position 3 of SEQ ID NO: 129; and / or c) at least one amino acid substitution relative to a wild-type equine IgG Fc polypeptide, wherein the variant IgG Fc polypeptide comprises a proline at position 20 of SEQ ID NO: 129 or at a position corresponding to position 20 of SEQ ID NO: 129. 12. The polypeptide according to any of the preceding items, wherein the variant IgG Fc polypeptide comprises a hinge region or a portion of a hinge region from an IgG Fc polypeptide of a different isotype. 13. The polypeptide according to any of the preceding items, wherein the variant IgG Fc polypeptide comprises a hinge region or a portion of a hinge region from a wild-type feline IgG-1a Fc polypeptide, from a wild-type feline IgG-1b Fc polypeptide, or from a wild-type equine IgG1 Fc polypeptide. 14. A polypeptide according to one of the preceding items, wherein the variant IgG Fc polypeptide comprises SEQ ID NO: 19, SEQ ID NO: 125 or SEQ ID NO: 126, SEQ ID NO: 127, SEQ ID NO: 128, SEQ ID NO: SEQ ID NO: 129, SEQ ID NO: 130, SEQ ID NO: 131, SEQ ID NO: 132, SEQ ID NO: 133, SEQ ID N: 134, SEQ ID NO: 135. 15. A polypeptide comprising the amino acid sequence of SEQ ID NO:19, SEQ ID NO:125 or SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135. 16. A polypeptide comprising a variant IgG2 Fc polypeptide comprising at least one amino acid substitution relative to a wild-type feline IgG2 Fc polypeptide, wherein the at least one amino acid substitution is cysteine, and wherein the variant IgG2 Fc polypeptide is capable of forming at least one additional interchain disulfide linkage relative to the wild-type feline IgG2 Fc polypeptide. 17. A polypeptide according to any of the preceding items, wherein the variant IgG Fc polypeptide comprises at least one amino acid substitution relative to a wild-type feline IgG Fc polypeptide, wherein the at least one amino acid substitution is cysteine, and wherein the variant IgG Fc polypeptide is capable of forming at least one additional interchain disulfide bond relative to the wild-type feline IgG Fc polypeptide. 18. A polypeptide according to any of the preceding items, wherein the variant IgG Fc polypeptide comprises a cysteine ​​at a position corresponding to position 8, position 9, position 10, position 11, position 12, position 13, position 14, position 15 or position 16 of SEQ ID NO: 16. 19. A polypeptide according to any of the preceding items, wherein the variant IgG Fc polypeptide comprises a cysteine ​​at the position corresponding to position 14 of SEQ ID NO: 16. 20. The polypeptide according to any of the preceding items, wherein the variant IgG Fc polypeptide comprises a cysteine ​​at position 14 of SEQ ID NO: 16. 21. The polypeptide according to any one of the preceding items, wherein the variant IgG Fc polypeptide has an amino acid sequence SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:100, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO:120, SEQ ID NO:121, SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ: 154, SEQ ID NO: 155, SEQ ID NO: 156 or SEQ ID NO: 157 are at least 90% identical, at least 95% identical, at least 97% identical or at least 99% identical. 22. A polypeptide according to any one of the preceding items, wherein the variant IgG Fc polypeptide comprises SEQ ID NO: 17. 23. A polypeptide comprising the amino acid sequence of SEQ ID NO: 17. 24. The polypeptide according to any one of the preceding items, wherein the variant IgG Fc polypeptide comprises: a) an amino acid substitution at the position corresponding to position 21 of SEQ ID NO: 1, an amino acid substitution at the position corresponding to position 23 of SEQ ID NO: 1, an amino acid substitution at the position corresponding to position 25 of SEQ ID NO: 1, an amino acid substitution at the position corresponding to position 80 of SEQ ID NO: 1, an amino acid substitution at the position corresponding to position 205 of SEQ ID NO: 1, and / or an amino acid substitution at the position corresponding to position 207 of SEQ ID NO: 1; b) an amino acid substitution at the position corresponding to position 21 of SEQ ID NO: 3, an amino acid substitution at the position corresponding to position 23 of SEQ ID NO: 3, and / or an amino acid substitution at the position corresponding to position 24 of SEQ ID NO: 3; c) an amino acid substitution at the position corresponding to position 21 of SEQ ID NO:4, an amino acid substitution at the position corresponding to position 23 of SEQ ID NO:4, an amino acid substitution at the position corresponding to position 25 of SEQ ID NO:4, an amino acid substitution at the position corresponding to position 80 of SEQ ID NO:4, and / or an amino acid substitution at the position corresponding to position 207 of SEQ ID NO:4; d) an amino acid substitution at the position corresponding to position 15 of SEQ ID NO: 64, and / or an amino acid substitution at the position corresponding to position 203 of SEQ ID NO: 64; e) an amino acid substitution at the position corresponding to position 199 of SEQ ID NO: 67, and / or an amino acid substitution at the position corresponding to position 200 of SEQ ID NO: 67; and / or f) an amino acid substitution at a position corresponding to position 199 of SEQ ID NO:68, an amino acid substitution at a position corresponding to position 200 of SEQ ID NO:68, an amino acid substitution at a position corresponding to position 201 of SEQ ID NO:68, and / or an amino acid substitution at a position corresponding to position 202 of SEQ ID NO:68. 25. The polypeptide according to any one of the preceding items, wherein the variant IgG Fc polypeptide comprises: a) an amino acid substitution at position 21 of SEQ ID NO: 1, an amino acid substitution at position 23 of SEQ ID NO: 1, an amino acid substitution at position 25 of SEQ ID NO: 1, an amino acid substitution at position 80 of SEQ ID NO: 1, an amino acid substitution at position 205 of SEQ ID NO: 1, and / or an amino acid substitution at position 207 of SEQ ID NO: 1; b) an amino acid substitution at position 21 of SEQ ID NO:3, an amino acid substitution at position 23 of SEQ ID NO:3, and / or an amino acid substitution at position 24 of SEQ ID NO:3; c) an amino acid substitution at position 21 of SEQ ID NO:4, an amino acid substitution at position 23 of SEQ ID NO:4, an amino acid substitution at position 25 of SEQ ID NO:4, an amino acid substitution at position 80 of SEQ ID NO:4, and / or an amino acid substitution at position 207 of SEQ ID NO:4; d) an amino acid substitution at position 15 of SEQ ID NO:64, and / or an amino acid substitution at position 203 of SEQ ID NO:64; e) an amino acid substitution at position 199 of SEQ ID NO:67, and / or an amino acid substitution at position 200 of SEQ ID NO:67; and / or f) an amino acid substitution at position 199 of SEQ ID NO:68, an amino acid substitution at position 200 of SEQ ID NO:68, an amino acid substitution at position 201 of SEQ ID NO:68, and / or an amino acid substitution at position 202 of SEQ ID NO:68. 26. The polypeptide according to any one of the preceding items, wherein the variant IgG Fc polypeptide comprises: a) a threonine at the position corresponding to position 21 of SEQ ID NO: 1, a leucine at the position corresponding to position 23 of SEQ ID NO: 1, an alanine at the position corresponding to position 25 of SEQ ID NO: 1, a glycine at the position corresponding to position 80 of SEQ ID NO: 1, an alanine at the position corresponding to position 205 of SEQ ID NO: 1, and / or a histidine at the position corresponding to position 207 of SEQ ID NO: 1; b) a threonine at the position corresponding to position 21 of SEQ ID NO:3, a leucine at the position corresponding to position 23 of SEQ ID NO:3, and / or an isoleucine at the position corresponding to position 24 of SEQ ID NO:3; c) a threonine at the position corresponding to position 21 of SEQ ID NO:4, a leucine at the position corresponding to position 23 of SEQ ID NO:4, an alanine at the position corresponding to position 25 of SEQ ID NO:4, a glycine at the position corresponding to position 80 of SEQ ID NO:4, and / or a histidine at the position corresponding to position 207 of SEQ ID NO:4; d) a threonine or valine at the position corresponding to position 15 of SEQ ID NO: 64, and / or a tyrosine or valine at the position corresponding to position 203 of SEQ ID NO: 64; e) a leucine at the position corresponding to position 199 of SEQ ID NO:67, and / or a histidine at the position corresponding to position 200 of SEQ ID NO:67; and / or f) a leucine at a position corresponding to position 199 of SEQ ID NO:68, a histidine at a position corresponding to position 200 of SEQ ID NO:68, an asparagine at a position corresponding to position 201 of SEQ ID NO:68, and / or a histidine at a position corresponding to position 202 of SEQ ID NO:68. 27. The polypeptide according to any one of the preceding items, wherein the variant IgG Fc polypeptide comprises: a) threonine at position 21 of SEQ ID NO: 1, leucine at position 23 of SEQ ID NO: 1, alanine at position 25 of SEQ ID NO: 1, glycine at position 80 of SEQ ID NO: 1, alanine at position 205 of SEQ ID NO: 1, and / or histidine at position 207 of SEQ ID NO: 1; b) threonine, which is at position 21 of SEQ ID NO:3, leucine, which is at position 23 of SEQ ID NO:3, and / or isoleucine, which is at position 24 of SEQ ID NO:3; c) threonine at position 21 of SEQ ID NO:4, leucine at position 23 of SEQ ID NO:4, alanine at position 25 of SEQ ID NO:4, glycine at position 80 of SEQ ID NO:4, and / or histidine at position 207 of SEQ ID NO:4; d) threonine or valine, which is at position 15 of SEQ ID NO: 64, and / or tyrosine or valine, which is at position 203 of SEQ ID NO: 64; e) leucine, which is at position 199 of SEQ ID NO:67, and / or histidine, which is at position 200 of SEQ ID NO:67; and / or f) leucine at position 199 of SEQ ID NO:68, histidine at position 200 of SEQ ID NO:68, asparagine at position 201 of SEQ ID NO:68, and / or histidine at position 202 of SEQ ID NO:68. 28. The polypeptide according to any of the preceding items, wherein the variant IgG Fc polypeptide comprises the following amino acid sequence: a) SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62 or SEQ ID NO:84; or b) SEQ ID NO:19, SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:75 or SEQ ID NO:76. 29. A polypeptide comprising the amino acid sequence of SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:84, SEQ ID NO:19, SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:75 or SEQ ID NO:76. 30. The polypeptide according to any one of the preceding items, wherein the variant IgG Fc polypeptide comprises: a) an amino acid substitution at the position corresponding to position 93 of SEQ ID NO: 2, or an amino acid substitution at the position corresponding to position 93 of SEQ ID NO: 3; b) an amino acid substitution at the position corresponding to position 87 of SEQ ID NO:63, an amino acid substitution at the position corresponding to position 87 of SEQ ID NO:65, an amino acid substitution at the position corresponding to position 87 of SEQ ID NO:66, or an amino acid substitution at the position corresponding to position 87 of SEQ ID NO:69; or c) an amino acid substitution at the position corresponding to position 198 of SEQ ID NO:80, or an amino acid substitution at the position corresponding to position 198 of SEQ ID NO:81. 31. The polypeptide according to any one of the preceding items, wherein the variant IgG Fc polypeptide comprises: a) an amino acid substitution at position 93 of SEQ ID NO:2, or an amino acid substitution at position 93 of SEQ ID NO:3; b) an amino acid substitution at position 87 of SEQ ID NO:63, an amino acid substitution at position 87 of SEQ ID NO:65, an amino acid substitution at position 87 of SEQ ID NO:66, or an amino acid substitution at position 87 of SEQ ID NO:69; or c) an amino acid substitution at position 198 of SEQ ID NO:80, or an amino acid substitution at position 198 of SEQ ID NO:81. 32. The polypeptide according to any one of the preceding items, wherein the variant IgG Fc polypeptide comprises: a) an arginine at a position corresponding to position 93 of SEQ ID NO: 2, or an arginine at a position corresponding to position 93 of SEQ ID NO: 3; b) a serine at a position corresponding to position 87 of SEQ ID NO:63, a serine at a position corresponding to position 87 of SEQ ID NO:65, a serine at a position corresponding to position 87 of SEQ ID NO:66, or a serine at a position corresponding to position 87 of SEQ ID NO:69; or c) an alanine at a position corresponding to position 198 of SEQ ID NO:80, or an alanine at a position corresponding to position 198 of SEQ ID NO:81. 33. A polypeptide according to any one of the preceding items, wherein the variant IgG Fc polypeptide comprises: a) arginine at position 93 of SEQ ID NO:2, or arginine at position 93 of SEQ ID NO:3; b) serine at position 87 of SEQ ID NO:63, serine at position 87 of SEQ ID NO:65, serine at position 87 of SEQ ID NO:66, or serine at position 87 of SEQ ID NO:69; or c) Alanine at position 198 of SEQ ID NO:80, or Alanine at position 198 of SEQ ID NO:81. 34. A polypeptide according to any of the preceding items, wherein the variant IgG Fc polypeptide comprises the following amino acid sequence: a) SEQ ID NO:78, SEQ ID NO:79 or SEQ ID NO:84; or b) SEQ ID NO:70, SEQ ID NO:73, SEQ ID NO:74 or SEQ ID NO:77; or c) SEQ ID NO:82 or SEQ ID NO:83. 35. A polypeptide comprising the amino acid sequence of SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:84, SEQ ID NO:70, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:77, SEQ ID NO:82 or SEQ ID NO:83. 36. The polypeptide according to any one of the preceding items, wherein the variant IgG Fc polypeptide comprises: a) an amino acid substitution at the position corresponding to position 5 of SEQ ID NO: 2, an amino acid substitution at the position corresponding to position 38 of SEQ ID NO: 2, an amino acid substitution at the position corresponding to position 39 of SEQ ID NO: 2, an amino acid substitution at the position corresponding to position 97 of SEQ ID NO: 2, and / or an amino acid substitution at the position corresponding to position 98 of SEQ ID NO: 2; or b) an amino acid substitution at the position corresponding to position 5 of SEQ ID NO:3, an amino acid substitution at the position corresponding to position 38 of SEQ ID NO:3, an amino acid substitution at the position corresponding to position 39 of SEQ ID NO:3, an amino acid substitution at the position corresponding to position 97 of SEQ ID NO:3, and / or an amino acid substitution at the position corresponding to position 98 of SEQ ID NO:3. 37. The polypeptide according to any one of the preceding items, wherein the variant IgG Fc polypeptide comprises: a) an amino acid substitution at position 5 of SEQ ID NO:2, an amino acid substitution at position 38 of SEQ ID NO:2, an amino acid substitution at position 39 of SEQ ID NO:2, an amino acid substitution at position 97 of SEQ ID NO:2, and / or an amino acid substitution at position 98 of SEQ ID NO:2; or b) an amino acid substitution at position 5 of SEQ ID NO:3, an amino acid substitution at position 38 of SEQ ID NO:3, an amino acid substitution at position 39 of SEQ ID NO:3, an amino acid substitution at position 97 of SEQ ID NO:3, and / or an amino acid substitution at position 98 of SEQ ID NO:3. 38. The polypeptide according to any one of the preceding items, wherein the variant IgG Fc polypeptide comprises: a) proline at the position corresponding to position 5 of SEQ ID NO:2, glycine at the position corresponding to position 38 of SEQ ID NO:2, arginine at the position corresponding to position 39 of SEQ ID NO:2, isoleucine at the position corresponding to position 97 of SEQ ID NO:2, and / or glycine at the position corresponding to position 98 of SEQ ID NO:2; or b) proline at the position corresponding to position 5 of SEQ ID NO:3, glycine at the position corresponding to position 38 of SEQ ID NO:3, arginine at the position corresponding to position 39 of SEQ ID NO:3, isoleucine at the position corresponding to position 97 of SEQ ID NO:3, and / or glycine at the position corresponding to position 98 of SEQ ID NO:3. 39. The polypeptide according to any one of the preceding items, wherein the variant IgG Fc polypeptide comprises: a) proline, which is at position 5 of SEQ ID NO:2, glycine, which is at position 38 of SEQ ID NO:2, arginine, which is at position 39 of SEQ ID NO:2, isoleucine, which is at position 97 of SEQ ID NO:2, and / or glycine, which is at position 98 of SEQ ID NO:2; or b) proline, which is at position 5 of SEQ ID NO:3, glycine, which is at position 38 of SEQ ID NO:3, arginine, which is at position 39 of SEQ ID NO:3, isoleucine, which is at position 97 of SEQ ID NO:3, and / or glycine, which is at position 98 of SEQ ID NO:3. 40. The polypeptide according to any of the preceding items, wherein the variant IgG Fc polypeptide comprises the following amino acid sequence: a) SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146 or SEQ ID NO:147; or b) SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156 or SEQ ID NO:157. 41. A polypeptide comprising the amino acid sequence of SEQ ID NO: 139, SEQ ID NO: 140, SEQ ID NO: 141, SEQ ID NO: 142, SEQ ID NO: 143, SEQ ID NO: 144, SEQ ID NO: 145, SEQ ID NO: 146, SEQ ID NO: 147, SEQ ID NO: 148, SEQ ID NO: 149, SEQ ID NO: 150, SEQ ID NO: 151, SEQ ID NO: 152, SEQ ID NO: 154, SEQ ID NO: 155, SEQ ID NO: 156 or SEQ ID NO: 157. 42. A polypeptide comprising a variant IgG Fc polypeptide, wherein the variant IgG Fc polypeptide comprises: a) a tyrosine or tryptophan at the position corresponding to position 138 of SEQ ID NO: 1, a tyrosine or tryptophan at the position corresponding to position 137 of SEQ ID NO: 2, a tyrosine or tryptophan at the position corresponding to position 137 of SEQ ID NO: 3, or a tyrosine or tryptophan at the position corresponding to position 138 of SEQ ID NO: 4; or b) a tyrosine or tryptophan at a position corresponding to position 154 of SEQ ID NO:16, a tyrosine or tryptophan at a position corresponding to position 154 of SEQ ID NO:80 or SEQ ID NO:117, or a tyrosine or tryptophan at a position corresponding to position 154 of SEQ ID NO:81 or SEQ ID NO:118. 43. A polypeptide according to any of the preceding items, wherein the variant IgG Fc polypeptide comprises: a) tyrosine or tryptophan at position 138 of SEQ ID NO: 1, tyrosine or tryptophan at position 137 of SEQ ID NO: 2, tyrosine or tryptophan at position 137 of SEQ ID NO: 3, or tyrosine or tryptophan at position 138 of SEQ ID NO: 4; or b) tyrosine or tryptophan at position 154 of SEQ ID NO:16, tyrosine or tryptophan at position 154 of SEQ ID NO:80 or SEQ ID NO:117, or tyrosine or tryptophan at a position corresponding to position 154 of SEQ ID NO:81 or SEQ ID NO:118. 44. A polypeptide according to any of the preceding items, wherein the variant IgG Fc polypeptide comprises the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:109, SEQ ID NO:111, SEQ ID NO:113, SEQ ID NO:115, SEQ ID NO:119, SEQ ID NO:121 or SEQ ID NO:123. 45. A polypeptide comprising the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:109, SEQ ID NO:111, SEQ ID NO:113, SEQ ID NO:115, SEQ ID NO:119, SEQ ID NO:121 or SEQ ID NO:123. 46. ​​A contiguous polypeptide comprising a polypeptide according to any one of the preceding items and a glucagon-like peptide-1 (GLP1) polypeptide. 47. A contiguous polypeptide comprising a polypeptide according to any one of the preceding items and a glucagon polypeptide. 48. A polypeptide comprising a variant IgG Fc polypeptide, wherein the variant IgG Fc polypeptide comprises: a) a serine at a position corresponding to position 138 of SEQ ID NO: 1, a serine at a position corresponding to position 137 of SEQ ID NO: 2, a serine at a position corresponding to position 137 of SEQ ID NO: 3, a serine at a position corresponding to position 138 of SEQ ID NO: 4, a serine at a position corresponding to position 154 of SEQ ID NO: 16, a serine at a position corresponding to position 154 of SEQ ID NO: 80 or SEQ ID NO: 117, or a serine at a position corresponding to position 154 of SEQ ID NO: 81 or SEQ ID NO: 118; b) an alanine at a position corresponding to position 140 of SEQ ID NO: 1, an alanine at a position corresponding to position 139 of SEQ ID NO: 2, an alanine at a position corresponding to position 139 of SEQ ID NO: 3, an alanine at a position corresponding to position 140 of SEQ ID NO: 4, an alanine at a position corresponding to position 156 of SEQ ID NO: 16, an alanine at a position corresponding to position 156 of SEQ ID NO: 80 or SEQ ID NO: 117, or an alanine at a position corresponding to position 156 of SEQ ID NO: 81 or SEQ ID NO: 118; and / or c) a threonine at a position corresponding to position 181 of SEQ ID NO:1, a threonine at a position corresponding to position 180 of SEQ ID NO:2, a threonine at a position corresponding to position 180 of SEQ ID NO:3, a threonine at a position corresponding to position 181 of SEQ ID NO:4, a threonine at a position corresponding to position 197 of SEQ ID NO:16, a threonine at a position corresponding to position 197 of SEQ ID NO:80 or SEQ ID NO:117, or a threonine at a position corresponding to position 197 of SEQ ID NO:81 or SEQ ID NO:118. 49. The polypeptide according to any of the preceding items, wherein the variant IgG Fc polypeptide comprises: a) serine at position 138 of SEQ ID NO: 1, serine at position 137 of SEQ ID NO: 2, serine at position 137 of SEQ ID NO: 3, serine at position 138 of SEQ ID NO: 4, serine at position 154 of SEQ ID NO: 16, serine at position 154 of SEQ ID NO: 80 or SEQ ID NO: 117, or serine at position 154 of SEQ ID NO: 81 or SEQ ID NO: 118; b) alanine at position 140 of SEQ ID NO: 1, alanine at position 139 of SEQ ID NO: 2, alanine at position 139 of SEQ ID NO: 3, alanine at position 140 of SEQ ID NO: 4, alanine at position 156 of SEQ ID NO: 16, alanine at position 156 of SEQ ID NO: 80 or SEQ ID NO: 117, or alanine at position 156 of SEQ ID NO: 81 or SEQ ID NO: 118; and / or; c) threonine at position 181 of SEQ ID NO:1, threonine at position 181 of SEQ ID NO:2, threonine at position 181 of SEQ ID NO:3, threonine at position 181 of SEQ ID NO:4, threonine at position 197 of SEQ ID NO:16, threonine at position 197 of SEQ ID NO:80 or SEQ ID NO:117, or threonine at position 197 of SEQ ID NO:81 or SEQ ID NO:118. 50. A polypeptide according to any of the preceding items, wherein the variant IgG Fc polypeptide comprises the amino acid sequence of SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:110, SEQ ID NO:112, SEQ ID NO:114, SEQ ID NO:116, SEQ ID NO:120, SEQ ID NO:122 or SEQ ID NO:124. 51. A polypeptide comprising the amino acid sequence of SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:110, SEQ ID NO:112, SEQ ID NO:114, SEQ ID NO:116, SEQ ID NO:120, SEQ ID NO:122 or SEQ ID NO:124. 52. A polypeptide according to any of the preceding items, wherein the polypeptide is glycosylated. 53. A polypeptide according to any one of items 1 to 51, wherein the polypeptide is not glycosylated. 54. A contiguous polypeptide comprising a polypeptide according to any one of items 48 to 53 and a glucagon-like peptide-1 (GLP1) polypeptide. 55. A contiguous polypeptide comprising a polypeptide according to any one of items 48 to 53 and a glucagon polypeptide. 56. A heterodimeric protein comprising a contiguous polypeptide according to item 46 and a contiguous polypeptide according to item 54. 57. A heterodimeric protein comprising the contiguous polypeptide according to item 47 and the contiguous polypeptide according to item 55. 58. The contiguous polypeptide or heterodimeric protein according to any one of items 46, 47 or 54 to 57, wherein the GLP1 polypeptide is a wild-type GLP1 polypeptide, which optionally comprises the amino acid sequence SEQ ID NO: 85. 59. The contiguous polypeptide or heterodimeric protein according to any one of items 46, 47 or 54 to 58, wherein the GLP1 polypeptide is a variant GLP1 polypeptide. 60. The contiguous polypeptide or heterodimeric protein according to any one of items 46, 47 or 54 to 59, wherein the GLP1 polypeptide comprises the amino acid sequence SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:98 or SEQ ID NO:99. 61. A contiguous polypeptide or heterodimeric protein according to any one of items 46, 47 or 54 to 60, wherein the glucagon polypeptide is a wild-type glucagon polypeptide, which optionally comprises the amino acid sequence SEQ ID NO:21. 62. A contiguous polypeptide or heterodimeric protein according to any one of items 46, 47 or 54 to 61, wherein the glucagon polypeptide is a variant glucagon polypeptide. 63. A heterodimeric protein comprising: i) a first variant canine IgG Fc polypeptide comprising at least one amino acid modification relative to a first wild-type canine IgG Fc polypeptide, and a second variant canine IgG Fc polypeptide comprising at least one amino acid modification relative to a second wild-type canine IgG Fc polypeptide; or ii) a first variant feline IgG Fc polypeptide comprising at least one amino acid modification relative to a first wild-type feline IgG Fc polypeptide, and a second variant feline IgG Fc polypeptide comprising at least one amino acid modification relative to a second wild-type feline IgG Fc polypeptide, wherein: a) the first variant canine IgG Fc polypeptide comprises an amino acid substitution at the position corresponding to position 138 of SEQ ID NO: 1, position 137 of SEQ ID NO: 2, position 137 of SEQ ID NO: 3, or position 138 of SEQ ID NO: 4; b) the second variant canine IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to position 138, position 140, and / or position 181 of SEQ ID NO: 1, position 137, position 139, and / or position 180 of SEQ ID NO: 2, position 137, position 139, and / or position 180 of SEQ ID NO: 3, or position 138, position 140, and / or position 181 of SEQ ID NO: 4; c) the first variant feline IgG Fc polypeptide comprises an amino acid substitution at position 154, position 156 and / or position 197 corresponding to SEQ ID NO:6, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:117 or SEQ ID NO:118; and / or d) the second variant feline IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to position 154, position 156 and / or position 197 of SEQ ID NO:6, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:117 or SEQ ID NO:118. 64. A heterodimeric protein according to claim 63, wherein the first wild-type canine IgG Fc polypeptide and the second wild-type canine IgG Fc polypeptide are from the same IgG subtype and / or the first wild-type feline IgG Fc polypeptide and the second wild-type feline IgG Fc polypeptide are from the same IgG subtype. 65. A heterodimeric protein according to claim 63, wherein the first wild-type canine IgG Fc polypeptide and the second wild-type canine IgG Fc polypeptide are from different IgG subtypes and / or the first wild-type feline IgG Fc polypeptide and the second wild-type feline IgG Fc polypeptide are from the same IgG subtype. 66. The heterodimeric protein according to any one of items 63 to 65, wherein: a) said first variant canine IgG Fc polypeptide comprises a tyrosine or tryptophan at the position corresponding to position 138 of SEQ ID NO: 1, position 137 of SEQ ID NO: 2, position 137 of SEQ ID NO: 3, or position 138 of SEQ ID NO: 4; and / or b) said first variant feline IgG Fc polypeptide comprises a tryptophan at the position corresponding to position 154 of SEQ ID NO:6, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:117 or SEQ ID NO:118. 67. The heterodimeric protein according to any one of items 63 to 66, wherein: a) said second variant canine IgG Fc polypeptide comprises a serine at a position corresponding to position 138 of SEQ ID NO: 1, an alanine at a position corresponding to position 140 of SEQ ID NO: 1, and / or a threonine at a position corresponding to position 181 of SEQ ID NO: 1, a serine at a position corresponding to position 137 of SEQ ID NO: 2, an alanine at a position corresponding to position 139 of SEQ ID NO: 2, and / or a threonine at a position corresponding to position 180 of SEQ ID NO: 2, a serine at a position corresponding to position 137 of SEQ ID NO: 3, an alanine at a position corresponding to position 139 of SEQ ID NO: 3, and / or a threonine at a position corresponding to position 180 of SEQ ID NO: 3, and / or a serine at a position corresponding to position 138 of SEQ ID NO: 4, an alanine at a position corresponding to position 140 of SEQ ID NO: 4, and / or a threonine at a position corresponding to position 181 of SEQ ID NO: 4; and / or b) the second variant feline IgG Fc polypeptide comprises a serine at a position corresponding to position 154 of SEQ ID NO:6, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:117 or SEQ ID NO:118, an alanine at a position corresponding to position 156 thereof, and / or a threonine at a position corresponding to position 197 thereof. 68. A heterodimeric protein according to any one of items 63 to 67, wherein: a) said first variant canine IgG Fc polypeptide comprises the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:109, SEQ ID NO:111, SEQ ID NO:113 or SEQ ID NO:115; and / or b) said first variant feline IgG Fc polypeptide comprises the amino acid sequence of SEQ ID NO:119, SEQ ID NO:121 or SEQ ID NO:123. 69. The heterodimeric protein according to any one of items 63 to 68, wherein: a) said second variant canine IgG Fc polypeptide comprises the amino acid sequence of SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:110, SEQ ID NO:112, SEQ ID NO:114 or SEQ ID NO:116; and / or b) said second variant feline IgG Fc polypeptide comprises the amino acid sequence of SEQ ID NO:120, SEQ ID NO:122 or SEQ ID NO:123. 70. A polypeptide, contiguous polypeptide or heterodimeric protein according to any one of items 42 to 69, wherein the variant IgG Fc polypeptide, the first variant IgG Fc polypeptide and / or the second variant IgG Fc polypeptide comprises at least one additional amino acid modification relative to the wild-type IgG Fc polypeptide and has an enhanced binding affinity to protein A relative to the wild-type IgG Fc polypeptide. 71. The polypeptide, contiguous polypeptide or heterodimeric protein of any one of items 42 to 70, wherein the variant IgG Fc polypeptide, the first variant IgG Fc polypeptide and / or the second variant IgG Fc polypeptide comprises: a) an amino acid substitution at the position corresponding to position 21 of SEQ ID NO: 1, an amino acid substitution at the position corresponding to position 23 of SEQ ID NO: 1, an amino acid substitution at the position corresponding to position 25 of SEQ ID NO: 1, an amino acid substitution at the position corresponding to position 80 of SEQ ID NO: 1, an amino acid substitution at the position corresponding to position 205 of SEQ ID NO: 1, and / or an amino acid substitution at the position corresponding to position 207 of SEQ ID NO: 1; b) an amino acid substitution at the position corresponding to position 21 of SEQ ID NO: 3, an amino acid substitution at the position corresponding to position 23 of SEQ ID NO: 3, and / or an amino acid substitution at the position corresponding to position 24 of SEQ ID NO: 3; or c) an amino acid substitution at the position corresponding to position 21 of SEQ ID NO:4, an amino acid substitution at the position corresponding to position 23 of SEQ ID NO:4, an amino acid substitution at the position corresponding to position 25 of SEQ ID NO:4, an amino acid substitution at the position corresponding to position 80 of SEQ ID NO:4, and / or an amino acid substitution at the position corresponding to position 207 of SEQ ID NO:4. 72. The polypeptide, contiguous polypeptide or heterodimeric protein of any one of items 42 to 71, wherein the variant IgG Fc polypeptide, the first variant IgG Fc polypeptide and / or the second variant IgG Fc polypeptide comprises: a) an amino acid substitution at position 21 of SEQ ID NO: 1, an amino acid substitution at position 23 of SEQ ID NO: 1, an amino acid substitution at position 25 of SEQ ID NO: 1, an amino acid substitution at position 80 of SEQ ID NO: 1, an amino acid substitution at position 205 of SEQ ID NO: 1, and / or an amino acid substitution at position 207 of SEQ ID NO: 1; b) an amino acid substitution at position 21 of SEQ ID NO:3, an amino acid substitution at position 23 of SEQ ID NO:3, and / or an amino acid substitution at position 24 of SEQ ID NO:3; or c) an amino acid substitution at position 21 of SEQ ID NO:4, an amino acid substitution at position 23 of SEQ ID NO:4, an amino acid substitution at position 25 of SEQ ID NO:4, an amino acid substitution at position 80 of SEQ ID NO:4, and / or an amino acid substitution at position 207 of SEQ ID NO:4. 73. The polypeptide, contiguous polypeptide or heterodimeric protein of any one of items 42 to 72, wherein the variant IgG Fc polypeptide, the first variant IgG Fc polypeptide and / or the second variant IgG Fc polypeptide comprises: a) a threonine at the position corresponding to position 21 of SEQ ID NO: 1, a leucine at the position corresponding to position 23 of SEQ ID NO: 1, an alanine at the position corresponding to position 25 of SEQ ID NO: 1, a glycine at the position corresponding to position 80 of SEQ ID NO: 1, an alanine at the position corresponding to position 205 of SEQ ID NO: 1, and / or a histidine at the position corresponding to position 207 of SEQ ID NO: 1; b) a threonine at the position corresponding to position 21 of SEQ ID NO: 3, a leucine at the position corresponding to position 23 of SEQ ID NO: 3, and / or an isoleucine at the position corresponding to position 24 of SEQ ID NO: 3; or c) a threonine at a position corresponding to position 21 of SEQ ID NO:4, a leucine at a position corresponding to position 23 of SEQ ID NO:4, an alanine at a position corresponding to position 25 of SEQ ID NO:4, a glycine at a position corresponding to position 80 of SEQ ID NO:4, and / or a histidine at a position corresponding to position 207 of SEQ ID NO:4. 74. The polypeptide, contiguous polypeptide or heterodimeric protein of any one of items 42 to 73, wherein the variant IgG Fc polypeptide, the first variant IgG Fc polypeptide and / or the second variant IgG Fc polypeptide comprises: a) threonine at position 21 of SEQ ID NO: 1, leucine at position 23 of SEQ ID NO: 1, alanine at position 25 of SEQ ID NO: 1, glycine at position 80 of SEQ ID NO: 1, alanine at position 205 of SEQ ID NO: 1, and / or histidine at position 207 of SEQ ID NO: 1; b) threonine, which is at position 21 of SEQ ID NO:3, leucine, which is at position 23 of SEQ ID NO:3, and / or isoleucine, which is at position 24 of SEQ ID NO:3; or c) threonine at position 21 of SEQ ID NO:4, leucine at position 23 of SEQ ID NO:4, alanine at position 25 of SEQ ID NO:4, glycine at position 80 of SEQ ID NO:4, and / or histidine at position 207 of SEQ ID NO:4. 75. A polypeptide, contiguous polypeptide or heterodimeric protein according to any one of items 42 to 74, wherein the variant IgG Fc polypeptide, the first variant IgG Fc polypeptide and / or the second variant IgG Fc polypeptide comprises at least one additional amino acid modification relative to the wild-type IgG Fc polypeptide and has a reduced binding affinity for CD16 relative to the wild-type IgG Fc polypeptide. 76. The polypeptide, contiguous polypeptide or heterodimeric protein of any one of items 42 to 75, wherein the variant IgG Fc polypeptide, the first variant IgG Fc polypeptide and / or the second variant IgG Fc polypeptide comprises: a) an amino acid substitution at the position corresponding to position 5 of SEQ ID NO: 2, an amino acid substitution at the position corresponding to position 38 of SEQ ID NO: 2, an amino acid substitution at the position corresponding to position 39 of SEQ ID NO: 2, an amino acid substitution at the position corresponding to position 97 of SEQ ID NO: 2, and / or an amino acid substitution at the position corresponding to position 98 of SEQ ID NO: 2; or b) an amino acid substitution at the position corresponding to position 5 of SEQ ID NO:3, an amino acid substitution at the position corresponding to position 38 of SEQ ID NO:3, an amino acid substitution at the position corresponding to position 39 of SEQ ID NO:3, an amino acid substitution at the position corresponding to position 97 of SEQ ID NO:3, and / or an amino acid substitution at the position corresponding to position 98 of SEQ ID NO:3. 77. The polypeptide, contiguous polypeptide or heterodimeric protein of any one of items 42 to 76, wherein the variant IgG Fc polypeptide, the first variant IgG Fc polypeptide and / or the second variant IgG Fc polypeptide comprises: a) an amino acid substitution at position 5 of SEQ ID NO:2, an amino acid substitution at position 38 of SEQ ID NO:2, an amino acid substitution at position 39 of SEQ ID NO:2, an amino acid substitution at position 97 of SEQ ID NO:2, and / or an amino acid substitution at position 98 of SEQ ID NO:2; or b) an amino acid substitution at position 5 of SEQ ID NO:3, an amino acid substitution at position 38 of SEQ ID NO:3, an amino acid substitution at position 39 of SEQ ID NO:3, an amino acid substitution at position 97 of SEQ ID NO:3, and / or an amino acid substitution at position 98 of SEQ ID NO:3. 78. The polypeptide, contiguous polypeptide or heterodimeric protein of any one of items 42 to 77, wherein the variant IgG Fc polypeptide, the first variant IgG Fc polypeptide and / or the second variant IgG Fc polypeptide comprises: a) proline at the position corresponding to position 5 of SEQ ID NO:2, glycine at the position corresponding to position 38 of SEQ ID NO:2, arginine at the position corresponding to position 39 of SEQ ID NO:2, isoleucine at the position corresponding to position 97 of SEQ ID NO:2, and / or glycine at the position corresponding to position 98 of SEQ ID NO:2; or b) proline at the position corresponding to position 5 of SEQ ID NO:3, glycine at the position corresponding to position 38 of SEQ ID NO:3, arginine at the position corresponding to position 39 of SEQ ID NO:3, isoleucine at the position corresponding to position 97 of SEQ ID NO:3, and / or glycine at the position corresponding to position 98 of SEQ ID NO:3. 79. The polypeptide, contiguous polypeptide or heterodimeric protein of any one of items 42 to 78, wherein the variant IgG Fc polypeptide, the first variant IgG Fc polypeptide and / or the second variant IgG Fc polypeptide comprises: a) proline, which is at position 5 of SEQ ID NO:2, glycine, which is at position 38 of SEQ ID NO:2, arginine, which is at position 39 of SEQ ID NO:2, isoleucine, which is at position 97 of SEQ ID NO:2, and / or glycine, which is at position 98 of SEQ ID NO:2; or b) proline, which is at position 5 of SEQ ID NO:3, glycine, which is at position 38 of SEQ ID NO:3, arginine, which is at position 39 of SEQ ID NO:3, isoleucine, which is at position 97 of SEQ ID NO:3, and / or glycine, which is at position 98 of SEQ ID NO:3. 80. A polypeptide, contiguous polypeptide or heterodimeric protein according to any one of items 42 to 79, wherein the variant IgG Fc polypeptide, the first variant IgG Fc polypeptide and / or the second variant IgG Fc polypeptide comprises at least one additional amino acid modification relative to the wild-type canine IgG Fc polypeptide and has a reduced binding affinity for C1q relative to the wild-type canine IgG Fc polypeptide. 81. A polypeptide, a contiguous polypeptide or a heterodimeric protein according to any one of items 42 to 80, wherein the variant IgG Fc polypeptide, the first variant IgG Fc polypeptide and / or the second variant IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to position 93 of SEQ ID NO:2, or an amino acid substitution at a position corresponding to position 93 of SEQ ID NO:3. 82. A polypeptide, a contiguous polypeptide or a heterodimeric protein according to any one of items 42 to 81, wherein the variant IgG Fc polypeptide, the first variant IgG Fc polypeptide and / or the second variant IgG Fc polypeptide comprises an amino acid substitution at position 93 of SEQ ID NO:2, or an amino acid substitution at position 93 of SEQ ID NO:3. 83. A polypeptide, a contiguous polypeptide or a heterodimeric protein according to any one of items 42 to 82, wherein the variant IgG Fc polypeptide, the first variant IgG Fc polypeptide and / or the second variant IgG Fc polypeptide comprises an arginine at a position corresponding to position 93 of SEQ ID NO:2, or an arginine at a position corresponding to position 93 of SEQ ID NO:3. 84. A polypeptide, contiguous polypeptide or heterodimeric protein according to any one of items 42 to 83, wherein the variant IgG Fc polypeptide, the first variant IgG Fc polypeptide and / or the second variant IgG Fc polypeptide comprises arginine at position 93 of SEQ ID NO:2, or arginine at position 93 of SEQ ID NO:3. 85. A polypeptide, contiguous polypeptide or heterodimeric protein according to any one of items 1 to 84, wherein the polypeptide is an antibody, antibody fusion or fusion polypeptide. 86. A contiguous polypeptide comprising: a) a first glucagon-like peptide-1 (GLP1) polypeptide (GLP1A); b) a first connector (L1); c) Fc polypeptide (Fc) of a companion animal species; d) an optional second linker (L2); and e) optionally a second GLP1 polypeptide (GLP1B). 87. The contiguous polypeptide according to item 65, comprising: Formula (I): GLP1A-L1-Fc; or Formula (II): Fc-L1-GLP1A. 88. The contiguous polypeptide according to item 65, comprising: Formula (III): GLP1A—L1—Fc—L2—GLP1B. 89. The contiguous polypeptide according to any one of items 86 to 88, wherein GLP1B, if present, comprises the same amino acid sequence as GLP1A. 90. A contiguous polypeptide comprising: a) glucagon-like peptide-1 (GLP1) polypeptide; b) a first connector (L1); c) Fc polypeptide (Fc); d) a second connector (L2); and e) Glucagon polypeptide (Gluc). 91. The contiguous polypeptide according to item 90, comprising: Formula (IV): GLP1-L1-Fc-L2-Gluc; or Formula (V): Gluc—L1—Fc—L2—GLP1. 92. The contiguous polypeptide according to any one of items 86 to 91, wherein GLP1A, GLP1 and / or GLP1B, if present, comprise a wild-type GLP1 polypeptide. 93. The contiguous polypeptide according to any one of items 86 to 92, wherein GLP1A, GLP1 and / or GLP1B, if present, comprise a variant GLP1 polypeptide. 94. The contiguous polypeptide according to any one of items 86 to 93, wherein GLP1A, GLP1 and / or GLP1B, if present, comprises the amino acid sequence of SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:98 or SEQ ID NO:99. 95. The contiguous polypeptide of any one of items 86 to 94, wherein the glucagon polypeptide comprises a wild-type glucagon polypeptide, optionally comprising the amino acid sequence of SEQ ID NO:21. 96. The contiguous polypeptide of any one of items 86 to 95, wherein the glucagon polypeptide is a variant glucagon polypeptide. 97. The contiguous polypeptide of any one of items 86 to 96, wherein the Fc polypeptide is human IgG Fc. 98. The contiguous polypeptide according to any one of items 86 to 97, wherein the Fc polypeptide is human IgG1 Fc, IgG2 Fc, IgG3 Fc or IgG4 Fc. 99. The contiguous polypeptide of any one of items 86 to 98, wherein the Fc polypeptide is an Fc of a companion animal species. 100. The contiguous polypeptide of any one of items 86 to 97 or 99, wherein the Fc polypeptide comprises: a) canine IgG-A Fc, IgG-B Fc, IgG-C Fc or IgG-D Fc; b) equine IgG1 Fc, IgG2 Fc, IgG3 Fc, IgG4 Fc, IgG5 Fc, IgG6 Fc or IgG7 Fc; or c) Feline IgG1a Fc, IgG1b Fc or IgG2 Fc. 101. The contiguous polypeptide of any one of items 86 to 100, wherein the Fc polypeptide is a wild-type IgG Fc polypeptide. 102. The contiguous polypeptide of any one of items 86 to 100, wherein the Fc polypeptide is a variant IgG Fc polypeptide. 103. A contiguous polypeptide according to any one of items 86 to 102, wherein the Fc polypeptide comprises a polypeptide, a contiguous polypeptide or a heterodimeric protein according to any one of items 1 to 84. 104. The contiguous polypeptide according to any one of items 85 to 102, wherein the contiguous polypeptide has a longer serum half-life compared to the wild-type GLP1 polypeptide. 105. A contiguous polypeptide according to any one of items 86 to 104, wherein L1 and L2, if present, are each independently a flexible linker. 106. A contiguous polypeptide according to any one of items 86 to 105, wherein the amino acid sequences of L1 and L2, if present, each independently comprises 100%, at least 95%, at least 90%, at least 85% serine and / or glycine amino acid residues. 107. A contiguous polypeptide according to any one of items 86 to 106, wherein the contiguous polypeptide comprises an extension of its C-terminus. 108. An adjacent polypeptide according to any one of items 86 to 107, wherein the adjacent polypeptide comprises one glycine residue, two glycine residues, three glycine residues, four glycine residues, five glycine residues, six glycine residues, seven glycine residues, eight glycine residues or more than eight glycine residues at its C-terminus. 109. The contiguous polypeptide according to any one of items 86 to 108, wherein the contiguous polypeptide comprises the amino acid sequence SEQ ID NO:88, SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94 or SEQ ID NO:95 at its C-terminus. 110. The contiguous polypeptide according to any one of items 86 to 109, wherein the contiguous polypeptide comprises: a) Amino acid sequence SEQ ID NO: 23; SEQ ID NO: 24; SEQ ID NO: 25; SEQ ID NO: 26; SEQ ID NO: 27; SEQ ID NO: 28; SEQ ID NO: 29; SEQ ID NO: 30; SEQ ID NO: 31; SEQ ID NO: 32; SEQ ID NO: 33; SEQ ID NO: 34; SEQ ID NO: 35; SEQ ID SEQ ID NO:37; SEQ ID NO:38; SEQ ID NO:39; SEQ ID NO:40; SEQ ID NO:41; SEQ ID NO:42; SEQ ID NO:43; SEQ ID NO:44; SEQ ID NO:45; SEQ ID NO:46; SEQ ID NO:47, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105 or SEQ ID NO:106; or b) the amino acid sequence of SEQ ID NO:52; SEQ ID NO:53; SEQ ID NO:54; SEQ ID NO:55; SEQ ID NO:56; SEQ ID NO:57; SEQ ID NO:58; or SEQ ID NO:59. 111. A polypeptide comprising the amino acid sequence SEQ ID NO:23; SEQ ID NO:24; SEQ ID NO:25; SEQ ID NO:26; SEQ ID NO:27; SEQ ID NO:28; SEQ ID NO:29; SEQ ID NO:30; SEQ ID NO:31; SEQ ID NO:36; SEQ ID NO:37; SEQ ID NO:38; SEQ ID NO:39; SEQ ID NO:40; SEQ ID NO:41; SEQ ID NO:42; SEQ ID NO:43; SEQ ID NO:44; SEQ ID NO:45; SEQ ID NO:46; SEQ ID NO:47, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:52; SEQ ID NO:53; SEQ ID NO:54; SEQ ID NO:55; SEQ ID NO:56; SEQ ID NO:57; SEQ ID NO:58; SEQ ID NO:59; SEQ ID NO:103; SEQ ID NO:104, SEQ ID NO:105 or SEQ ID NO:106. 112. A polypeptide, heterodimeric protein or contiguous polypeptide according to any of the preceding items, wherein at least one amino acid modification or substitution comprises an amino acid substitution with an amino acid derivative. 113. An isolated nucleic acid encoding a polypeptide, heterodimeric protein or contiguous polypeptide according to any of the preceding items. 114. A host cell comprising the nucleic acid according to item 113. 115. A method for producing a polypeptide, comprising culturing the host cell according to item 114 and isolating the polypeptide. 116. A pharmaceutical composition comprising the polypeptide, heterodimeric protein or contiguous polypeptide according to any one of items 1 to 112, and a pharmaceutically acceptable carrier. 117. A method for increasing cAMP production in a cell, the method comprising exposing the cell to a polypeptide, heterodimeric protein, adjacent polypeptide or pharmaceutical composition according to any one of items 1 to 112 or 116 under conditions that allow the polypeptide, heterodimeric protein, or adjacent polypeptide to bind to GLP1R. 118. A method according to item 117, wherein the cell is exposed to the polypeptide, heterodimeric protein, adjacent polypeptide or pharmaceutical composition ex vivo. 119. A method according to item 117, wherein the cell is exposed to the polypeptide, heterodimeric protein, adjacent polypeptide or pharmaceutical composition in vivo. 120. A method according to any one of items 118 to 119, wherein the cell is a human cell, a canine cell, a feline cell or an equine cell. 121. A method of delivering a polypeptide to a subject, comprising parenterally administering the polypeptide, heterodimeric protein, contiguous polypeptide or pharmaceutical composition of any one of items 1 to 112 or 116. 122. A method for delivering a polypeptide to a subject, comprising administering the polypeptide, heterodimeric protein, contiguous polypeptide or pharmaceutical composition according to any one of items 1 to 112 or 116 via an intramuscular route, an intraperitoneal route, an intracerebrospinal route, a subcutaneous route, an intraarterial route, an intrasynovial route, an intrathecal route or an inhalation route. 123. A method for treating a subject suffering from diabetes or obesity, the method comprising administering to the subject a therapeutically effective amount of a polypeptide, heterodimeric protein, contiguous polypeptide or pharmaceutical composition according to any one of items 1 to 112 or 116. 124. The method of claim 123, comprising administering insulin, a DPP4 inhibitor, an SGLT2 inhibitor, a biguanide, a sulfonylurea, a chloramphenicol derivative, an α-glucosidase inhibitor, a thiazolidinedione (TZD), an amylinomimetic, a bile acid sequestrant, or a dopamine agonist. 125. A method according to any one of items 121 to 124, wherein the subject is a human subject. 126. A method according to any one of items 121 to 124, wherein the subject is a companion animal species. 127. The method of claim 126, wherein the companion animal species is canine, equine, or feline. BRIEF DESCRIPTION OF THE DRAWINGS

[0006] Figure 1 An alignment of canine IgG-A, B, C, and D Fc sequences is shown. Boxes indicate regions that may contact protein A.

[0007] Figure 2 A shows SDS-PAGE analysis of GLP1-G8 / GLP-2G_III_WTfeIgG2 (SEQ ID NO:23; "GLP1 A variant" in the figure) and GLP1-G8_I_WTfeIgG2 (SEQ ID NO:24; "GLP1 B variant" in the figure) having a wild-type feline IgG2 hinge with one disulfide bond, which was performed in the absence or presence of a reducing agent (DTT).

[0008] Figure 2 B shows SDS-PAGE analysis of GLP1-G8 / GLP-2G_III_VARfeIgG2 (SEQ ID NO:25; “GLP1 MA variant” in the figure) and GLP1-G8_I_VARfeIgG2 (SEQ ID NO:26; “GLP1 MB variant” in the figure) having a variant feline IgG2 hinge with two disulfide bonds, which was performed in the absence or presence of a reducing agent (DTT).

[0009] Figure 3 Shown is the cAMP CHO-K1 GLP1R bioassay evaluating the activity of GLP1-G8 / GLP1-2G_III_VARfeIgG2 (SEQ ID NO: 25) and GLP1-G8_I_VARfeIgG2 (SEQ ID NO: 26) compared to controls (GLP1(7-37) and Extendin-4).

[0010] Figure 4 Shown is a cell-based bioassay evaluating the activity of GLP1-G8_I_VARfeIgG2 (SEQ ID NO: 26) ("GLP1-B" in the figure) after one year of storage with CHOK1-GLP1R cells and cAMP-glo (n=2).

[0011] Figure 5 Western blot analysis of GLP1-G8_I_VARfeIgG2 (SEQ ID NO: 26) ("GLP1B" in the figure) incubated at 37°C in serum for 24 hours (lane 1), incubated at 37°C in PBS for 24 hours (lane 2), and incubated at 47°C in PBS for 24 hours (lane 9) is shown. Mouse anti-GLP1 antibody was used.

[0012] Figure 6 Figure 2 is the serum concentration curve of GLP1-G8_I_VARfeIgG2 (SEQ ID NO: 26) over time after subcutaneous administration to 5 cats as measured by quantitative ELISA.

[0013] Figure 7 The serum concentration curve of GLP1-G8_I_VARfeIgG2 (SEQ ID NO: 26) over time as measured by a cell-based activity assay after subcutaneous administration to 5 cats is shown. The average AUC from 0 to 168 hours was approximately 840 μg (h) / mL and the average t 1 / 2 For 36 hours. Sequence Description

[0014] Table 1 provides a list of exemplary sequences described herein. DETAILED DESCRIPTION

[0015] Variant IgG Fc polypeptides from companion animals such as canines, equines, and cats are described. In some embodiments, the variant IgG Fc polypeptides have increased protein A binding, decreased C1q binding, decreased CD16 binding to, enhanced stability, increased recombinant production, increased hinge disulfide bond formation, and / or form heterodimeric polypeptides. In some embodiments, antibodies, antibody fragments, or fusion proteins comprise the variant IgG Fc polypeptides. Methods of producing or purifying variant IgG Fc polypeptides and methods of administering variant IgG Fc polypeptides to companion animals are also provided.

[0016] Also provided are various embodiments involving contiguous polypeptides and heterodimeric polypeptides, comprising one or more variant GLP1 polypeptides with improved serum half-life. In some embodiments, the contiguous polypeptide or heterodimeric polypeptide comprises a GLP1 polypeptide and a glucagon polypeptide as a dual GLP1 receptor and glucagon receptor agonist. In some embodiments, such polypeptides can be used to treat, for example, diabetes, obesity, or related indications in companion animals such as canines, cats, and horses.

[0017] For the convenience of the reader, the following definitions of terms used herein are provided.

[0018] As used herein, numerical terms such as KD are calculated based on scientific measurements and are therefore subject to appropriate measurement errors. In some cases, numerical terms may include values ​​rounded to the nearest significant figure.

[0019] As used herein, "a" or "an" means "at least one" or "one or more" unless otherwise specified. As used herein, the term "or" means "and / or" unless otherwise specified. In the context of multiple dependent claims, the use of "or" when it refers to prior other claims refers only to those claims in the alternative. Exemplary variant IgG Fc polypeptides

[0020] Novel variant IgG Fc polypeptides are provided, e.g., for increased binding to Protein A, decreased binding to C1q, decreased binding to CD16, enhanced stability, enhanced recombinant production, increased hinge disulfide bond formation, and / or formation of heterodimeric protein analytes.

[0021] "Amino acid sequence" means the sequence of amino acid residues in a peptide or protein. The terms "polypeptide" and "protein" are used interchangeably to refer to polymers of amino acid residues, without limiting the minimum length. Such polymers of amino acid residues may contain natural or non-natural amino acid residues, and include, but are not limited to, peptides, oligopeptides, dimers, trimers and polymers of amino acid residues. The definition includes both full-length proteins and fragments thereof. The term also includes post-expression modifications of polypeptides, such as glycosylation, sialylation, acetylation, phosphorylation, etc. In addition, for the purposes of this disclosure, "polypeptide" refers to proteins including modifications to the native sequence, such as deletions, additions and substitutions (usually conservative substitutions in nature), as long as the protein maintains the desired activity. These modifications may be intentional, such as by site-directed mutagenesis, or may be accidental, such as by mutations in the host producing the protein or errors caused by PCR amplification.

[0022] A "fragment crystallizable polypeptide" or "Fc polypeptide" is a portion of an antibody molecule that interacts with effector molecules and cells. It comprises the C-terminal portion of an immunoglobulin heavy chain. As used herein, an Fc polypeptide includes a fragment of an Fc domain having one or more biological activities in a complete Fc polypeptide. In some embodiments, the biological activity of an Fc polypeptide is the ability to bind to FcRn. In some embodiments, the biological activity of an Fc polypeptide is the ability to bind to C1q. In some embodiments, the biological activity of an Fc polypeptide is the ability to bind to CD16. In some embodiments, the biological activity of an Fc polypeptide is the ability to bind to protein A. The "effector function" of an Fc polypeptide is an action or activity that an antibody performs in whole or in part in response to a stimulus, and may include complement fixation and / or ADCC (antibody-dependent cellular cytotoxicity) induction.

[0023] "IgX Fc" refers to an Fc polypeptide derived from a specific antibody isotype (e.g., IgG, IgA, IgD, IgE, IgM, etc.), where "X" represents the antibody isotype. Thus, "IgG Fc" means that the Fc polypeptide is derived from a γ chain, "IgA Fc" means that the Fc polypeptide is derived from an α chain, "IgD Fc" means that the Fc polypeptide is derived from a δ chain, "IgE Fc" means that the Fc polypeptide is derived from an ε chain, "IgM Fc" means that the Fc polypeptide is derived from a μ chain, and so on. In some embodiments, the IgG Fc polypeptide comprises a hinge, CH2, and CH3, but does not comprise CH1 or CL. In some embodiments, the IgG Fc polypeptide comprises CH2 and CH3, but does not comprise CH1, hinge, or CL. In some embodiments, the IgG Fc polypeptide comprises CH1, hinge, CH2, CH3, with or without CL. "IgX-N Fc" or "IgGXN Fc" indicates that the Fc polypeptide is derived from an antibody isotype of a particular subclass (such as canine IgG subclass IgG-A, IgG-B, IgG-C or IgG-D; feline IgG subclass IgG1a, IgG1b or IgG2; or equine IgG subclass IgG1, IgG2, IgG3, IgG4, IgG5, IgG6 or IgG7, etc.), wherein "N" indicates subclass.

[0024] "Hinge" refers to any portion of an Fc polypeptide or variant Fc polypeptide that is rich in proline and comprises at least one cysteine ​​residue located between CH1 and CH2 of a full-length heavy chain constant region.

[0025] In some embodiments, the hinge is capable of forming a disulfide linkage within the same hinge region, within the same Fc polypeptide, within the hinge regions of separate Fc polypeptides, or within separate Fc polypeptides. In some embodiments, the hinge comprises at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten proline residues.

[0026] The term "companion animal species" refers to an animal suitable for companionship with humans. In some embodiments, the companion animal species is canine (or dog), feline (or cat), or equine (or horse). In some embodiments, the companion animal species is a small mammal, such as canine, feline, dog, cat, rabbit, ferret, guinea pig, rodent, etc. In some embodiments, the companion animal species is a farm animal, such as a horse, cow, pig, etc.

[0027] In some embodiments, the IgX Fc polypeptide or IgX-N Fc polypeptide is derived from a companion animal, such as a dog, cat, or horse. In some embodiments, the IgG Fc polypeptide is isolated from a canine gamma heavy chain, such as IgG-A, IgG-B, IgG-C, or IgG-D. In some examples, the IgG Fc polypeptide is isolated from a feline gamma heavy chain, such as IgG1a, IgG1b, or IgG2. In other cases, the IgG Fc polypeptide is isolated from an equine gamma heavy chain, such as IgG1, IgG2, IgG3, IgG4, IgG5, IgG6, or IgG7.

[0028] Unless otherwise indicated, the terms "IgX Fc" and "IgX Fc polypeptide" include wild-type IgX Fc polypeptides and variant IgX Fc polypeptides.

[0029] "Wild-type" refers to a non-mutated version of a naturally occurring polypeptide or fragment thereof. A wild-type polypeptide can be produced recombinantly.

[0030] In some embodiments, the wild-type IgG Fc polypeptide comprises the amino acid sequence of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:16, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:100, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:117, SEQ ID NO:118.

[0031] A "variant" is a polypeptide that differs from a reference polypeptide by single or multiple non-natural amino acid substitutions, deletions, and / or additions. In some embodiments, the variant retains at least one biological activity of the reference polypeptide. In some embodiments, the variant (e.g., a variant canine IgG-A Fc, a variant canine IgG-C Fc, a variant canine IgG-D Fc, a variant equine IgG2 Fc, a variant equine IgG5 Fc, or a variant equine IgG6 Fc) has an activity that is substantially lacking in the reference polypeptide. For example, in some embodiments, a variant canine IgG-A Fc, a variant canine IgG-C Fc, a variant canine IgG-D Fc, a variant equine IgG2 Fc, a variant equine IgG5 Fc, or a variant equine IgG6 Fc binds to Protein A.

[0032] As used herein, "percent (%) amino acid sequence identity" and "homology" with respect to nucleic acid molecules or polypeptide sequences are defined as the percentage of nucleotides or amino acid residues in a reference sequence that are identical to the nucleotides or amino acid residues in a particular nucleic acid molecule or polypeptide sequence, after aligning the sequences and introducing gaps (if necessary) to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for the purpose of determining percent sequence identity can be achieved in a variety of ways within the skill in the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEGALINE TM (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.

[0033] In some embodiments, after alignment and introduction of gaps (if necessary) to achieve maximum percentage sequence identity, and without considering any conservative substitutions as part of sequence identity, the variant has at least about 50% sequence identity with the reference nucleic acid molecule or polypeptide. Such variants include, for example, polypeptides in which one or more amino acid residues are added or deleted at the N-terminus or C-terminus of the polypeptide. In some embodiments, the variant has at least about 50% sequence identity, at least about 60% sequence identity, at least about 65% sequence identity, at least about 70% sequence identity, at least about 75% sequence identity, at least about 80% sequence identity, at least about 85% sequence identity, at least about 90% sequence identity, at least about 95% sequence identity, at least about 97% sequence identity, at least about 98% sequence identity, at least about 99% sequence identity with the sequence of the reference nucleic acid or polypeptide.

[0034] A "point mutation" is a mutation involving a single amino acid residue. The mutation can be the loss of an amino acid, the substitution of one amino acid residue for another, or the insertion of another amino acid residue.

[0035] "Amino acid substitution" refers to replacing an amino acid in a polypeptide with another amino acid. In some embodiments, the amino acid substitution is a conservative substitution. Non-limiting exemplary conservative amino acid substitutions are shown in Table 2. Amino acid substitutions can be introduced into a molecule of interest, and the desired activity of the product can be screened, for example, retained / improved antigen binding, reduced immunogenicity, or improved ADCC or CDC, or improved pharmacokinetics.

[0036] Table 2

[0037] Amino acids can be grouped according to common side chain properties: (1) Hydrophobicity: norleucine, Met, Ala, Val, Leu, Ile; (2) Neutral hydrophilicity: Cys, Ser, Thr, Asn, Gln; (3) Acidic: Asp, Glu; (4) Basic: His, Lys, Arg; (5) Residues that affect chain orientation: Gly, Pro; (6) Aromatic: Trp, Tyr, Phe.

[0038] Non-conservative substitutions will entail exchanging a member of one of these classes for another class.

[0039] As used herein, a "variant IgG Fc" is an IgG Fc polypeptide that differs from a reference IgG Fc polypeptide by single or multiple amino acid substitutions, deletions and / or additions and substantially retains at least one biological activity of the reference IgG Fc polypeptide.

[0040] As used herein, "amino acid derivatives" refers to any amino acid, modified amino acid and / or amino acid analog, rather than one of the 20 common natural amino acids found in humans. Exemplary amino acid derivatives include natural amino acids not found in humans (e.g., selenocysteine ​​and pyrrolysine that may be found in some microorganisms) and non-natural amino acids. Exemplary amino acid derivatives include, but are not limited to, amino acid derivatives available from chemical product manufacturers (e.g., sigmaaldrich.com / chemistry / chemistry-products.html? TablePage=16274965 accessed on May 6, 2017, which is incorporated herein by reference). One or more amino acid derivatives can be incorporated into a polypeptide at a specific position using a translation system utilizing a host cell, an orthogonal aminoacyl-tRNA synthetase derived from a true bacterial synthetase, an orthogonal tRNA, and an amino acid derivative. For further description, see, e.g., U.S. Patent No. 9,624,485.

[0041] In some embodiments, the variant IgG Fc polypeptide comprises an amino acid substitution with an amino acid derivative. In some embodiments, the amino acid derivative is an alanine derivative, a cysteine ​​derivative, an aspartic acid derivative, a glutamic acid derivative, a phenylalanine derivative, a glycine derivative, a histidine derivative, an isoleucine derivative, a lysine derivative, a leucine derivative, a methionine derivative, an asparagine derivative, a proline derivative, a glutamine derivative, an arginine derivative, a serine derivative, a threonine derivative, a valine derivative, a tryptophan derivative, or a tyrosine derivative.

[0042] In some embodiments, the variant IgG Fc polypeptide comprises a variant IgG Fc polypeptide of a companion animal species. In some embodiments, the variant IgG Fc polypeptide comprises a variant canine IgG Fc polypeptide, a variant equine IgG Fc polypeptide, or a feline IgG Fc polypeptide. Exemplary variant IgG Fc polypeptides with modified protein A binding

[0043] In some embodiments, the variant IgG Fc polypeptide has a modified binding affinity to Protein A. In some embodiments, the variant IgG Fc polypeptide has an increased binding affinity to Protein A. In some embodiments, the variant IgG Fc polypeptide can be purified using Protein A column chromatography.

[0044] In some embodiments, the variant IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to position 21, position 23, position 25, position 80, position 205, and / or position 207 of SEQ ID NO: 1. In some embodiments, the variant IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to position 21, position 23, and / or position 24 of SEQ ID NO: 3. In some embodiments, the variant IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to position 21, position 23, position 25, position 80, and / or position 207 of SEQ ID NO: 4.

[0045] In some embodiments, the variant IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to position 15 and / or position 203 of SEQ ID NO: 64. In some embodiments, the variant IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to position 199 and / or position 200 of SEQ ID NO: 67. In some embodiments, the variant IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to position 199, position 200, position 201 and / or 202 of SEQ ID NO: 68.

[0046] In some embodiments, the variant IgG Fc polypeptide comprises an amino acid substitution at position 21, position 23, position 25, position 80, position 205, and / or position 207 of SEQ ID NO: 1. In some embodiments, the variant IgG Fc polypeptide comprises an amino acid substitution at position 21, position 23, and / or position 24 of SEQ ID NO: 3. In some embodiments, the variant IgG Fc polypeptide comprises an amino acid substitution at position 21, position 23, position 25, position 80, and / or position 207 of SEQ ID NO: 3.

[0047] In some embodiments, the variant IgG Fc polypeptide comprises an amino acid substitution at position 15 and / or position 203 of SEQ ID NO: 64. In some embodiments, the variant IgG Fc polypeptide comprises an amino acid substitution at position 199 and / or position 200 of SEQ ID NO: 67. In some embodiments, the variant IgG Fc polypeptide comprises an amino acid substitution at position 199, position 200, position 201, and / or position 202 of SEQ ID NO: 68.

[0048] In some embodiments, the variant IgG Fc polypeptide comprises a threonine at a position corresponding to position 21 of SEQ ID NO: 1, a leucine at a position corresponding to position 23 of SEQ ID NO: 1, an alanine at a position corresponding to position 25 of SEQ ID NO: 1, a glycine at a position corresponding to position 80 of SEQ ID NO: 1, an alanine at a position corresponding to position 205 of SEQ ID NO: 1, and / or a histidine at a position corresponding to position 207 of SEQ ID NO: 1. In some embodiments, the variant IgG Fc polypeptide comprises a threonine at a position corresponding to position 21 of SEQ ID NO: 3, a leucine at a position corresponding to position 23 of SEQ ID NO: 3, and / or an isoleucine at a position corresponding to position 24 of SEQ ID NO: 3. In some embodiments, the variant IgG Fc polypeptide comprises a threonine at a position corresponding to position 21 of SEQ ID NO:4, a leucine at a position corresponding to position 23 of SEQ ID NO:4, an alanine at a position corresponding to position 25 of SEQ ID NO:4, a glycine at a position corresponding to position 80 of SEQ ID NO:3, and / or a histidine at a position corresponding to position 207 of SEQ ID NO:4.

[0049] In some embodiments, the variant IgG Fc polypeptide comprises a threonine or valine at a position corresponding to position 15 of SEQ ID NO: 64, and / or a tyrosine or valine at a position corresponding to position 203 of SEQ ID NO: 64. In some embodiments, the variant IgG Fc polypeptide comprises a leucine at a position corresponding to position 199 of SEQ ID NO: 67, and / or a histidine at a position corresponding to position 200 of SEQ ID NO: 67. In some embodiments, the variant IgG Fc polypeptide comprises an isoleucine at a position corresponding to position 199 of SEQ ID NO: 68, a histidine at a position corresponding to position 200 of SEQ ID NO: 68, an asparagine at a position corresponding to position 201 of SEQ ID NO: 68, and / or a histidine at a position corresponding to position 202 of SEQ ID NO: 68.

[0050] In some embodiments, the variant IgG Fc polypeptide comprises a threonine at position 21 of SEQ ID NO: 1, a leucine at position 23 of SEQ ID NO: 1, an alanine at position 25 of SEQ ID NO: 1, a glycine at position 80 of SEQ ID NO: 1, an alanine at position 205 of SEQ ID NO: 1, and / or a histidine at position 207 of SEQ ID NO: 1. In some embodiments, the variant IgG Fc polypeptide comprises a threonine at position 21 of SEQ ID NO: 3, a leucine at position 23 of SEQ ID NO: 3, and / or an isoleucine at position 24 of SEQ ID NO: 3. In some embodiments, the variant IgG Fc polypeptide comprises a threonine at position 21 of SEQ ID NO: 4, a leucine at position 23 of SEQ ID NO: 4, an alanine at position 25 of SEQ ID NO: 4, a glycine at position 80 of SEQ ID NO: 4, and / or a histidine at position 207 of SEQ ID NO: 4.

[0051] In some embodiments, the variant IgG Fc polypeptide comprises a threonine or valine at position 15 of SEQ ID NO: 64, and / or a tyrosine or valine at position 203 of SEQ ID NO: 64. In some embodiments, the variant IgG Fc polypeptide comprises a leucine at position 199 of SEQ ID NO: 67, and / or a histidine at position 200 of SEQ ID NO: 67. In some embodiments, the variant IgG Fc polypeptide comprises an isoleucine at position 199 of SEQ ID NO: 68, a histidine at position 200 of SEQ ID NO: 68, an asparagine at position 201 of SEQ ID NO: 68, and / or a histidine at position 202 of SEQ ID NO: 68.

[0052] In some embodiments, the variant IgG Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, or SEQ ID NO: 84. In some embodiments, the variant IgG Fc polypeptide comprises SEQ ID NO: 19, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 75, or SEQ ID NO: 76. Exemplary variant IgG Fc polypeptides with modified CD16 binding

[0053] In some embodiments, the variant IgG Fc polypeptide has a modified binding affinity for CD 16. In some embodiments, the variant IgG Fc polypeptide has a reduced binding affinity for CD 16. In some embodiments, the variant IgG Fc may have a reduced ADCC immune response.

[0054] In some embodiments, the variant IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to position 5, position 38, position 39, position 97 and / or position 98 of SEQ ID NO: 2. In some embodiments, the variant IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to position 5, position 38, position 39, position 97 and / or position 98 of SEQ ID NO: 3.

[0055] In some embodiments, the variant IgG Fc polypeptide comprises an amino acid substitution at position 5, position 38, position 39, position 97 and / or position 98 of SEQ ID NO: 2. In some embodiments, the variant IgG Fc polypeptide comprises an amino acid substitution at position 5, position 38, position 39, position 97 and / or position 98 of SEQ ID NO: 3.

[0056] In some embodiments, the variant IgG Fc polypeptide comprises a proline at a position corresponding to position 5 of SEQ ID NO: 2, a glycine at a position corresponding to position 38, an arginine at a position corresponding to position 39, an isoleucine at a position corresponding to position 97, and / or a glycine at a position corresponding to position 98. In some embodiments, the variant IgG Fc polypeptide comprises a proline at a position corresponding to position 5 of SEQ ID NO: 3, a glycine at a position corresponding to position 38, an arginine at a position corresponding to position 39, an isoleucine at a position corresponding to position 97, and / or a glycine at a position corresponding to position 98.

[0057] In some embodiments, the variant IgG Fc polypeptide comprises a proline at position 5 of SEQ ID NO: 2, a glycine at position 38 of SEQ ID NO: 2, an arginine at position 39 of SEQ ID NO: 2, an isoleucine at position 97 of SEQ ID NO: 2, and / or a glycine at position 98 of SEQ ID NO: 2. In some embodiments, the variant IgG Fc polypeptide comprises a proline at position 5 of SEQ ID NO: 3, a glycine at position 38 of SEQ ID NO: 3, an arginine at position 39 of SEQ ID NO: 3, an isoleucine at position 97 of SEQ ID NO: 3, and / or a glycine at position 98 of SEQ ID NO: 3.

[0058] In some embodiments, the variant IgG Fc polypeptide comprises the amino acid sequence of SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, or SEQ ID NO:157. Exemplary variant IgG Fc polypeptides with modified C1q binding

[0059] In some embodiments, the variant IgG Fc polypeptide has a modified binding affinity for C1q. In some embodiments, the variant IgG Fc polypeptide has a reduced binding affinity for C1q. In some embodiments, the variant IgG Fc polypeptide may have reduced complement fixation. In some embodiments, the variant IgG Fc may have a reduced complement-mediated immune response.

[0060] In some embodiments, the variant IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to position 93 of SEQ ID NO: 2. In some embodiments, the variant IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to position 93 of SEQ ID NO: 3. In some embodiments, the variant IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to position 87 of SEQ ID NO: 63. In some embodiments, the variant IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to position 87 of SEQ ID NO: 65. In some embodiments, the variant IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to position 87 of SEQ ID NO: 66. In some embodiments, the variant IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to position 198 of SEQ ID NO: 80. In some embodiments, the variant IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to position 198 of SEQ ID NO: 81.

[0061] In some embodiments, the variant IgG Fc polypeptide comprises an amino acid substitution at position 93 of SEQ ID NO:2. In some embodiments, the variant IgG Fc polypeptide comprises an amino acid substitution at position 93 of SEQ ID NO:3. In some embodiments, the variant IgG Fc polypeptide comprises an amino acid substitution at position 87 of SEQ ID NO:63. In some embodiments, the variant IgG Fc polypeptide comprises an amino acid substitution at position 87 of SEQ ID NO:65. In some embodiments, the variant IgG Fc polypeptide comprises an amino acid substitution at position 87 of SEQ ID NO:66. In some embodiments, the variant IgG Fc polypeptide comprises an amino acid substitution at position 198 of SEQ ID NO:80. In some embodiments, the variant IgG Fc polypeptide comprises an amino acid substitution at position 198 of SEQ ID NO:81.

[0062] In some embodiments, the variant IgG Fc polypeptide comprises an arginine at a position corresponding to position 93 of SEQ ID NO:2. In some embodiments, the variant IgG Fc polypeptide comprises an arginine at a position corresponding to position 93 of SEQ ID NO:3. In some embodiments, the variant IgG Fc polypeptide comprises a serine at a position corresponding to position 87 of SEQ ID NO:63. In some embodiments, the variant IgG Fc polypeptide comprises a serine substitution at a position corresponding to position 87 of SEQ ID NO:65. In some embodiments, the variant IgG Fc polypeptide comprises a serine at a position corresponding to position 87 of SEQ ID NO:66. In some embodiments, the variant IgG Fc polypeptide comprises an alanine at a position corresponding to position 198 of SEQ ID NO:80. In some embodiments, the variant IgG Fc polypeptide comprises an alanine at a position corresponding to position 198 of SEQ ID NO:81.

[0063] In some embodiments, the variant IgG Fc polypeptide comprises an arginine at position 93 of SEQ ID NO:2. In some embodiments, the variant IgG Fc polypeptide comprises an amino acid substitution at position 93 of SEQ ID NO:3. In some embodiments, the variant IgG Fc polypeptide comprises a serine at position 87 of SEQ ID NO:63. In some embodiments, the variant IgG Fc polypeptide comprises a serine at position 87 of SEQ ID NO:65. In some embodiments, the variant IgG Fc polypeptide comprises a serine at position 87 of SEQ ID NO:66. In some embodiments, the variant IgG Fc polypeptide comprises an alanine at position 198 of SEQ ID NO:80. In some embodiments, the variant IgG Fc polypeptide comprises an alanine at position 198 of SEQ ID NO:81.

[0064] In some embodiments, the variant IgG Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 78, SEQ ID NO: 79, or SEQ ID NO: 84. In some embodiments, the variant IgG Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 70, SEQ ID NO: 73, SEQ ID NO: 74, or SEQ ID NO: 77. In some embodiments, the variant IgG Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 82 or SEQ ID NO: 83. Exemplary variant IgG Fc polypeptides with modified interchain disulfide linkages

[0065] In some embodiments, the variant feline IgG Fc polypeptide has at least one additional interchain disulfide bond relative to the wild-type feline IgG Fc polypeptide. In some embodiments, the variant feline IgG Fc polypeptide has at least one additional interchain disulfide bond in the hinge region. In some embodiments, the variant feline IgG2 Fc polypeptide with at least one additional interchain disulfide bond has increased interchain stability relative to the wild-type feline IgG Fc polypeptide. In some embodiments, the variant IgG polypeptide has at least one amino acid modification to the hinge region relative to the wild-type IgG Fc polypeptide. In some embodiments, the wild-type IgG Fc polypeptide is a wild-type feline or equine IgG Fc polypeptide. In some embodiments, the variant IgG Fc polypeptide comprises a hinge region or a portion of a hinge region that is from an IgG Fc polypeptide of a different isotype. In some embodiments, the variant IgG Fc polypeptide comprises a hinge region from a wild-type feline IgG-1a Fc polypeptide, from a wild-type feline IgG-1b Fc polypeptide, or from a wild-type equine IgG1 Fc polypeptide. In some embodiments, the variant IgG2 Fc polypeptide has increased recombinant production and / or increased hinge disulfide bond formation relative to the wild-type IgG Fc polypeptide. In some embodiments, the increased recombinant production and / or increased hinge disulfide bond formation can be determined by SDS-PAGE analysis under reducing and / or non-reducing conditions.

[0066] In some embodiments, the variant IgG Fc polypeptide comprises a cysteine ​​at a position corresponding to position 8, position 9, position 10, position 11, position 12, position 13, position 14, position 15, or position 16 of SEQ ID NO: 16. In some embodiments, the variant IgG Fc polypeptide comprises a cysteine ​​at position 8, position 9, position 10, position 11, position 12, position 13, position 14, position 15, or position 16 of SEQ ID NO: 16. In some embodiments, the variant IgG Fc polypeptide comprises SEQ ID NO: 17.

[0067] In some embodiments, the variant IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to position 16 of SEQ ID NO: 16, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 117, or SEQ ID NO: 118. In some embodiments, the variant IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to position 3 of SEQ ID NO: 129 and / or at a position corresponding to position 20 of SEQ ID NO: 129.

[0068] In some embodiments, the variant IgG Fc polypeptide comprises an amino acid substitution at position 16 of SEQ ID NO: 16, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 117, or SEQ ID NO: 118. In some embodiments, the variant IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to position 3 of SEQ ID NO: 129 and / or at a position corresponding to position 20 of SEQ ID NO: 129.

[0069] In some embodiments, the variant IgG Fc polypeptide comprises a proline at a position corresponding to position 16 of SEQ ID NO: 16, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 117, or SEQ ID NO: 118. In some embodiments, the variant IgG Fc polypeptide comprises a serine at a position corresponding to position 3 of SEQ ID NO: 129 and / or a proline at a position corresponding to position 20 of SEQ ID NO: 129.

[0070] In some embodiments, the variant IgG Fc polypeptide comprises a proline at position 16 of SEQ ID NO: 16, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 117, or SEQ ID NO: 118. In some embodiments, the variant IgG Fc polypeptide comprises a serine at position 3 of SEQ ID NO: 129, and / or a proline at position 20 of SEQ ID NO: 129.

[0071] In some embodiments, the variant IgG Fc polypeptide comprises SEQ ID NO:19, SEQ ID NO:125 or SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID N:134, SEQ ID NO:135. Exemplary variant IgG Fc polypeptides of heterodimeric polypeptides

[0072] In certain embodiments, the heterodimeric polypeptides provided herein are bispecific antibodies. Bispecific antibodies have binding specificity for two different epitopes or target molecules. In some embodiments, the bispecific antibodies bind to two different epitopes of the same target molecule. The bispecific antibodies can be full-length antibodies or antibody fragments.

[0073] In some embodiments, the heterodimeric polypeptide comprises a first variant IgG Fc polypeptide and a second variant IgG Fc polypeptide, wherein the first variant IgG Fc polypeptide comprises a "knob" mutation and the second variant IgG Fc polypeptide comprises a "hole" mutation. Non-limiting exemplary knob and hole mutations are described, for example, in Merchant, AM et al. An efficient route to human bispecific IgG. Nat Biotechnol, 16(7): 677-81 (1998).

[0074] In some embodiments, the variant canine or variant feline IgG Fc polypeptide comprises a section mutation. In some embodiments, the variant IgG Fc polypeptide comprises a tyrosine or tryptophan at a position corresponding to position 138 of SEQ ID NO: 1. In some embodiments, the variant IgG Fc polypeptide comprises a tyrosine or tryptophan at a position corresponding to position 137 of SEQ ID NO: 2. In some embodiments, the variant IgG Fc polypeptide comprises a tyrosine or tryptophan at a position corresponding to position 137 of SEQ ID NO: 3. In some embodiments, the variant IgG Fc polypeptide comprises a tyrosine or tryptophan at a position corresponding to position 138 of SEQ ID NO: 4. In some embodiments, the variant IgG Fc polypeptide comprises a tryptophan at a position corresponding to position 154 of SEQ ID NO: 16, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 117 or SEQ ID NO: 118.

[0075] In some embodiments, the variant IgG Fc polypeptide comprises a tyrosine or tryptophan at position 138 of SEQ ID NO: 1. In some embodiments, the variant IgG Fc polypeptide comprises a tyrosine or tryptophan at position 137 of SEQ ID NO: 2. In some embodiments, the variant IgG Fc polypeptide comprises a tyrosine or tryptophan at position 137 of SEQ ID NO: 3. In some embodiments, the variant IgG Fc polypeptide comprises a tyrosine or tryptophan at position 138 of SEQ ID NO: 4. In some embodiments, the variant IgG Fc polypeptide comprises a tryptophan at position 154 of SEQ ID NO: 16, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 117, or SEQ ID NO: 118.

[0076] In some embodiments, the variant IgG Fc polypeptide comprising a knob mutation comprises the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:109, SEQ ID NO:111, SEQ ID NO:113, SEQ ID NO:115, SEQ ID NO:119, SEQ ID NO:121, or SEQ ID NO:123.

[0077] In some embodiments, the variant canine or variant feline IgG Fc polypeptide comprises a hole mutation. In some embodiments, the variant IgG Fc polypeptide comprises a serine at a position corresponding to position 138, an alanine at a position corresponding to position 140, and / or a threonine at a position corresponding to position 181 of SEQ ID NO: 1. In some embodiments, the variant IgG Fc polypeptide comprises a serine at a position corresponding to position 137 of SEQ ID NO: 2, an alanine at a position corresponding to position 139 of SEQ ID NO: 2, and / or a threonine at a position corresponding to position 180 of SEQ ID NO: 2. In some embodiments, the variant IgG Fc polypeptide comprises a serine at a position corresponding to position 137 of SEQ ID NO: 3, an alanine at a position corresponding to position 139 of SEQ ID NO: 3, and / or a threonine at a position corresponding to position 180 of SEQ ID NO: 3. In some embodiments, the variant IgG Fc polypeptide comprises a serine at a position corresponding to position 138 of SEQ ID NO: 4, an alanine at a position corresponding to position 140 of SEQ ID NO: 4, and / or a threonine at a position corresponding to position 181 of SEQ ID NO: 4. In some embodiments, the variant IgG Fc polypeptide comprises a serine at a position corresponding to position 154 of SEQ ID NO: 16, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 117, or SEQ ID NO: 118, an alanine at a position corresponding to position 156 of SEQ ID NO: 16, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 117, or SEQ ID NO: 118, and / or a threonine at a position corresponding to position 197 of SEQ ID NO: 16, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 117, or SEQ ID NO: 118.

[0078] In some embodiments, the variant IgG Fc polypeptide comprises a serine at position 138 of SEQ ID NO: 1, an alanine at position 140 of SEQ ID NO: 1, and / or a threonine at position 181 of SEQ ID NO: 1. In some embodiments, the variant IgG Fc polypeptide comprises a serine at position 137 of SEQ ID NO: 2, an alanine at position 139 of SEQ ID NO: 2, and / or a threonine at position 181 of SEQ ID NO: 2. In some embodiments, the variant IgG Fc polypeptide comprises a serine at position 137 of SEQ ID NO: 3, an alanine at position 139 of SEQ ID NO: 3, and / or a threonine at position 181 of SEQ ID NO: 3. In some embodiments, the variant IgG Fc polypeptide comprises a serine at position 138 of SEQ ID NO: 4, an alanine at position 140 of SEQ ID NO: 4, and / or a threonine at position 181 of SEQ ID NO: 4. In some embodiments, the variant IgG Fc polypeptide comprises a serine at position 197 of SEQ ID NO: 16, position 154 of SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 117, or SEQ ID NO: 118, an alanine at position 197 of SEQ ID NO: 16, position 156 of SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 117, or SEQ ID NO: 118, and / or a threonine at position 197 of SEQ ID NO: 16, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 117, or SEQ ID NO: 118.

[0079] In some embodiments, the variant IgG Fc polypeptide comprising a hole mutation comprises the amino acid sequence of SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:110, SEQ ID NO:112, SEQ ID NO:114, SEQ ID NO:116, SEQ ID NO:120, SEQ ID NO:122, or SEQ ID NO:124.

[0080] In some embodiments, the adjacent polypeptide comprises a GLP1 polypeptide and a variant canine or feline IgG Fc polypeptide comprising a knob mutation. In some embodiments, the adjacent polypeptide comprises a glucagon polypeptide and a variant canine or feline IgG Fc polypeptide comprising a knob mutation. In some embodiments, the adjacent polypeptide comprises a GLP1 polypeptide and a variant canine or feline IgG Fc polypeptide comprising a hole mutation. In some embodiments, the adjacent polypeptide comprises a glucagon polypeptide and a variant canine or feline IgG Fc polypeptide comprising a knob mutation.

[0081] In some embodiments, the heterodimeric polypeptide comprises a first adjacent polypeptide comprising a GLP1 polypeptide and a variant canine or feline IgG Fc polypeptide comprising a knob mutation, and a second adjacent polypeptide comprising a glucagon polypeptide and a variant canine or feline IgG Fc polypeptide comprising a hole mutation. In some embodiments, the heterodimeric polypeptide comprises a first adjacent polypeptide comprising a glucagon polypeptide and a variant canine or feline IgG Fc polypeptide comprising a knob mutation, and a second adjacent polypeptide comprising a GLP1 polypeptide and a variant canine or feline IgG Fc polypeptide comprising a hole mutation. Exemplary GLP1 Polypeptides and Glucagon Polypeptides

[0082] As used herein, "GLP1" or "GLP1 polypeptide" is a polypeptide comprising whole or fragmented glucagon-like peptide-1 that binds to the glucagon-like peptide 1 receptor (GLP1R).

[0083] For example, "GLP1" refers to a GLP1 polypeptide from any vertebrate source, including mammals such as primates (e.g., humans and macaques), rodents (e.g., mice and rats), and companion animals (e.g., dogs, cats, and horses), unless otherwise indicated. In some embodiments, the GLP1 polypeptide is a wild-type GLP1 polypeptide, such as GLP1 (7-37) (SEQ ID N: 85). In some embodiments, the GLP1 polypeptide is a variant GLP1 polypeptide, such as GLP1 (7-36) (SEQ ID NO: 98), GLP1 (7-35) (SEQ ID NO: 99), GLP1-S8 (7-35) (SEQ ID NO: 86), or GLP1-G8 (7-35) (SEQ ID NO: 87). In some embodiments, GLP1 comprises the amino acid sequence SEQ ID NO: 20.

[0084] As used herein, "GLP1R" is a polypeptide comprising the whole or fragmented glucagon-like peptide 1 receptor capable of binding to wild-type GLP1.

[0085] For example, "GLP1R" refers to a GLP1R polypeptide from any vertebrate source, including mammals such as primates (e.g., humans and macaques), rodents (e.g., mice and rats), and companion animals (e.g., dogs, cats, and horses), unless otherwise indicated. In some embodiments, the GLP1R is an extracellular domain fragment that binds a wild-type GLP1 polypeptide. In some embodiments, the feline GLP1R comprises the amino acid sequence of SEQ ID NO: 49. In some embodiments, the feline GLP1R comprises the amino acid sequence of SEQ ID NO: 48.

[0086] An "extracellular domain" ("ECD") is the portion of a polypeptide that extends from the transmembrane domain and into the extracellular space. As used herein, the term "extracellular domain" may include a complete extracellular domain or may include a truncated extracellular domain lacking one or more amino acids that bind to its ligand. The combination of extracellular domains may depend on the algorithm used to determine what the amino acids are in the membrane. Different algorithms may predict different extracellular domains for a given protein, and different systems may express different extracellular domains.

[0087] "Glucagon" or "glucagon polypeptide" as used herein is a polypeptide comprising whole or fragmented glucagon that binds to the glucagon receptor.

[0088] For example, "glucagon" refers to a glucagon polypeptide from any vertebrate source, including mammals such as primates (e.g., humans and macaques), rodents (e.g., mice and rats), and companion animals (e.g., dogs, cats, and horses), unless otherwise indicated. In some embodiments, the glucagon polypeptide is a wild-type glucagon polypeptide, such as SEQ ID NO: 21. Exemplary variant IgG Fc polypeptides and fusion molecules

[0089] Polypeptides and other molecules may comprise variant IgG Fc polypeptides. In some embodiments, fusion molecules comprise variant IgG Fc polypeptides, such as variant IgG Fc polypeptides described herein. In some embodiments, antibodies or antibody fragments comprise variant IgG Fc polypeptides, such as variant IgG Fc polypeptides described herein.

[0090] As used herein, "fusion molecule" refers to a molecule comprising one or more "fusion partners". In some embodiments, the fusion partners are covalently linked ("fused"). If both fusion partners are polypeptides, the fusion partner polypeptides may be part of adjacent amino acid sequences (i.e., adjacent polypeptides). The first fusion partner polypeptide may be linked to the N-terminus or C-terminus of the second fusion partner. In some embodiments, the fusion partner is translated into a single polypeptide from the coding sequence encoding the two fusion partners. Fusion partners may be covalently linked in other ways, such as chemical links other than peptide bonds. A variety of known methods for covalently linking polypeptides to other molecules (e.g., fusion partners) may be used. In other embodiments, the fusion partners are fused by a "joint", which comprises at least one amino acid or chemical part. In some embodiments, the fusion partners are non-covalently linked. In some such embodiments, they may be connected, for example, using a binding pair. Exemplary binding pairs include, but are not limited to, biotin and avidin or streptavidin, antibodies and their antigens, and the like.

[0091] In some embodiments, the fusion partner includes an IgG Fc polypeptide and at least one GLP1 polypeptide. In some embodiments, the fusion partner includes an IgG Fc polypeptide, a GLP1 polypeptide, and a glucagon polypeptide. In some embodiments, the GLP1 polypeptide may be linked to the N-terminus or C-terminus of the IgG Fc polypeptide. In some embodiments, the glucagon polypeptide may be linked to the N-terminus or C-terminus of the IgG Fc polypeptide.

[0092] The term "contiguous polypeptide" herein is used to refer to an uninterrupted sequence of amino acids. A contiguous polypeptide is usually translated from a single continuous DNA sequence. It can be prepared by genetic engineering, for example, by removing the stop codon from the DNA sequence of the first protein and then attaching the DNA sequence in frame of the second protein so that the DNA sequence is expressed as a single protein. Typically, this is achieved by cloning a cDNA into an in-frame vector of an existing gene.

[0093] "Linker" refers to one or more amino acid residues that connect a first polypeptide to a second polypeptide.

[0094] In some embodiments, the joint is a flexible, non-structural joint. In some embodiments, the joint is a joint rich in glycine, rich in serine, or rich in glycine and serine. In some embodiments, the joint comprises 100%, at least 95%, at least 90% or at least 85% serine and / or glycine amino acid residues.

[0095] As used herein, "extension" refers to one or more amino acid residues attached to the C-terminus or N-terminus of a polypeptide.

[0096] In some embodiments, the extension is flexible. In some embodiments, the extension increases the flexibility of the polypeptide without interfering with the biological activity of the polypeptide. In some embodiments, the extension increases the solubility of the polypeptide. In some embodiments, the extension comprises one or more glycine residues. In some embodiments, the extension comprises one glycine (SEQ ID NO: 88), two glycine residues (SEQ ID NO: 89), three glycine residues (SEQ ID NO: 90), four glycine residues (SEQ ID NO: 91), five glycine residues (SEQ ID NO: 92), six glycine residues (SEQ ID NO: 93), seven glycine residues (SEQ ID NO: 94), eight glycine residues (SEQ ID NO: 95) or more glycine residues.

[0097] In some embodiments, the adjacent polypeptide comprises: an IgG Fc polypeptide comprising any of the following amino acid sequences: SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 100 , 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 139, 1 40, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 167, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172 2, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198 or 199; and a GLP1 polypeptide comprising the amino acid sequence of SEQ ID NO:85.In some embodiments, the adjacent polypeptide comprises: an IgG Fc polypeptide comprising any of the following amino acid sequences: SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 100 , 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 139, 1 40, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 167, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172 2, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198 or 199; and a GLP1 polypeptide comprising the amino acid sequence of SEQ ID NO:86.In some embodiments, the adjacent polypeptide comprises: an IgG Fc polypeptide comprising any of the following amino acid sequences: SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 100 , 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 139, 1 40, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 167, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172 2, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198 or 199; and a GLP1 polypeptide comprising the amino acid sequence of SEQ ID NO:87.In some embodiments, the adjacent polypeptide comprises: an IgG Fc polypeptide comprising any of the following amino acid sequences: SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 100 , 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 139, 1 40, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 167, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172 2, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198 or 199; and a GLP1 polypeptide comprising the amino acid sequence of SEQ ID NO:98.In some embodiments, the adjacent polypeptide comprises: an IgG Fc polypeptide comprising any of the following amino acid sequences: SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 100 , 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 139, 1 40, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 167, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172 2, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198 or 199; and a GLP1 polypeptide comprising the amino acid sequence of SEQ ID NO:99.

[0098] In some embodiments, the adjacent polypeptide comprises: an IgG Fc polypeptide comprising any of the following amino acid sequences: SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 100 , 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 139, 1 40, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 167, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172 , 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198 or 199; and a glucagon polypeptide comprising the amino acid sequence of SEQ ID NO:21.

[0099] In some embodiments, the contiguous polypeptide comprises a first GLP1 polypeptide (GLP1A), a first linker (L1), an Fc polypeptide of a companion animal species, an optional second linker (L2), and an optional second GLP1 polypeptide (GLP1B). In some embodiments, the contiguous polypeptide comprises: Formula (I): GLP1A-L1-Fc; Formula (II): Fc-L1-GLP1A; or Formula (III): GLP1A—L1—Fc—L2—GLP1B.

[0100] In some embodiments, the adjacent polypeptide comprises a GLP1 polypeptide, a first linker (L1), an Fc polypeptide, a second linker (L2), and a glucagon polypeptide (Gluc). In some embodiments, the adjacent polypeptide comprises: Formula (IV): GLP1-L1-Fc-L2-Gluc; or Formula (V): Gluc—L1—Fc—L2—GLP1.

[0101] In some embodiments, the GLP1 fusion molecule has an increased serum half-life peptide compared to wild-type GLP1. The increased half-life of the GLP1 fusion molecules described herein may require lower doses and less frequent dosing regimens compared to wild-type GLP1 polypeptides.

[0102] In some embodiments, GLP1B, if present, comprises the same amino acid sequence as GLP1A.

[0103] In some embodiments, GLP1, GLP1A or GLP1B, if present, comprises a wild-type GLP1 polypeptide. In some embodiments, GLP1, GLP1A or GLP1B, if present, comprises a variant GLP1 polypeptide. In some embodiments, GLP1, GLP1A or GLP1B, if present, comprises the amino acid sequence SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 98 or SEQ ID NO: 99.

[0104] In some embodiments, the glucagon polypeptide comprises a wild-type glucagon polypeptide. In some embodiments, the glucagon polypeptide comprises the amino acid sequence of SEQ ID NO: 21. In some embodiments, the glucagon polypeptide comprises a variant glucagon polypeptide.

[0105] In some embodiments, the Fc polypeptide is human IgG Fc. In some embodiments, the Fc polypeptide is human IgG1 Fc, human IgG2 Fc, human IgG3 Fc or human IgG4 Fc. In some embodiments, the Fc polypeptide is a variant human IgG Fc.

[0106] In some embodiments, the Fc polypeptide is an IgG Fc from a companion animal. In some embodiments, the Fc polypeptide is canine IgG-A Fc, canine IgG-B Fc, canine IgG-CFc, canine IgG-D Fc. In some embodiments, the Fc is equine IgG1 Fc, equine IgG2 Fc, equine IgG3 Fc, equine IgG4 Fc, equine IgG5 Fc, equine IgG6 Fc, or equine IgG7 Fc. In some embodiments, the Fc is feline IgG1a Fc, feline IgG1b Fc, or feline IgG2 Fc.

[0107] In some embodiments, the Fc polypeptide is a variant IgG Fc. In some embodiments, the FC polypeptide is a variant canine IgG-A Fc, a variant canine IgG-B Fc, a variant canine IgG-CFc, a variant canine IgG-D Fc. In some embodiments, the Fc is a variant equine IgG1 Fc, a variant equine IgG2 Fc, a variant equine IgG3 Fc, a variant equine IgG4 Fc, a variant equine IgG5 Fc, a variant equine IgG6 Fc, or a variant equine IgG7 Fc. In some embodiments, the Fc is a variant feline IgG1a Fc, a variant feline IgG1b Fc, or a variant feline IgG2 Fc.

[0108] In some embodiments, L1 and L2, if present, are each independently a flexible linker. In some embodiments, the amino acid sequences of L1 and L2, if present, each independently comprise 100%, at least 95%, at least 90%, at least 85% of serine and / or glycine amino acid residues.

[0109] In some embodiments, the adjacent polypeptide comprises an extension at its C-terminus. In some embodiments, the adjacent polypeptide comprises one glycine, two glycine residues, three glycine residues, four glycine residues, five glycine residues, six glycine residues, seven glycine residues, eight glycine residues, or more than eight glycine residues at its C-terminus. In some embodiments, the adjacent polypeptide comprises the amino acid sequence SEQ ID NO:88, SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, or SEQ ID NO:95 at its C-terminus.

[0110] In some embodiments, the contiguous polypeptide comprises the amino acid sequence of SEQ ID NO:23; SEQ ID NO:24; SEQ ID NO:25; SEQ ID NO:26; SEQ ID NO:27; SEQ ID NO:28; SEQ ID NO:29; SEQ ID NO:30; SEQ ID NO:31; SEQ ID NO:32; SEQ ID NO:33; SEQ ID NO:34; SEQ ID NO:35; SEQ ID NO:36; SEQ ID NO:37; SEQ ID NO:38; SEQ ID NO:39; SEQ ID NO:40; SEQ ID NO:41; SEQ ID NO:42; SEQ ID NO:43; SEQ ID NO:44; SEQ ID NO:45; SEQ ID NO:46; SEQ ID NO:47, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:52; SEQ ID NO:53; SEQ ID NO:54; SEQ ID NO:55; SEQ ID NO:56; SEQ ID NO:57; SEQ ID NO:58; SEQ ID NO:59; SEQ ID NO:103; SEQ ID NO:104; SEQ ID NO:105; or SEQ ID NO:106.

[0111] The nucleotide sequence encoding the polypeptide of interest described herein, such as the variant IgG Fc polypeptide or other polypeptide, can be inserted into an expression vector suitable for expression in a selected host cell. The variant IgG Fc polypeptide or other polypeptide described herein can be expressed by culturing a host cell transfected with an expression vector containing the nucleotide sequence.

[0112] A "vector" is a plasmid that can be used to transfer a DNA sequence from one organism to another or to express a gene of interest. A vector typically includes an origin of replication and regulatory sequences that regulate the expression of the gene of interest, and may or may not carry a selectable marker gene, such as an antibiotic resistance gene. The vector is suitable for use in a host cell in which it is to be expressed. When a gene of interest is present in a vector, the vector may be referred to as a "recombinant vector."

[0113] "Host cell" refers to a cell that can or has received a vector or isolated polynucleotide. Host cells can be prokaryotic or eukaryotic. Exemplary eukaryotic cells include mammalian cells, such as primate or non-primate cells; fungal cells, such as yeast; plant cells; and insect cells. Non-limiting exemplary mammalian cells include, but are not limited to, NS0 cells, Host cells include cells (Cru cells), 293 cells and CHO cells, and derivatives thereof, such as 293-6E, DG44, CHO-S and CHO-K cells. Host cells include progeny of a single host cell, and due to natural, accidental or deliberate mutations, the progeny are not necessarily identical to the original parent cell (in morphology or in genomic DNA complement). Host cells include cells transfected in vivo with polynucleotides encoding the amino acid sequences provided herein.

[0114] As used herein, the term "isolated" refers to a molecule that has been separated from at least some of the components that are commonly found or produced in nature. For example, a polypeptide is referred to as "isolated" when it is separated from at least some of the components of the cell that produced the polypeptide. In the case where the polypeptide is secreted by a cell after expression, the supernatant containing the polypeptide is physically separated from the cell that produced the polypeptide, and is considered to be "isolating" the polypeptide. Similarly, a polynucleotide is referred to as "isolated" when it is not part of a larger polynucleotide that is commonly found in nature (such as, for example, in the case of a DNA polynucleotide, genomic DNA or mitochondrial DNA) or is separated therein from at least some of the components of the cell that produced it (for example, in the case of an RNA polynucleotide). Therefore, a DNA polynucleotide contained in a vector within a host cell can be referred to as "isolated".

[0115] "Signal sequence" refers to a sequence of amino acid residues, or a polynucleotide sequence encoding the same, that promotes secretion of a polypeptide of interest and is typically cleaved by exporting the polypeptide to the outside of the cell surface membrane.

[0116] In some embodiments, the variant IgG Fc polypeptides or adjacent polypeptides containing the variant Fc polypeptides are separated using chromatography, such as size exclusion chromatography, ion exchange chromatography, protein A column chromatography, hydrophobic interaction chromatography, and CHT chromatography.

[0117] The label can be attached to the variant IgG Fc polypeptide or an adjacent polypeptide containing the variant Fc polypeptide. "Label" means a portion attached to a molecule to make it detectable. In some embodiments, the variant IgG Fc polypeptide or an adjacent polypeptide containing the variant Fc polypeptide is labeled with a detectable portion, including but not limited to radioisotopes, fluorescent labels, and various enzyme substrate labels known in the art. In some embodiments, the label is a detectable marker that can produce a signal that can be detected visually or instrumentally, for example, a polypeptide incorporating a radiolabeled amino acid or attached to a biotin portion that can be detected by a labeled avidin (e.g., streptavidin containing a fluorescent marker or enzymatic activity, which can be detected by optical or colorimetric methods). Examples of labels for polypeptides include, but are not limited to, the following: a radioisotope or radionuclide (e.g., 3 H.14 C. 35 S. 90 Y. 99 Tc, 111 In, 125 I. 131 I. 177 Lu, 166 Ho or 153 Sm); chromogens, fluorescent labels (e.g., FITC, rhodamine, lanthanide phosphors), enzyme labels (e.g., beta-galactosidase, horseradish peroxidase, luciferase, alkaline phosphatase); chemiluminescent labels; biotinyl; a predicted polypeptide epitope recognized by a secondary reporter molecule (e.g., a leucine zipper pair sequence, a binding site for a secondary antibody, a metal binding domain, an epitope tag); and magnetic agents, such as gadolinium chelates. Representative examples of labels commonly used in immunoassays include light-generating moieties (e.g., acridine compounds) and fluorescence-generating moieties, such as fluorescein. In this regard, the moiety itself may be undetectably labeled, but may become detectable after reaction with another moiety. The general techniques described above for conducting a variety of immunoassays are known to those skilled in the art. Affinity of Exemplary Variant IgG Fc Polypeptides for Protein A and / or C1q and / or CD16

[0118] The binding affinity of the variant IgG Fc polypeptides described herein to protein A and / or C1q and / or CD16 may be altered. In some embodiments, the variant IgG Fc polypeptide has an enhanced binding affinity to protein A relative to the wild-type IgG Fc polypeptide. Such variant IgG Fc polypeptides can be purified by protein A column chromatography. In some embodiments, the variant IgG Fc polypeptide has a reduced binding affinity to C1q relative to the wild-type IgG Fc polypeptide. Such variant IgG Fc polypeptides may have a reduced complement-mediated immune response. In some embodiments, the variant IgG Fc polypeptide has a reduced binding affinity to CD16 relative to the wild-type IgG Fc polypeptide. Such variant IgG Fc polypeptides may have a reduced ADCC immune response. In some embodiments, the variant IgG Fc polypeptide has an enhanced binding affinity to protein A relative to the wild-type IgG Fc polypeptide and / or has a reduced binding affinity to C1q relative to the wild-type IgG Fc polypeptide and / or has a reduced binding affinity to CD16 relative to the wild-type IgG Fc polypeptide.

[0119] As used herein, "Protein A" is a polypeptide comprising all or part of Protein A that is capable of binding to wild-type canine IgG-B Fc, wild-type equine IgG1 Fc, wild-type equine IgG3 Fc, wild-type equine IgG4 Fc, wild-type equine IgG7 Fc, wild-type feline IgG1a Fc, wild-type feline IgG1b Fc, or wild-type feline IgG2 Fc.

[0120] "C1q" or "C1q complex" are used interchangeably and refer to a protein complex involved in the complement system, or a portion thereof, that binds wild-type canine IgG-B Fc, wild-type canine IgG-C Fc, wild-type equine IgG1 Fc, wild-type equine IgG3 Fc, wild-type equine IgG4 Fc, wild-type equine IgG7 Fc, wild-type feline IgG1a Fc, or wild-type feline IgG1b Fc.

[0121] As used herein, "CD16" is a polypeptide comprising a whole or part of CD16 that is capable of binding to wild-type canine IgG-AFc or wild-type canine IgG-D Fc. The term "binding" to a substance is a term well known in the art, and methods for determining such binding are also well known in the art. A molecule is said to exhibit "binding" if it reacts, associates, or has an affinity for a specific cell or substance, and the reaction, association, or affinity can be detected by one or more methods known in the art, such as immunoblotting, ELISA, KinEx A, biofilm interferometry (BLI), surface plasmon resonance devices, and the like.

[0122] As used herein, "Protein A+" means that the Fc polypeptide has binding affinity to Protein A. In some embodiments, the Protein A+Fc polypeptide comprises at least one amino acid modification that increases the binding affinity to Protein A.

[0123] As used herein, "Protein A-" means that the Fc polypeptide has low or no Protein A binding affinity.

[0124] As used herein, "C1q+" means that the Fc polypeptide has C1q binding affinity.

[0125] As used herein, "C1q-" means that the Fc polypeptide has low or no C1q binding affinity. In some embodiments, the C1q-Fc polypeptide has at least one amino acid modification that reduces C1q binding affinity.

[0126] As used herein, "CD16+" means that the Fc polypeptide has CD16 binding affinity.

[0127] As used herein, "CD16-" means that the Fc polypeptide has low or no CD16 binding affinity. In some embodiments, the CD16-Fc polypeptide has at least one amino acid modification that reduces CD16 binding affinity.

[0128] The term "affinity" refers to the sum of the strengths of non-covalent interactions between a single binding site of a molecule (e.g., a receptor) and its binding partner (e.g., a ligand). The affinity of a molecule X for its partner Y can generally be expressed by the dissociation constant (K D ) Affinity can be measured by conventional methods known in the art, such as, for example, immunoblotting, ELISA, KinEx A, biolayer interference assay (BLI) or surface plasmon resonance device.

[0129] "Surface plasmon resonance" refers to an optical phenomenon that enables the analysis of real-time biospecific interactions by detecting changes in protein concentration within a biosensor matrix, for example using BIAcore TM System (BIAcore International AB, GE Healthcare company, Uppsala, Sweden and Piscataway, NJ). For further description see Jonsson et al., (1993) Ann. Biol. Clin. 51: 19-26.

[0130] "Bio-film interferometry" refers to an optical analysis technique that analyzes the interference pattern of light reflected from an immobilized protein layer and an internal standard layer at the tip of a biosensor. Changes in the number of molecules bound to the sensor tip cause a shift in the interference pattern that can be measured in real time. Non-limiting exemplary apparatus for bio-film interferometry is System (Pall ForteBio LLC). See, for example, Abdiche et al., 2008, Anal. Biochem. 377: 209-277.

[0131] As the term "K D ”, “K d ”, “Kd” or “Kd value” refers to the equilibrium dissociation constant of a receptor-ligand interaction or an antibody-antigen interaction.

[0132] In some embodiments, the variant IgG Fc polypeptide binds to Protein A with a dissociation constant (K D ) is less than 5x 10 -6 M, less than 1x 10 -6 M, less than 5x 10 -7 M, less than 1x 10 -7 M, less than 5x 10-8 M, less than 1x 10 -8 M, less than 5x10 -9 M, less than 1x 10 -9 M, less than 5x 10 -10 M, less than 1x 10 -10 M, less than 5x 10 -11 M, less than 1x 10 -11 M, less than 5x10 -12 M or less than 1x 10 -12 M, as determined by biofilm interferometry.

[0133] In some embodiments, the variant IgG Fc polypeptide binds to C1q or CD16 with a dissociation constant (K D ) is greater than 5x 10 -6 M, greater than 1x 10 -5 M, greater than 5x 10 -5 M, greater than 1x10 -4 M, greater than 5x 10 -4 M or greater than 1x 10 -3 M, as determined by biofilm interferometry.

[0134] In some embodiments, the IgG Fc polypeptide (such as a variant IgG Fc polypeptide) has a Kp1 affinity for protein A or for C1q or for CD16. D is through the use of biofilm interference assays using biosensors such as The system (Pall ForteBio LLC, Fremont, CA) was used to measure the association rate constant (k) according to the supplier's instructions. Briefly, biotinylated protein A or C1q or CD16 was bound to the sensor tip and the association of IgG Fc polypeptide was monitored at the specified time or until steady state was reached. Dissociation can be monitored at the specified time or until steady state was reached. A blank curve of buffer only was subtracted to correct for any drift. The data were fit to a 2:1 binding model using ForteBio data analysis software to determine the association rate constant (k on ), dissociation rate constant (k off ) and Kd. Equilibrium dissociation constant (K D ) is calculated as k off / k on The term "kon" refers to the rate constant for the association of molecule X to its partner Y, and the term "koff" refers to the rate constant for the dissociation of molecule X or partner Y from the molecule X / partner Y complex.

[0135] "Increase" or "stimulate" refers to increase, improve or increase activity, function or quantity compared to a reference. In some embodiments, "increase" or "stimulate" refers to being able to cause an overall increase of about 5% or more, about 10% or more, about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, about 100% or more, about 125% or more, about 200% or more relative to a reference value. In some embodiments, "increase" or "stimulate" refers to being able to cause an overall increase of about 5% to about 50%, about 10% to about 20%, about 50% to about 100%, about 25% to about 70% relative to a reference value. In some embodiments, "increase" or "stimulate" refers to being able to cause an overall increase of 50% or more. In some embodiments, "increase" or "stimulate" refers to being able to cause an overall increase of 75%, 85%, 90%, 95% or more. In some embodiments, the above amount refers to the amount of stimulation or increase over a certain period of time relative to administration of a control (such as a placebo) over the same period of time.

[0136] In some embodiments, the variant IgG Fc polypeptide is capable of binding to Protein A with an affinity increased by about 5% or more, about 10% or more, about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, about 100% or more, about 125% or more, about 150% or more, about 200% or more relative to a reference IgG Fc polypeptide. In some embodiments, the variant IgG Fc polypeptide is capable of binding to Protein A with an affinity increased by about 5% to about 50%, about 10% to about 20%, about 50% to about 100%, about 25% to about 70% relative to a reference IgG Fc polypeptide. In some embodiments, the reference IgG Fc polypeptide is a wild-type IgG Fc polypeptide. In some embodiments, the reference IgG Fc polypeptide is a different variant IgG Fc polypeptide.

[0137] "Reducing" or "inhibiting" means reducing, decreasing or stopping an activity, function or quantity relative to a reference. In some embodiments, "reducing" or "inhibiting" means being able to cause an overall reduction of about 5% or more, about 10% or more, about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more or about 90% or more relative to a reference IgG Fc polypeptide. In some embodiments, "reducing" or "inhibiting" means being able to cause an overall reduction of about 5% to about 50%, about 10% to about 20%, about 50% to about 100%, about 25% to about 70% relative to a reference value. In some embodiments, "reducing" or "inhibiting" means being able to cause an overall reduction of 50% or more. In some embodiments, "reducing" or "inhibiting" means being able to cause an overall reduction of 75%, 85%, 90%, 95% or more. In some embodiments, the above amount refers to the amount inhibited or reduced over a certain period of time relative to a control (such as a placebo) administered over the same period of time.

[0138] In some embodiments, the variant IgG Fc polypeptide can bind to C1q or CD16 with an affinity that is reduced by about 5% or more, about 10% or more, about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more relative to a reference IgG Fc polypeptide. In some embodiments, the variant IgG Fc polypeptide can bind to C1q or CD16 with an affinity that is reduced by about 5% to about 50%, about 10% to about 20%, about 50% to about 100%, about 25% to about 70% relative to a reference IgG Fc polypeptide. In some embodiments, the reference IgG Fc polypeptide is a wild-type IgG Fc polypeptide. In some embodiments, the reference IgG Fc polypeptide is a different variant IgG Fc polypeptide.

[0139] As used herein, "reference" refers to any sample, standard or level used for comparison purposes. The reference can be a wild-type reference or a variant reference. The reference can be obtained from a healthy or non-diseased sample. In some instances, the reference is obtained from a non-diseased or untreated sample of a companion animal. In some instances, the reference is obtained from one or more healthy animals of a particular species rather than the animal being tested or treated. Exemplary Biological Activities of Variant GLP1 Fusion Molecules

[0140] In some embodiments, the GLP1 fusion molecule binds to the GLP1R and activates cAMP production. In some embodiments, the GLP1 fusion polypeptide increases the production of intracellular cAMP by 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 60%, at least 70%, at least 80%, at least 90%, or 100% compared to the signaling function in the absence of the GLP1 fusion polypeptide. Exemplary Pharmaceutical Compositions

[0141] The terms "pharmaceutical formulation" and "pharmaceutical composition" refer to a preparation that is in such form as to render the biological activity of one or more active ingredients effective, and that contains no other components that are unacceptably toxic to a subject to which the formulation would be administered.

[0142] "Pharmaceutically acceptable carrier" refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material, formulation aid or carrier conventional in the art for use with a therapeutic agent, which together comprise a "pharmaceutical composition" for administration to a subject. A pharmaceutically acceptable carrier is non-toxic to the recipient at the dosage and concentration employed and is compatible with the other ingredients of the formulation. The pharmaceutically acceptable carrier is suitable for the formulation employed. Examples of pharmaceutically acceptable carriers include alumina; aluminum stearate; lecithin; serum proteins such as human serum albumin, canine or other animal albumin; buffers such as phosphate, citrate, tromethamine or HEPES buffers; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide or magnesium trisilicate; polyvinyl pyrrolidone, a cellulose-based substance; polyethylene glycol; sucrose; mannitol; or amino acids, including but not limited to arginine.

[0143] The pharmaceutical composition can be stored in a lyophilized form; therefore, in some embodiments, the preparation process includes a lyophilization step. The lyophilized composition can then be reconstituted before being applied to a dog, cat or horse, typically as an aqueous composition suitable for parenteral administration. In other embodiments, particularly when the variant IgG Fc polypeptide or other polypeptides described herein are highly stable to thermal and oxidative denaturation, the pharmaceutical composition can be stored as a liquid, i.e., as an aqueous composition, which can be applied directly or in the case of appropriate dilution to a dog, cat or horse. The lyophilized composition can be reconstituted with sterile water for injection (WFI). An antibacterial agent such as benzyl alcohol may be included. Therefore, the present invention provides a pharmaceutical composition in solid or liquid form.

[0144] When administered, the pH of the pharmaceutical composition may be in the range of about pH 5 to about pH 8. If the compositions of the present invention are used for therapeutic purposes, they are sterile. Sterility can be achieved by any of several methods known in the art, including filtration through a sterile filtration membrane (e.g., a 0.2 micron membrane). Sterility may be maintained with or without the use of an antibacterial agent. Certain uses of Fc polypeptides and pharmaceutical compositions

[0145] Variant Fc polypeptide-containing polypeptides of the invention (such as variant IgG Fc polypeptides) or pharmaceutical compositions containing variant Fc polypeptides of the invention may be useful for extending product half-life in vivo in companion animals (including but not limited to canines, cats or horses).

[0146] As used herein, "treatment" is a method for obtaining a beneficial or desired clinical outcome. As used herein, "treatment" includes any administration or application of a therapeutic agent for a disease in a mammal (including a companion animal). For the purposes of this disclosure, a beneficial or desired clinical outcome includes, but is not limited to, any one or more of the following: alleviating one or more symptoms, reducing the extent of the disease, preventing or delaying the spread of the disease, preventing or delaying the recurrence of the disease, delaying or slowing the progression of the disease, improving the disease state, inhibiting the disease or disease progression, inhibiting or slowing the disease or disease progression, stagnating the development of the disease and alleviating (whether in part or in whole). "Treatment" also encompasses the pathological consequences of reducing proliferative diseases. The method provided herein takes into account any one or more of these treatment aspects. Consistent with the above, the term treatment does not require 100 percent removal of all aspects of the disease.

[0147] A "therapeutically effective amount" of a substance / molecule, agonist or antagonist may vary according to factors such as the type of disease to be treated, the disease state, the severity and course of the disease, the type of therapeutic objective, any previous therapy, clinical history, response to previous treatment, the judgment of the attending veterinarian, the age, sex and weight of the animal, and the ability of the substance / molecule, agonist or antagonist to elicit a desired response in the animal. A therapeutically effective amount is also an amount in which the beneficial effects of the treatment outweigh any toxic or deleterious effects of the substance / molecule, agonist or antagonist. A therapeutically effective amount may be delivered in one or more administrations. A "therapeutically effective amount" refers to an amount that is effective to achieve a desired therapeutic or preventive result at the necessary dosage and for the necessary period of time.

[0148] In some embodiments, the variant IgG Fc polypeptides or other polypeptides described herein or pharmaceutical compositions comprising the same are administered parenterally by subcutaneous administration, intravenous infusion or intramuscular injection. In some embodiments, the variant IgG Fc polypeptides or other polypeptides described herein or pharmaceutical compositions comprising the same are administered as a push injection or continuous infusion for a period of time. In some embodiments, the variant IgG Fc polypeptides or other polypeptides described herein or pharmaceutical compositions comprising the same are administered by intramuscular, intraperitoneal, intracerebrospinal, subcutaneous, intraarterial, intrasynovial, intrathecal or inhalation routes.

[0149] In some embodiments, the GLP1 fusion polypeptide or pharmaceutical composition comprising the same can be used to treat hyperglycemia-related conditions according to the methods herein. In some embodiments, the GLP1 fusion polypeptide or pharmaceutical composition is administered to a companion animal, such as a canine, feline, or equine, to treat a hyperglycemia-related condition.

[0150] In some embodiments, the variant IgG Fc polypeptide or other polypeptide described herein or a pharmaceutical composition containing the same can be administered in an amount ranging from 0.0001 mg / kg body weight to 100 mg / kg body weight / dose. In some embodiments, the GLP1 analog can be administered in an amount ranging from 0.005 mg / kg body weight to 20 mg / kg body weight / dose. In some embodiments, the GLP1 analog can be administered in an amount ranging from 1 mg / kg body weight to 10 mg / kg body weight / dose. In some embodiments, the GLP1 analog can be administered in an amount ranging from 0.5 mg / kg body weight to 100 mg / kg body weight, ranging from 1 mg / kg body weight to 100 mg / kg body weight, ranging from 5 mg / kg body weight to 100 mg / kg body weight, ranging from 10 mg / kg body weight to 100 mg / kg body weight, ranging from 20 mg / kg body weight to 100 mg / kg body weight, ranging from 50 mg / kg body weight to 100 mg / kg body weight, ranging from 1 mg / kg body weight to 10 mg / kg body weight, ranging from 5 mg / kg body weight to 10 mg / kg body weight, ranging from 0.5 mg / kg body weight to 10 mg / kg body weight, or ranging from 5 mg / kg body weight to 50 mg / kg body weight.

[0151] In some embodiments, the variant IgG Fc polypeptides or other polypeptides described herein or pharmaceutical compositions containing the same may be administered to companion animals once or over a series of treatments. In some embodiments, the dosage is administered once a week for at least two or three consecutive weeks, and in some embodiments, the treatment cycle is repeated two or three times, optionally with one or more weeks without treatment. In other embodiments, the therapeutically effective dosage is administered once a day for two to five consecutive days, and in some embodiments, the treatment cycle is repeated two or more times, optionally with one or more days or one or more weeks without treatment.

[0152] "Combination" with one or more other therapeutic agents is used, including simultaneous (concurrent) and continuous or sequential administration in any order. The term "concurrent" is used herein to refer to the administration of two or more therapeutic agents in the case where at least part of the administration is overlapping in time, or the administration of one therapeutic agent occurs in a short time relative to the administration period of other therapeutic agents. For example, two or more therapeutic agents are administered at a time interval of no more than about a specified number of minutes. The term "sequentially" is used herein to refer to the continued administration of one or more medicaments after interrupting the administration of one or more other medicaments, or the administration of two or more therapeutic agents in the case of starting to administer one or more medicaments before administering one or more other medicaments. For example, two or more therapeutic agents are administered at a time interval greater than about a specified number of minutes. As used herein, the term "in combination with..." refers to the administration of a therapeutic form in addition to another form of treatment. Therefore, "in combination with..." refers to the administration of a therapeutic form before, during, or after administering another form of treatment to an animal.

[0153] In some embodiments, the dosage is administered once a week for at least two or three consecutive weeks, and in some embodiments, the treatment cycle is repeated twice or more, optionally with one or more weeks without treatment. In other embodiments, the therapeutically effective dosage is administered once a day for two to five consecutive days, and in some embodiments, the treatment cycle is repeated twice or more, optionally with one or more days or one or more weeks without treatment.

[0154] "Combination" administration with one or more other therapeutic agents includes simultaneous (concurrent) and continuous or sequential administration in any order. The term "concurrent" is used herein to refer to the administration of two or more therapeutic agents when at least part of the administration overlaps in time or the administration of one therapeutic agent occurs in a short time relative to the administration of another therapeutic agent. For example, the two or more therapeutic agents are administered at a time interval of no more than about a specified number of minutes. The term "sequentially" is used herein to refer to the continued administration of one or more medicaments after interrupting the administration of one or more other medicaments, or the administration of two or more therapeutic agents when one or more medicaments are started before the administration of one or more other medicaments. For example, the two or more therapeutic agents are administered at a time interval exceeding about a specified number of minutes. As used herein, the term "in combination with..." refers to the administration of a therapeutic form in addition to another form of treatment. Therefore, "in combination with..." refers to the administration of a therapeutic form before, during or after the administration of another form of treatment to an animal.

[0155] In some embodiments, the method comprises administering in combination with GLP1 fusion polypeptide insulin, DPP4 inhibitors, SGLT2 inhibitors, biguanide drugs sulfonylureas, meglitinide derivatives, α-glucosidase inhibitors, thiazolidinediones (TZDs), amylin mimetics, bile acid sequestrants, and dopamine agonists.

[0156] The following examples illustrate specific aspects of the disclosure and are not intended to limit the disclosure in any way. Example Example 1 Variant canine IgG Fc polypeptides with increased protein A binding and / or decreased complement binding and / or decreased CD16 binding

[0157] The use of protein A affinity to purify antibodies is a well-established process. However, of the four subtypes of canine IgG, only IgG-B Fc (e.g., SEQ ID NO: 2 or SEQ ID NO: 107) has protein A binding affinity. Canine IgG-A Fc (e.g., SEQ ID NO: 1), IgG-C Fc (e.g., SEQ ID NO: 3 or SEQ ID NO: 108), and IgG-D Fc (e.g., SEQ ID NO: 4) have weak or unmeasurable protein A binding affinity. Variant canine IgG-A Fc, IgG-C Fc, and IgG-D Fc polypeptides were designed to alter protein A binding.

[0158] Furthermore, canine IgG-B Fc and IgG-C Fc have complement activity and bind to C1q, whereas canine IgG-A Fc and IgG-D Fc have weak or unmeasurable binding affinity for C1q.To potentially reduce C1q binding and / or potentially reduce complement-mediated immune responses, variant canine IgG-B Fc and IgG-C Fc polypeptides were designed.

[0159] In addition, canine IgG-B Fc and IgG-C Fc have CD 16 binding activity. In order to potentially reduce the binding of CD16 to IgG-B Fc and IgG-C Fc, and / or to potentially reduce ADCC, variant canine IgG-B Fc and IgG-C Fc polypeptides were designed.

[0160] Table 3 below summarizes the Protein A and C1q binding properties of canine IgG Fc subtypes. Note that none of the wild-type canine IgG Fc subtypes lack C1q binding and bind Protein A.

[0161] Table 3 Wild-type canine IgG Fc Protein A binding C1q binding CD16 binding IgG-A Fc - - - IgG-B Fc + + + IgG-C Fc - + + IgG-D Fc - - - (-) indicates low or unmeasurable binding activity.

[0162] Using three-dimensional protein modeling and protein sequence analysis, sequences of canine IgG-B Fc that have the potential to contact Protein A were identified. Figure 1 An alignment of canine IgG-A, B, C and D Fc sequences is shown. Boxes indicate regions that are likely to contact protein A.

[0163] Variant canine IgG-A, IgG-C, and IgG-D Fc polypeptides can be designed to increase protein A binding using two approaches. For the first approach, variant canine IgG-A, IgG-C, and IgG-D Fc polypeptides are designed to have the same protein A binding motif sequence as canine IgG-B Fc (e.g., SEQ ID NO:5, SEQ ID NO:6, and SEQ ID NO:7, respectively). For the second approach, variant canine IgG-A Fc I(21)T / Q(207)H (SEQ ID NO:60), variant canine IgG-C Fc I(21)T (SEQ ID NO:61), and variant canine IgG-D Fc I(21)T / Q(207)H (SEQ ID NO:62) are designed to have one or two amino acid substitutions in the protein A binding region to correspond to the canine IgG-B Fc sequence.

[0164] Additionally, variant canine IgG-A Fc, IgG-C Fc, and IgG-D Fc polypeptides with increased Protein A binding may be prepared having one or more of the amino acid substitutions listed in Table 4.

[0165] Table 4 *Amino acid positions listed are relative to the indicated SEQ ID NO.

[0166] To potentially reduce the binding of C1q to canine IgG-B Fc and IgG-C Fc, and / or to potentially reduce complement-mediated immune responses, variant canine IgG-B Fc and IgG-C Fc polypeptides can be prepared that have an amino acid substitution corresponding to position 93 of SEQ ID NO:2 or SEQ ID NO:3, respectively, replacing Lys with any amino acid other than Lys. These amino acid substitutions can be determined following comparative analysis of the protein sequence and 3-D structural models of canine IgG-B Fc and IgG-C Fc with canine IgG-A Fc and IgG-D Fc, which are understood not to exhibit complement activity. For example, a variant canine IgG-B Fc K(93)R (SEQ ID NO:78) and a variant canine IgG-C Fc K(93)R (SEQ ID NO:79) can be prepared. Reduced binding of human C1q to a fusion protein comprising the variant canine IgG-B Fc K(93)R was observed when compared to a fusion protein comprising wild-type canine IgG-B Fc.

[0167] To potentially reduce CD16 binding to IgG-B Fc and IgG-C Fc, and / or to potentially reduce ADCC, variant canine IgG-B Fc and IgG-C Fc polypeptides may be prepared having one or more amino acid substitutions as listed in Table 5. The amino acid substitutions may be determined following comparative analysis of the protein sequences and 3-D structural models of canine IgG-B and IgG-C with IgG-A and IgG-D, which are understood not to exhibit ADCC activity.

[0168] Table 5 *Amino acid positions listed are relative to the indicated SEQ ID NO.

[0169] Since wild-type canine IgG-C Fc lacks protein A binding and has C1q binding, a double variant canine IgG-C that binds to protein A and has reduced binding to C1q can be prepared by combining one or more amino acid substitutions listed in Table 4 with K(93)R substitutions or K(93)X substitutions, wherein X is any amino acid except Lys. A double variant canine IgG-B Fc or double variant canine IgG-C Fc that has reduced binding to C1q and reduced binding to CD16 can be prepared by combining one or more amino acid substitutions listed in Table 5 with K(93)R substitutions or K(93)X substitutions, wherein X is any amino acid except Lys. A triple variant canine-IgG-C Fc that binds to protein A and has reduced binding to C1q and CD16 can be prepared by combining one or more amino acid substitutions listed in Table 4, one or more amino acid substitutions listed in Table 5 with K(93)R substitutions or K(93)X substitutions, wherein X is any amino acid except Lys.

[0170] Binding of any variant canine IgG Fc to Protein A, CD16 and / or C1q can be determined and compared to binding of another IgG Fc to Protein A, CD16 and / or C1q (e.g., a corresponding wild-type canine IgG Fc, another wild-type or variant canine IgG Fc, or a wild-type or variant IgG Fc from another companion animal, etc.).

[0171] Binding analysis can be performed using the Octet biosensor. Briefly, a target molecule (e.g., Protein A, C1q, CD16, etc.) can be biotinylated and free, unreacted biotin removed (e.g., by dialysis). The biotinylated target molecule is captured on a streptavidin sensor tip. The association between the target molecule and various concentrations (e.g., 10 μg / mL) of IgG Fc polypeptide is monitored for a specified time, or until steady state is reached. Dissociation is monitored for a specified time, or until steady state is reached. A blank curve with only buffer can be subtracted from this to correct for any offset. Using the ForteBio TM The data analysis software fits the data to a 1:1 binding model to determine k on , k off and K d . Example 2 Variant equine IgG Fc polypeptides with increased protein A binding and / or decreased complement fixation

[0172] Of the seven subtypes of equine IgG, IgG1 Fc (e.g., SEQ ID NO: 63), IgG3 Fc (e.g., SEQ ID NO: 65), IgG4 Fc (e.g., SEQ ID NO: 66), IgG7 Fc (e.g., SEQ ID NO: 69) have protein A binding affinity. Equine IgG2 Fc (e.g., SEQ ID NO: 18, SEQ ID NO: 64), IgG5 Fc (e.g., SEQ ID NO: 67), and IgG6 Fc (e.g., SEQ ID NO: 68) have weak or unmeasurable protein A binding affinity. Variant equine IgG2 Fc, IgG5 Fc, and IgG6 Fc polypeptides are designed to alter protein A binding.

[0173] Furthermore, equine IgG2 Fc, IgG5 Fc, and IgG6 Fc have weak or unmeasurable binding affinity for C1q, whereas equine IgG1 Fc, IgG3 Fc, IgG4 Fc, and IgG7 Fc bind to C1q. To potentially reduce C1q binding and / or potentially reduce complement-mediated immune responses, variant equine IgG1 Fc, IgG3 Fc, IgG4 Fc, and IgG7 Fc polypeptides were designed.

[0174] Table 6 below summarizes the Protein A and C1q binding properties of equine IgG Fc subtypes. Note that none of the wild-type equine IgG Fc subtypes lacked C1q binding and bound to Protein A.

[0175] Table 6 Wild-type horse IgG Fc Protein A binding C1q binding IgG1 Fc + + IgG2 Fc - - IgG3 Fc + + IgG4 Fc + + IgG5 Fc - - IgG6 Fc - - IgG7 Fc + + (-) indicates low or unmeasurable binding activity.

[0176] Using three-dimensional protein modeling and protein sequence analysis, sequences of equine IgG1 Fc, IgG3 Fc, IgG4 Fc, and IgG7 Fc that are likely to contact Protein A were identified. Variant equine IgG2 Fc, IgG5 Fc, and IgG6 Fc polypeptides with increased Protein A binding can be prepared having one or more of the amino acid substitutions listed in Table 7.

[0177] Table 7 *Amino acid positions listed are relative to the indicated SEQ ID NO.

[0178] For example, variant equine IgG2 Fc, IgG5 Fc, and IgG6 Fc polypeptides are designed to have one or more amino acid substitutions in the protein A binding region to correspond to wild-type equine IgG Fc that does bind protein A. Variant equine IgG2 Fc F(203)Y (SEQ ID NO:71) with increased protein A binding can be prepared; variant equine IgG2 Fc A(15)T / F(203)Y (SEQ ID NO:72); variant equine IgG5 Fc V(199)L / E(200)Y (SEQ ID NO:75); and variant equine IgG6 Fc I(199)L / R(200)H / H(201)N / T(202)H (SEQ ID NO:76).

[0179] To potentially reduce the binding of C1q to equine IgG1 Fc, IgG3 Fc, IgG4 Fc and IgG7 Fc, and / or to potentially reduce complement-mediated immune responses, variant canine IgG1 Fc, IgG3 Fc, IgG4 Fc and IgG7 Fc polypeptides may be prepared having an amino acid substitution of Lys with any amino acid other than Lys at the amino acid position corresponding to position 87 of SEQ ID NO: 63, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 69, respectively. These amino acid substitutions may be determined following comparative analysis of the protein sequences and 3-D structural models of equine IgG1 Fc, IgG3 Fc, IgG4 Fc and IgG7 Fc with equine IgG2 Fc, IgG5 Fc and IgG6 Fc, which are understood to exhibit no complement activity. For example, variant equine IgG1 Fc K(87)S (SEQ ID NO:70), variant equine IgG3 Fc K(87)S (SEQ ID NO:73), variant equine IgG4 Fc K(87)S (SEQ ID NO:74), and variant equine IgG7 Fc K(87)S (SEQ ID NO:77) can be prepared.

[0180] Binding of any variant equine IgG Fc to Protein A and / or C1q can be determined and compared to binding of another IgG Fc to Protein A and / or C1q (e.g., corresponding wild-type equine IgG Fc, another wild-type or variant equine IgG Fc, or a wild-type or variant IgG Fc from another companion animal, etc.) The binding assays described in Example 1 can be used. Example 3 Variant feline IgG Fc polypeptides with reduced complement fixation

[0181] Each of the three subtypes of feline IgG (IgG1a Fc (SEQ ID NO: 80 or SEQ ID NO: 117), IgG1b Fc (SEQ ID NO: 81 or SEQ ID NO: 118), and IgG2 Fc (SEQ ID NO: 16)) has protein A binding affinity. However, only feline IgG2 Fc has weak or unmeasurable binding affinity for C1q, while feline IgG1a Fc, IgG1b Fc bind to C1q. Variant feline IgG1a Fc and IgG1b Fc polypeptides were designed to potentially reduce C1q binding and / or potentially reduce complement-mediated immune responses.

[0182] The Protein A and C1q binding properties of feline IgG Fc subtypes are summarized in Table 8 below. Note that none of the wild-type feline IgG Fc subtypes lacks binding to C1q and binds to Protein A.

[0183] Table 8 (-) indicates low or unmeasurable binding activity.

[0184] To potentially reduce the binding of C1q to feline IgG1a Fc and IgG1b Fc, and / or to potentially reduce complement-mediated immune responses, variant feline IgG1a Fc and IgG1b Fc polypeptides can be prepared that have an amino acid substitution at the amino acid position corresponding to position 198 of SEQ ID NO: 80 or SEQ ID NO: 81, respectively, replacing Pro with any amino acid other than Pro. These amino acid substitutions can be determined after comparative analysis of the protein sequence and 3-D structural model of feline IgG1a Fc and IgG1b with feline IgG2 Fc, which is understood to exhibit no complement activity. For example, variant feline IgG1a Fc P(198)A (SEQ ID NO: 82) and variant feline IgG1b Fc P(198)A (SEQ ID NO: 83) can be prepared.

[0185] Binding of any variant feline IgG Fc to C1q can be determined and compared to binding of another IgG Fc to C1q (e.g., corresponding wild-type feline IgG Fc, another wild-type or variant feline IgG Fc, or a wild-type or variant IgG Fc from another companion animal, etc.) The binding assays described in Example 1 can be used. Example 4 Variant canine and feline IgG Fc polypeptides having heterodimeric proteins

[0186] In order to be able to prepare bispecific canine or feline antibodies or bifunctional canine or feline Fc fusion proteins using the knob-in-hole heterodimerization approach, pairing of variant canine IgG Fc polypeptides and variant feline IgG Fc polypeptides was investigated.

[0187] The following amino acid substitutions may be introduced into one Fc chain (heterodimer chain 1): an amino acid substitution (T138Y or T137Y) of threonine to tyrosine at a position corresponding to position 138 of canine IgG-A (SEQ ID NO: 1), at a position corresponding to position 137 of canine IgG-B Fc (SEQ ID NO: 2), at a position corresponding to position 137 of canine IgG-C Fc (SEQ ID NO: 3), or at a position corresponding to position 138 of canine IgG-D Fc (SEQ ID NO: 4). Examples of the amino acid sequences of variant canine IgG-A Fc, IgG-B Fc, IgG-C Fc, and IgG-D Fc heterodimer chain 1 are SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, and SEQ ID NO: 14, respectively.

[0188] The following amino acid substitutions may be introduced into the second Fc chain (heterodimer chain 2): an amino acid substitution (Y181T or Y180T) from tyrosine to threonine at a position corresponding to position 181 of canine IgG-A (SEQ ID NO: 1), at a position corresponding to position 180 of canine IgG-B Fc (SEQ ID NO: 2), at a position corresponding to position 180 of canine IgG-C Fc (SEQ ID NO: 3), or at a position corresponding to position 181 of canine IgG-D Fc (SEQ ID NO: 4). Examples of amino acid sequences of variant canine IgG-AFc, IgG-B Fc, IgG-C Fc, and IgG-D Fc heterodimer chain 2 are SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 13, and SEQ ID NO: 15, respectively.

[0189] The second pairing of variant canine IgG Fc heterodimer chains 3 and 4 was also studied. The following amino acid substitutions can be introduced into one Fc chain (heterodimer chain 3): an amino acid substitution (T138W) of threonine to tryptophan at a position corresponding to position 138 of canine IgG-A (SEQ ID NO: 1) or canine IgG-D (SEQ ID NO: 4), or an amino acid substitution (T137W) of threonine to tryptophan at a position corresponding to position 137 of canine IgG-B Fc (SEQ ID NO: 2) or canine IgG-C Fc (SEQ ID NO: 3). Examples of amino acid sequences of variant canine IgG-A Fc, IgG-B Fc, IgG-C Fc, and IgG-D Fc heterodimer chain 3 are SEQ ID NO: 109, SEQ ID NO: 111, SEQ ID NO: 113, and SEQ ID NO: 115.

[0190] The following amino acid substitutions may be introduced into the second Fc chain (heterodimer chain 4): an amino acid substitution from threonine to serine at a position corresponding to position 138 of canine IgG-A (SEQ ID NO: 1) or IgG-D (SEQ ID NO: 4), an amino acid substitution from leucine to alanine at a position corresponding to position 140 thereof, and an amino acid substitution from tyrosine to threonine at a position corresponding to position 181 thereof (T138S, L140A, Y181T); or, an amino acid substitution from threonine to serine at a position corresponding to position 137 of canine IgG-B Fc (SEQ ID NO: 2) or IgG-C (SEQ ID NO: 3), an amino acid substitution from leucine to alanine at a position corresponding to position 139 thereof, and an amino acid substitution from tyrosine to threonine at a position corresponding to position 180 thereof (T137S, L139A, Y180T). Examples of amino acid sequences of variant canine IgG-AFc, IgG-B Fc, IgG-C Fc and IgG-D Fc heterodimer chain 4 are SEQ ID NO:110, SEQ ID NO:112, SEQ ID NO:114 and SEQ ID NO:116.

[0191] The following amino acid substitution may be introduced into one Fc chain (heterodimer chain 1): an amino acid substitution of threonine to tryptophan (T154W) at a position corresponding to position 154 of feline IgG2 (SEQ ID NO: 16), feline IgG1a Fc (SEQ ID NO: 80 or SEQ ID NO: 117) or feline IgG1b Fc (SEQ ID NO: 81 or SEQ ID NO: 118). Examples of amino acid sequences of variant feline IgG2 Fc, IgG1a Fc and IgG1b Fc heterodimer chain 1 are SEQ ID NO: 119, SEQ ID NO: 121 and SEQ ID NO: 123, respectively.

[0192] The following amino acid substitutions may be introduced into the second Fc chain (heterodimer chain 4): an amino acid substitution of threonine to serine at a position corresponding to position 154 of feline IgG2 Fc (SEQ ID NO: 16), IgG-1a (SEQ ID NO: 80 or SEQ ID NO: 117) or IgG-1b Fc (SEQ ID NO: 81 or SEQ ID NO: 118), an amino acid substitution of leucine to alanine at a position corresponding to position 156 thereof, and an amino acid substitution of tyrosine to threonine at a position corresponding to position 197 thereof (T154S, L156A, Y197T). Examples of amino acid sequences of variant feline IgG2 Fc, IgG1a Fc and IgG1bB Fc heterodimer chain 4 are SEQ ID NO: 120, SEQ ID NO: 122 and SEQ ID NO: 124, respectively.

[0193] The pairing of variant canine IgG Fc heterodimer chains 1 and 2, the pairing of variant canine IgG Fc heterodimer chains 3 and 4, or the pairing of variant feline IgG Fc heterodimer chains 1 and 2 can allow Fc heterodimerization and prevent or reduce Fc homodimerization. Heterodimer chain 1 of a canine IgG subtype can be combined with heterodimer chain 2 of the same or different canine IgG subtype. Heterodimer chain 3 of a canine IgG subtype can be combined with heterodimer chain 4 of the same or different canine IgG subtype. Heterodimer chain 1 of a feline IgG subtype can be combined with heterodimer chain 2 of the same or different feline IgG subtype. This design enables bispecific canine or feline antibodies to dimerize. In addition, two different peptides or proteins or a combination of different proteins can be fused to the heterodimer Fc chain. For example, variant canine IgG Fc heterodimer chains or variant feline IgG Fc heterodimer chains can be used to obtain dual molecules of GLP1 and glucagon, such as a GLP1 polypeptide (e.g., SEQ ID NO: SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, or SEQ ID NO: 91) fused to a variant canine IgG-D Fc heterodimer chain 1 (e.g., SEQ ID NO: 14), and a glucagon polypeptide (e.g., SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, or SEQ ID NO: 95) fused to a variant canine IgG-D Fc heterodimer chain 2 (e.g., SEQ ID NO: 15). Example 5 GLP1 fusion protein

[0194] The amino acid sequence of GLP1 is conserved in humans, cats, dogs, and horses, among other species. The proteolytic breakdown products of GLP1, such as GLP1 (amino acids 7-37) (SEQ ID NO: 85), are rapidly degraded by dipeptidyl peptidase-4 (DPP-4), and it is understood that they have a short serum half-life of only a few minutes.

[0195] The design of contiguous polypeptides comprising at least one GLP1 polypeptide and a feline, canine, or equine IgG Fc polypeptide was investigated to generate a long-acting GLP1 fusion protein. The following constructs were designed: Formula (I): GLP1A-L1-Fc; Formula (II): Fc-L1-GLP1A; or Formula (III): GLP1A—L1—Fc—L2—GLP1B. wherein GLP1A is the first GLP1 polypeptide, GLP1B is the second GLP1 polypeptide, L1 and L2 are linkers; and Fc is the IgG Fc polypeptide of the companion animal species.

[0196] GLP1 was modified to confer resistance to DPP-4 by replacing alanine with glycine or serine at position 8 corresponding to wild-type GLP1 (7-37) (SEQ ID NO: 85). The minimal sequence of wild-type GLP1 (7-37) (SEQ ID NO: 87) binding to the N-terminal domain of mature feline GLP1R (SEQ ID NO: 49) was analyzed by a three-dimensional protein model of the complex. Based on this model, the two C-terminal amino acids were removed from the DPP-4 resistant GLP1 to generate GLP1-S8 (7-35) (SEQ ID NO: 86) and GLP1-G8 (7-35) (SEQ ID NO: 87) polypeptides.

[0197] When the GLP1 polypeptide is located at the C-terminus of the construct, such as in Formula II and III, the GLP1 polypeptide is not susceptible to degradation by DPP-4. Therefore, for a GLP1 polypeptide located at the C-terminus, the alanine does not need to be replaced by glycine or serine. Therefore, wild-type GLP1 (7-37) (SEQ ID NO: 85) can be used at the C-terminus.

[0198] The linker may be a flexible, non-structural linker, such as a linker rich in glycine and serine. A flexible extension may be added to the C-terminus of the adjacent polypeptide. The extension may comprise one glycine residue (SEQ ID NO: 88), two glycine residues (SEQ ID NO: 89), three glycine residues (SEQ ID NO: 90), four glycine residues (SEQ ID NO: 91), five glycine residues (SEQ ID NO: 92), six glycine residues (SEQ ID NO: 93), seven glycine residues (SEQ ID NO: 94), eight glycine residues (SEQ ID NO: 95) or more glycine residues. Example 6 GLP1 and feline IgG Fc fusion protein

[0199] Nucleotide sequences encoding: (1) a contiguous polypeptide of Formula I with a signal sequence, GLP1-G8(7-35) (SEQ ID NO: 87), a flexible linker, and wild-type feline IgG2 Fc (ssGLP1-G8_I_WTeIgG2; SEQ ID NO: 96); and (2) a contiguous polypeptide of Formula III with a signal sequence, GLP1-G8(7-35) (SEQ ID NO: 87), GLP1(7-35) (SEQ ID NO: 89), two flexible linkers, a 2G C-terminal extension, and wild-type feline IgG2 Fc (ssGLP1-G8 / GLP1-2G_III_WTeIgG2; SEQ ID NO: 97) were synthesized and cloned into separate mammalian expression vectors. Wild-type feline IgG2 Fc (SEQ ID NO: 16) with reduced complement activity and protein A binding was selected for ease of purification based on its low or no C1Q binding.

[0200] The obtained vectors were transfected into CHO cells respectively. The supernatant containing adjacent polypeptides without signal peptides (SEQ ID NO: 24 and 23) was collected and filtered. Protein A column ( Both proteins were affinity purified using Protein A affinity resin (Repligen). The proteins were determined to be monomeric as assessed by HPLC gel filtration. However, SDS-PAGE analysis in the absence or presence of a reducing agent (DTT) showed that a certain percentage of the two adjacent polypeptides moved to the same position in the gel ( Figure 2 A). This result suggests that the hinge of wild-type feline IgG2 Fc, which has only one pair of cysteine ​​residues, may not be sufficient to form efficient disulfide linkages.

[0201] The approximate position of the feline IgG2 hinge modified using three-dimensional protein model analysis of several orthologous hinge structures was determined to increase disulfide bond formation. In order to increase disulfide bond formation in the feline IgG2 hinge, the hinge sequence can be modified by replacing amino acids with cysteine. For example, a variant feline IgG2 Fc (SEQ ID NO: 17) with a modified hinge is prepared by replacing Gly with Cys at the amino acid position corresponding to position 14 of SEQ ID NO: 16. The corresponding adjacent polypeptides ssGLP1-G8_I_VARfeIgG2 (SEQ ID NO: 39) and ssGLP1-G8 / GLP1-2G_III_WTfeIgG2 (SEQ ID NO: 38) were designed, which contained variant feline IgG Fc of SEQ ID NO: 17, expressed in CHO cells, and purified by protein A chromatography. After the signal sequence was cut, the amino acid sequences of the secreted proteins were SEQ ID NOs: 26 and 25, respectively. SDS-PAGE analysis of the variant feline IgG2 constructs showed that the amount of protein in the low molecular weight band was reduced compared to the wild-type feline IgG2 construct in the absence of reducing agent ( Figure 2 B and Figure 2 A for comparison). These results indicate that Fc covalent pairing is improved for both variant feline IgG2 constructs.

[0202] In addition, differential scanning fluorescence analysis was used to assess the stability of adjacent polypeptides at each pH, ​​as reflected by the average melting point temperature (n=3) (Table 9 below). The enhancement of the stability of the variant feline IgG2 hinge was most obvious at pH 6. For example, the constructs with variant feline IgG2 (SEQ ID NOs: 25 and 26) showed higher Tm (56.9 and 59.7°C) at pH 6 compared to the corresponding constructs with wild-type feline IgG2 (SEQ ID NOs: 23 and 24) (whose Tm were 55.2 and 56.9°C, respectively).

[0203] Table 9 NC = No curve exists because no clear phase transition point is observed.

[0204] Contiguous polypeptides of Formulas I, II and III comprising GLP1-S8(7-35) (SEQ ID NO: 86) (instead of GLP1-G8(7-35) (SEQ ID NO: 87)) can be similarly designed and prepared. For example, ssGLP1-S8_I_WTfeIgG2 (SEQ ID NO: 40), GLP1-S8_I_WTfeIgG2 (SEQ ID NO: 28), ssGLP1-S8 / GLP1-3G_III_WTfeIgG2 (SEQ ID NO: 37) and GLP1-S8 / GLP1-3G_III_WTfeIgG2 (SEQ ID NO: 27) can be prepared. Similar constructs with variants rather than wild-type feline IgG Fc can also be prepared, such as GLP1-S8_I_VARfeIgG2, GLP1-S8_I_VARfeIgG2, GLP1-S8 / GLP1-2G_III_VARfeIgG2, and GLP1-S8 / GLP1-3G_III_VARfeIgG2.

[0205] Although feline IgG2 Fc is used in this example, contiguous polypeptides of Formulas I, II, and III comprising feline IgG1a Fc or IgG1b Fc (instead of IgG2) can also be designed and prepared. For example, similar contiguous polypeptides having wild-type feline IgG1a Fc, wild-type feline IgG1b Fc, variant feline IgG1a Fc, or variant feline IgG1b Fc (SEQ ID NOs: 80 to 83, respectively) can be designed and prepared. Example 7 GLP1 and canine IgG Fc fusion protein

[0206] A variety of Formula I, II and III contiguous polypeptides comprising variant GLP1 and canine IgG Fc can be designed and prepared. For example, a variant canine IgGD Fc (e.g., SEQ ID NO: 7 or SEQ ID NO: 62) with reduced complement activity and protein A binding can be selected for ease of purification based on its low or no C1q binding. In addition, flexible, non-structural linkers, such as glycine and / or serine-rich linkers, can be used.

[0207] Examples of contiguous polypeptides of Formula I are GLP1-G8_I_VARcaIgGD (SEQ ID NO:30) and GLP1-S8_I_VARcaIgGD (SEQ ID NO:32), which comprise: (1) one of GLP1-G8(7-35) or GLP1-S8(7-35), (2) a flexible linker, and (3) a variant canine IgGD Fc (e.g., SEQ ID NO:7). Examples of contiguous polypeptides of Formula III are GLP1-G8 / GLP1-3G_III_VARcaIgGD (SEQ ID NO:29) and GLP1-S8 / GLP1-3G_III_VARcaIgGD (SEQ ID NO:31), which comprise: (1) one of GLP1-G8 (SEQ ID NO:87) or GLP1-S8 (SEQ ID NO:86), (2) GLP1 (7-35) (SEQ ID NO:61), (3) two flexible linkers, (4) a 3G C-terminal extension, and (5) a variant canine IgGD Fc.

[0208] The adjacent polypeptide can be designed to have a signal sequence, a different GLP1 polypeptide (e.g., SEQ ID NO: 85, 86, 87, 98, or 99), or different modifications to canine IgG Fc. Examples with such changes include ssGLP1-S8 / GLP1-2G_III_VARcaIgGD (SEQ ID NO: 41), ssGLP1-G8 / GLP1-2G_III_VARcaIgGD (SEQ ID NO: 42), ssGLP1-S8 / GLP1-3G_III_VARcaIgGD (SEQ ID NO: 43), GLP1-S8 / GLP1-2G_III_VARcaIgGD (SEQ ID NO: 105), and GLP1-G8 / GLP1-2G_III_VARcaIgGD (SEQ ID NO: 106).

[0209] In addition, the adjacent polypeptides of Formulas I, II and III may include wild-type canine IgGD or wild-type or variant canine IgGA, IgGB or IgGC, in place of variant canine IgGD. For example, similar adjacent polypeptides having wild-type canine IgGA Fc, IgGB Fc, IgGC Fc or IgGD Fc (e.g., SEQ ID NO: 1, 2, 3 or 4, respectively) can be designed and prepared. Additional examples include adjacent polypeptides containing variant canine IgGA Fc (e.g., SEQ ID NO: 5 or 60), variant canine IgGB Fc (e.g., SEQ ID NO: 78) or variant canine IgGC Fc (e.g., SEQ ID NO: 6, 61, 79 or 84).

[0210] GLP1-G8 / GLP1-3G_III_VARcaIgGD (SEQ ID NO: 29) and GLP1-G8_I_VARcaIgGD (SEQ ID NO: 30) were expressed in CHO cells, and the supernatant containing the protein was collected and filtered. Both adjacent polypeptides were affinity purified by protein A chromatography. The SDS-PAGE profiles of the two adjacent polypeptides were compared in the absence or presence of a reducing agent (DTT), and the results showed that Fc disulfide bonds were effectively formed for both polypeptides (data not shown). Example 8 GLP1 and equine IgG Fc fusion protein

[0211] A variety of Formula I, II and III contiguous polypeptides comprising variant GLP1 and equine IgG Fc can be designed and prepared. For example, a variant canine IgG2 Fc (e.g., SEQ ID NO: 19, 71 or 72) with reduced complement activity and protein A binding can be selected for ease of purification based on its low or no C1q binding. In addition, flexible, non-structural linkers, such as glycine and / or serine-rich linkers, can be used.

[0212] Examples of contiguous polypeptides of Formula I are GLP1-G8_I_VAReqIgG2 (SEQ ID NO:34) and GLP1-S8_I_VAReqIgG2 (SEQ ID NO:36), which comprise (1) one of GLP1-G8 or GLP1-S8, (2) a flexible linker, and (3) a variant equine IgG2 Fc (e.g., SEQ ID NO:19). Examples of contiguous polypeptides of Formula III are GLP1-G8 / GLP1-3G_III_VAReqIgG2 (SEQ ID NO:33) and GLP1-S8 / GLP1-3G_III_VAReqIgG2 (SEQ ID NO:35), which comprise (1) one of GLP1-G8(7-35) (SEQ ID NO:87) or GLP1-S8(7-35) (SEQ ID NO:86), (2) GLP1(7-35) (SEQ ID NO:61), (3) two flexible linkers, (4) a 3G C-terminal extension, and (5) a variant equine IgGD Fc.

[0213] The adjacent polypeptide can be designed to have a signal sequence, a different GLP1 analog (e.g., SEQ ID NO: 86, 87, 98, or 99), a glycine extension (e.g., SEQ ID NO: 88 to 95), or additional modifications to equine IgG Fc. Examples with such changes include ssGLP1-G8 / GLP1-3G_III_VAReqIgG2 (SEQ ID NO: 44), ssGLP1-G8_I_VAReqIgG2 (SEQ ID NO: 45), ssGLP1-S8 / GLP1-3G_III_VAReqIgG2 (SEQ ID NO: 46), and ssGLP1-S8_I_VAReqIgG2 (SEQ ID NO: 47).

[0214] In addition, the adjacent polypeptides of Formulas I, II and III may include wild-type equine IgG2 or wild-type or variant equine IgG1, IgG3, IgG4, IgG5, IgG6, IgG7, instead of variant equine IgG2. For example, similar adjacent polypeptides having wild-type equine IgG1 Fc (e.g., SEQ ID NO: 63), IgG2 Fc (e.g., SEQ ID NO: 18 or 64), IgG3 Fc (e.g., SEQ ID NO: 65), IgG4 Fc (e.g., SEQ ID NO: 66), IgG5 Fc (e.g., SEQ ID NO: 67), IgG6 Fc (e.g., SEQ ID NO: 68) or IgG7 Fc (e.g., SEQ ID NO: 69) can be designed and prepared. Additional examples include contiguous polypeptides comprising a variant equine IgG1 Fc (e.g., SEQ ID NO:70), a variant equine IgG3 Fc (e.g., SEQ ID NO:73), a variant equine IgG4 Fc (e.g., SEQ ID NO:74), a variant equine IgG5 Fc (e.g., SEQ ID NO:75), a variant equine IgG6 Fc (e.g., SEQ ID NO:76), or a variant equine IgG7 Fc (e.g., SEQ ID NO:77).

[0215] The nucleotide sequences encoding ssGLP1-G8 / GLP1-3G_III_VAReqIgG2 (SEQ ID NO: 44) and ssGLP1-G8_I_VAReqIgG2 (SEQ ID NO: 45) were synthesized and cloned into separate mammalian expression vectors. The resulting vectors were transfected into CHO cells, respectively. After cleavage of the signal peptides (SEQ ID NO: 103 and 104), the supernatant containing the adjacent polypeptides was collected and filtered. The protein A column ( The two proteins were affinity purified using protein A affinity resin (Repligen). They were expressed in CHO cells, and the supernatants containing the proteins were collected and filtered. The two adjacent polypeptides were affinity purified using protein A chromatography. The SDS-PAGE profiles of the two adjacent polypeptides were compared in the absence or presence of a reducing agent (DTT), and the results showed that Fc disulfide bonds were effectively formed for the two polypeptides (data not shown). Example 9 Expression and purification of the feline GLP1R N-terminal soluble domain

[0216] From the full-length feline GLP1R amino acid sequence (SEQ ID NO:48), the N-terminal domain of the mature feline GLP1R responsible for binding GLP1 to GLP1R was identified (SEQ ID NO:49). Nucleotide sequences encoding (1) signal sequence, feline N-terminal GLP1R, human Fc and poly-His tag (ssFeGLP1R-N-huFc_PolyHis; SEQ ID NO:50) and (2) signal sequence, feline N-terminal GLP1R and poly-His tag (ssFeGLP1R-N_polyHis; SEQ ID NO:51) were synthesized and cloned into separate mammalian expression vectors. The resulting vectors were transfected into CHO cells separately. The supernatant containing the polypeptides was collected and filtered. The supernatant was purified using a Ni-agarose column or a protein A column (SEQ ID NO:52) for human Fc constructs. The protein was affinity purified using Protein A affinity resin (Repligen). Both proteins were used for GLP1 functional binding and ELISA. Example 10 GLP1 fusion protein binding kinetics

[0217] The binding affinity of GLP1-G8_I_VARfeIgG2 (SEQ ID NO: 26) to FeGLP1R-N-huFc_PolyHis was determined using biofilm interferometry (Octet). In brief, FeGLP1R-N-huFc_PolyHis was biotinylated, free unreacted biotin was removed, and the biotinylated protein was captured on the tip of the streptavidin sensor. The binding of different concentrations of GLP1-G8_I_VARfeIgG2 was monitored for 90 seconds. Dissociation was monitored for 600 seconds. A blank curve with only buffer was subtracted from it to correct for any offset. Using ForteBio TM The data analysis software fits the data to a 1:1 binding model to determine k on , k off and the K dThe buffer used for dilution and all binding steps was: 20 mM phosphate, 150 mM NaCl, pH 7.2. K between the feline GLP1R N-terminal domain and GLP1-G8_I_VARfeIgG2 d Between 8.0x10 -9 and 16x10 -9 Between M. Embodiment 11 GLP1 fusion protein bioactivity in cell-based assays

[0218] GLP1 cellular activity was determined using the CHOK-1-GL1R cell line (Discoverx, catalog number 95-0062C2), a hamster ovary cell line that overexpresses the Gs-coupled human glucagon ligand peptide-1 receptor (GLP1R) on the cell surface, using the cAMP Hunter Bioassay kit (Discoverx, catalog number 95-0062Y2). Cells were seeded in 96-well plates and incubated at 37°C, 5% CO2 for 24 hours. Cells were then treated with a control agonist or an adjacent polypeptide, which was GLP1 human (37a.a.) (Prospec, catalog number HOR-236) or Extendin-4 (Discoverx, catalog number 92-1115), which contained a variant GLP1, by performing a 3-fold serial dilution followed by incubation at 37°C for 30 minutes. The adjacent polypeptides tested were GLP1-G8 / GLP1-2G_III_VARfeIgG2 (SEQ ID NO: 25) and GLP1-G8_I_VARfeIgG2 (SEQ ID NO: 26).

[0219] Once GLP1 binds to the Gs-coupled GLP1R receptor, Gs stimulates adenylate cyclase to generate cAMP. At the end of the incubation, cAMP antibody reagent and cAMP working detection solution (which contains lysis buffer, cAMP conjugated to a small fragment of β-galactosidase (β-gal) and substrate) are added to the cells. The cells are incubated at room temperature in the dark for 1 hour to allow an immunocompetitive reaction of cAMP antibody binding between endogenous cAMP and cAMP conjugated to a small fragment of β-gal.

[0220] At the end of the 1 hour incubation, cAMP solution A containing the large β-gal fragment (which can be supplemented with free (non-antibody-bound) small β-gal fragment-cAMP to form a functional enzyme) is added to the cell lysate. The lysate is incubated at room temperature in the dark for 3 to 6 hours to allow β-gal to hydrolyze the substrate and generate a luminescent signal.

[0221] The more unbound free β-gal fragments - cAMP remain, the more functional β-gal enzymes will be formed. Therefore, the amount of signal generated is directly proportional to the amount of cAMP in the cell lysate. At the end of the incubation, the luminescence is read by a Synergy HT microplate reader (Biotek, Winooski, VT). EC50 is calculated using GraphPad Prism software (GraphPad Software, Inc., La Jolla, USA).

[0222] Figure 3 A curve showing relative light units (RLU) versus the concentration of each test sample is shown. The EC50 is listed in Table 10 below. Both GLP1-G8 / GLP1-2G_III_VARfeIgG2 (SEQ ID NO: 25) and GLP1-G8_I_VARfeIgG2 (SEQ ID NO: 26) are more active than GLP1 (7-37) and Extendin-4. GLP1-G8 / GLP1-2G_III_VARfeIgG2 (SEQ ID NO: 25) is more effective than GLP1-G8_I_VARfeIgG2 (SEQ ID NO: 26), suggesting that C-terminal GLP1 may additionally enhance activity.

[0223] Table 10 Example 12 Long-term stability of GLP1 fusion protein

[0224] GLP1-G8_I_VARfeIgG2 (SEQ ID NO: 26) was stored in PBS (pH 7.2) in 1.5 mL Eppendorf tubes at a concentration of 1.3 mg / mL and stored at 2-8°C for one year (Lot No. 2-29-2016). GLP1-G8_I_VARfeIgG2 (SEQ ID NO: 26) was also stored in PBS (pH 7.2) at a concentration of 10 mg / mL in 1.5 mL Eppendorf tubes and stored at 2-8°C for one day (Lot No. 2-2-2017). To evaluate stability, the stored samples were analyzed by a cell-based assay using the same CHOK-1-GL1R cell line (Discoverx, catalog number 95-0062C2) as described in Example 11, using cAMP-Glo TM Cell viability was determined using the Max assay (Promega, catalog number PAV1682).

[0225] F-12K medium (ATCC, catalog no. CHOK-1-GL1R cells in 1% FBS (30-2004, supplemented with 10% fetal bovine serum) were seeded in 96-well plates (Corning, catalog number 3610), heat-inactivated (Sigma, catalog number 2868) and incubated at 37° C., 5% CO 2 for 24 hours. The cells were then stimulated with a control agonist, batch 2-20-2016, or batch 2-2-2017, which was GLP1 human (37a.a.) (Prospec, catalog number HOR-236) or Extendin-4 (Discoverx, catalog number 92-1115), by serial dilution in serum-free medium in 3-folds, followed by the addition of complete induction buffer containing MgCl2 to a final concentration of 20 mM, isobutyl-1-methylxanthine (IBMX) (Sigma-Aldrich catalog number I7018) to a final concentration of 500 μM, and Ro 20-1724 [4-(3-butoxy-4-methoxy-benzyl)imidazolidinone] (Sigma Aldrich, catalog number B8279) to a final concentration of 100 μM.

[0226] The cells were incubated at room temperature for 30 minutes. During this process, once GLP1 binds to the Gs-coupled GLP1R receptor, Gs stimulates adenylate cyclase to form cAMP. At the end of the incubation, cAMP detection buffer (which contains inactive protein kinase A holoenzyme, protein kinase A substrate, and lysis buffer) was added to the cells. The plate was placed on an orbital shaker for 1-2 minutes and then incubated at room temperature (23°C) for 20 minutes. Cellular cAMP will activate protein kinase A by binding to its regulatory inhibitory subunit and releasing the catalytic subunit. The free catalytic subunit catalyzes the transfer of the terminal phosphate of ATP to the protein kinase A substrate, thereby consuming cellular ATP in the process. At the end of the incubation, the luciferase-based The reagents were added to the cell lysate and the plate was shaken on an orbital shaker for 2 minutes and then incubated for 10 minutes at room temperature in the dark.

[0227] The Mg present in the cell lysate 2+ In the presence of ATP, luciferase catalyzes the monooxygenation of luciferin, obtaining a luminescent signal proportional to the amount of ATP in the cell. At the end of the 10-minute incubation, the plate was read on a SynergyHT microplate reader (Biotek, Winooski, VT). Luminescence is proportional to ATP levels, but inversely proportional to cAMP levels. Therefore, luminescence decreases as cAMP concentration increases.

[0228] Figure 4Results of the cell-based assay are shown, plotting luminescence versus concentration for batch 2-29-2016 compared to batch 2-2-2017 and GLP1 (31 a.a.). The GLP1-G8_I_VARfeIgG2 sample maintained cellular viability after one year of storage at 2-8°C in PBS. Embodiment 13 GLP1 fusion protein serum stability

[0229] GLP1-G8_I_VARfeIgG2 (SEQ ID NO: 26) was stored in PBS (pH 7.2) containing feline serum at 37°C for 24 hours to test in vitro serum stability. The cell-based assay was performed as described in Example 12, and the results showed that activity was maintained (data not shown). In addition, no visible degradation was observed by Western blot analysis ( Figure 5 ). Embodiment 14 In vivo pharmacokinetics of GLP1 fusion proteins

[0230] GLP1-G8_I_VARfeIgG2 (SEQ ID NO: 26) was administered to 5 cats by subcutaneous injection in a single dose (2 mg / kg). Serum samples were taken before administration (time 0) and 4 hours, 8 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours and 168 hours after administration. The concentration of GLP1-G8_I_VARfeIgG2 in serum samples was determined by quantitative ELISA. The GLP1-G8_I_VARfeIgG2 polypeptide with a detection limit of 4 ng / mL was used as a reference. The serum concentration of GLP1-G8_I_VARfeIgG2 was plotted as a curve over time ( Figure 6 The average serum half-life of GLP1-G8_I_VARfeIgG2 (t 1 / 2 ) is 39 hours. Average T max For 22 hours, the average C max The average area under the curve (AUC) was about 950 μg(h) / mL.

[0231] The quantitative ELISA uses anti-GLP1 antibody (4F3, Novus Biologicals, catalog number NBP1-97413) and goat anti-cat IgG-Fc, HRP conjugated antibody (Bethyl Laboratories, Inc., catalog number A20-117P) to quantify GLP1-G8_I_VARfeIgG2 in feline serum samples in in vivo pharmacokinetic studies. A 96-well plate was coated with anti-GLP1 antibody (5 μg / mL, 100 μl / well in coating buffer). The plate was sealed and incubated overnight at 4°C. The plate was washed three times with 1X TBST (10X TBST, Teknova, catalog number T9511), and blocking buffer was added. After removing the blocking buffer, serially diluted reference standards and samples in blocking buffer were added (100 μl / well), and the plate was incubated at room temperature for 2 hours. The plate was washed three times with 1XTBST and goat anti-cat IgG Fc antibody (0.1 μg / mL, 100 μl / well in blocking buffer) was added. After incubation at room temperature for 1 hour, the plate was washed five times with 1XTBST. TMB substrate (ScyTek, catalog number TM1999) (100 μl / well) was added and incubated at room temperature for 1 minute. The reaction was stopped by adding 2M H2SO4 (50 μl / well). The absorption at 450 nm was measured to calculate the concentration of GLP1-G8_I_VARfeIgG2 in the serum sample.

[0232] In addition, GLP1-G8_I_VARfeIgG2 was measured in the same serum samples (without addition of DPP-4 inhibitors) using a cell-based activity assay. The same CHOK-1-GL1R cell line (Discoverx, catalog number 95-0062C2) and cAMP-Glo ​​were used as in Example 12. TM Max analysis (Promega, catalog number PAV1682). However, in this example, the cells were stimulated with a control agonist GLP1 human (37a.a.) (Prospec, catalog number HOR-236) or a cat serum sample taken before administration (time 0) and 4 hours, 8 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours and 168 hours after administration and diluted in serum-free medium (5%, 0.5% and 0.05% dilution). SoftMax pro 7 (Molecular Devices, Sunnyvale, CA) was used to calculate the concentration of GLP1-G8_I_VARfeIgG2 in each sample. The concentration of GLP1-G8_I_VARfeIgG2 of five cats was plotted against time ( Figure 7 The average AUC was about 840 μg (h) / mL, and the average t 1 / 2The concentrations calculated from the cell-based activity assay were consistent with those obtained from ELISA, indicating that the variant GLP1 detected by ELISA was biologically active. Embodiment 15 GLP1, Glucagon and IgG Fc Fusion Protein

[0233] In order to study long-acting GLP1 receptor and glucagon receptor dual agonists, a contiguous polypeptide comprising a GLP1 polypeptide, a glucagon polypeptide and an IgG Fc polypeptide was designed with the following construct: Formula (IV): GLP1-L1-Fc-L2-Gluc; and Formula (V): Gluc—L1—Fc—L2—GLP1, Wherein GLP1 is a GLP1 polypeptide, Gluc is a glucagon polypeptide, L1 and L2 are linkers, and Fc is an Fc polypeptide.

[0234] As discussed above, GLP1 is modified to be resistant to DPP-4 by replacing the alanine at position 8 corresponding to wild-type GLP1 (7-37) (SEQ ID NO: 85) with glycine or serine. In addition, the DPP-4-resistant GLP1 is further modified by removing the two C-terminal amino acids to generate variant GLP1-S8 (7-35) (SEQ ID NO: 86) and variant GLP1-G8 (7-35) (SEQ ID NO: 87) polypeptides.

[0235] When the GLP1 polypeptide is located at the C-terminus of the construct, such as in formula (V), it is not susceptible to degradation by DPP-4. Therefore, for a GLP1 polypeptide located at the C-terminus, it is not necessary to replace alanine with glycine or serine. Accordingly, wild-type GLP1 (7-37) (SEQ ID NO: 85) can be used at the C-terminus.

[0236] The linker can be a flexible, non-structural linker, such as a glycine-rich and serine-rich linker. A flexible extension can be added to the C-terminus of the adjacent polypeptide. The extension can contain one glycine residue (SEQ ID NO: 88), two glycine residues (SEQ ID NO: 89), three glycine residues (SEQ ID NO: 90), four glycine residues (SEQ ID NO: 91), five glycine residues (SEQ ID NO: 92), six glycine residues (SEQ ID NO: 93), seven glycine residues (SEQ ID NO: 94), eight glycine residues (SEQ ID NO: 95) or more glycine residues.

[0237] The contiguous polypeptide may comprise a wild-type glucagon polypeptide (eg, SEQ ID NO: 21) or a variant glucagon polypeptide.

[0238] The adjacent polypeptide may comprise human IgG Fc or an IgG Fc of a companion animal species such as canine, feline or equine. The IgG Fc subtype used may be based on having low or no C1q binding activity and / or having protein A binding ability. For example, wild-type or variant human, canine, equine or feline IgG Fc (e.g., SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83 or 84) having low or no C1q binding and / or having protein A binding ability may be used.

[0239] Exemplary contiguous polypeptides comprising a GLP1 polypeptide, a glucagon polypeptide, and a feline IgG Fc polypeptide include GLP1-G8 / Gluc-3G_IV_WTfeIgG2 (SEQ ID NO: 52) and Gluc / GLP1-2G_V_WTfeIgG2 (SEQ ID NO: 53).

[0240] Exemplary contiguous polypeptides comprising a GLP1 polypeptide, a glucagon polypeptide, and a canine IgG Fc polypeptide include GLP1-G8 / Gluc-4G_IV_VARcaIgGD (SEQ ID NO: 54) and Gluc / GLP1-3G_V_VARcaIgGD (SEQ ID NO: 55).

[0241] Exemplary contiguous polypeptides comprising a GLP1 polypeptide, a glucagon polypeptide, and an equine IgG Fc polypeptide include GLP1-G8 / Gluc-4G_IV_VAReqIgGD (SEQ ID NO: 56) and Gluc / GLP1-3G_V_VAReqIgG2 (SEQ ID NO: 57).

[0242] Exemplary contiguous polypeptides comprising a GLP1 polypeptide, a glucagon polypeptide, and a human IgG Fc polypeptide include GLP1-G8 / Gluc-4G_IV_huIgG4 (SEQ ID NO: 8) and Gluc / GLP1-3G_V_huIgG4 (SEQ ID NO: 59). Example 16 Variant IgG Fc polypeptides with enhanced hinge disulfide bond formation

[0243] Other three-dimensional protein model analysis of several orthologous hinge structures was used to modify feline and equine IgG hinges to enhance disulfide bond formation. To enhance disulfide bond formation in the feline IgG hinge, the hinge sequence can be modified by replacing lysine with proline (e.g., K16P) at a position corresponding to position 16 of feline IgG2 (SEQ ID NO: 16), feline IgG1a (SEQ ID NO: 80 or SEQ ID NO: 117), or feline IgG1b (SEQ ID NO: 81 or SEQ ID NO: 118). Examples of amino acid sequences of variant feline IgG polypeptides with modified hinges include SEQ ID NO: 125, SEQ ID NO: 126, and SEQ ID NO: 127.

[0244] To increase disulfide bond formation in the equine IgG hinge, the hinge sequence can be modified by replacing cysteine ​​with serine at position 3 corresponding to equine IgG (e.g., IgG2 Fc (SEQ ID NO: 129)) and / or replacing glutamine with proline (e.g., C3S, Q20P) at position 20 corresponding to equine IgG (e.g., IgG2 Fc (SEQ ID NO: 129)). Examples of amino acid sequences of variant equine IgG polypeptides with modified hinges include SEQ ID NO: 130, SEQ ID NO: 131, SEQ ID NO: 132, SEQ ID NO: 134, and SEQ ID NO: 135. Embodiment 17 Recombinant production of variant IgG Fc polypeptides with enhanced and / or hinge disulfide bond formation

[0245] Three-dimensional protein models were used to design feline and equine variant IgG Fc polypeptides comprising sequences from hinge regions of different IgG isotypes to enhance recombinant production and improve hinge disulfide bond formation. Variant feline IgG2 Fc polypeptides comprising sequences from feline IgG1a or IgG1b hinge regions (e.g., SEQ ID NO: 125) can be prepared. In addition, variant equine IgG2 Fc polypeptides comprising sequences from the hinge region of equine IgG1 (e.g., SEQ ID NO: 19) can be prepared.

[0246] The level of recombinant production and / or the level of hinge disulfide bond formation of the variant IgG Fc polypeptide can be determined and compared to its level in another IgG Fc (e.g., a corresponding wild-type IgG Fc of the same or different isotype, or a wild-type or variant IgG Fc from another companion animal) by SDS-PAGE analysis under reducing and non-reducing conditions.

Claims

1. A polypeptide comprising a variant IgG Fc polypeptide comprising at least one amino acid modification relative to a wild-type IgG Fc polypeptide of a companion animal species, wherein the variant IgG Fc polypeptide has enhanced binding affinity to Protein A relative to the wild-type IgG Fc polypeptide, decreased binding affinity to C1q and / or CD16 relative to the wild-type IgG Fc polypeptide, and / or increased recombinant production and / or increased hinge disulfide bond formation relative to the wild-type IgG Fc polypeptide as determined by SDS-PAGE analysis under reducing and / or non-reducing conditions; wherein the companion animal species is canine, feline or equine and / or wherein the wild-type IgG Fc polypeptide is a) canine IgG-A Fc, IgG-B Fc, IgG-C Fc or IgG-D Fc; b) equine IgG1 Fc, IgG2 Fc, IgG3 Fc, IgG4 Fc, IgG5 Fc, IgG6 Fc or IgG7 Fc; or c) Feline IgG1a Fc, IgG1b Fc or IgG2 Fc.

2. The polypeptide of claim 1, wherein the variant IgG Fc polypeptide binds to C1q and / or CD16 with a dissociation constant (K d ) is greater than 5x 10 -6 M, greater than 1x 10 -5 M, greater than 5x 10 -5 M, greater than 1x 10 -4 M, greater than 5x 10 -4 M or greater than 1x 10 -3 M, as determined by biofilm interferometry; and / or wherein the variant IgG Fc polypeptide binds to protein A with a dissociation constant (K d ) is less than 5x 10 -6 M, less than 1x 10 -6 M, less than 5x 10 -7 M, less than 1x 10 -7 M, less than 5x 10 -8 M, less than 1x 10 -8 M, less than 5x 10 -9 M, less than 1x 10 -9 M, less than 5x 10 -10 M, less than 1x 10 -10 M, less than 5x 10 -11 M, less than 1x 10 -11 M, less than 5x 10 -12 M or less than 1x 10 -12 M, as determined by biofilm interferometry.

3. A polypeptide according to any one of the preceding claims, wherein the variant IgG Fc polypeptide comprises: a) at least one amino acid substitution relative to a wild-type feline IgG Fc polypeptide, wherein the variant IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to or located at position 16 of SEQ ID NO: 16, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 117 or SEQ ID NO: 118; b) at least one amino acid substitution relative to a wild-type equine IgG Fc polypeptide, wherein the variant IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to or located at position 3 of SEQ ID NO: 129; c) at least one amino acid substitution relative to a wild-type equine IgG Fc polypeptide, wherein the variant IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to or located at position 20 of SEQ ID NO: 129; d) at least one amino acid substitution relative to a wild-type feline IgG Fc polypeptide, wherein the variant IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to or located at position 16 of SEQ ID NO: 16, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 117 or SEQ ID NO: 118; e) at least one amino acid substitution relative to a wild-type equine IgG Fc polypeptide, wherein the variant IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to or located at position 3 of SEQ ID NO: 129; and / or f) at least one amino acid substitution relative to a wild-type equine IgG Fc polypeptide, wherein the variant IgG Fc polypeptide comprises an amino acid substitution at a position corresponding to or located at position 20 of SEQ ID NO:

129.

4. A polypeptide according to any one of the preceding claims, wherein the variant IgG Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 19, SEQ ID NO: 125 or SEQ ID NO: 126, SEQ ID NO: 127, SEQ ID NO: 128, SEQ ID NO: 129, SEQ ID NO: 130, SEQ ID NO: 131, SEQ ID NO: 132, SEQ ID NO: 133, SEQ ID NO: 134 or SEQ ID NO:

135.

5. A polypeptide according to any one of the preceding claims, wherein the variant IgG Fc polypeptide comprises: a) a cysteine ​​at a position corresponding to position 8, position 9, position 10, position 11, position 12, position 13, position 14, position 15 or position 16 of SEQ ID NO: 16; b) a cysteine ​​at a position corresponding to position 8, position 9, position 10, position 11, position 12, position 13, position 14, position 15 or position 16 of SEQ ID NO: 16; c) a cysteine ​​at a position corresponding to position 14 of SEQ ID NO: 16; d) a cysteine ​​at a position at position 14 of SEQ ID NO: 16; or e) SEQ ID NO:

17.

6. The polypeptide according to any one of the preceding claims, wherein the variant IgG Fc polypeptide is identical to SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:100, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO:120, SEQ ID NO:121, SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ: The amino acid sequences of SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156 or SEQ ID NO:157 are at least 90% identical, at least 95% identical, at least 97% identical or at least 99% identical.

7. A polypeptide according to any one of the preceding claims, wherein the variant IgG Fc polypeptide comprises: a) an amino acid substitution at a position corresponding to or located at position 21 of SEQ ID NO: 1, an amino acid substitution at a position corresponding to or located at position 23 of SEQ ID NO: 1, an amino acid substitution at a position corresponding to or located at position 25 of SEQ ID NO: 1, an amino acid substitution at a position corresponding to or located at position 80 of SEQ ID NO: 1, an amino acid substitution at a position corresponding to or located at position 205 of SEQ ID NO: 1, and / or an amino acid substitution at a position corresponding to or located at position 207 of SEQ ID NO: 1; b) an amino acid substitution at a position corresponding to or located at position 21 of SEQ ID NO: 3, an amino acid substitution at a position corresponding to or located at position 23 of SEQ ID NO: 3, and / or an amino acid substitution at a position corresponding to or located at position 24 of SEQ ID NO: 3; c) an amino acid substitution at a position corresponding to or located at position 21 of SEQ ID NO:4, an amino acid substitution at a position corresponding to or located at position 23 of SEQ ID NO:4, an amino acid substitution at a position corresponding to or located at position 25 of SEQ ID NO:4, an amino acid substitution at a position corresponding to or located at position 80 of SEQ ID NO:4, and / or an amino acid substitution at a position corresponding to or located at position 207 of SEQ ID NO:4; d) an amino acid substitution at a position corresponding to or located at position 15 of SEQ ID NO:64, and / or an amino acid substitution at a position corresponding to or located at position 203 of SEQ ID NO:64; e) an amino acid substitution at a position corresponding to or located at position 199 of SEQ ID NO:67, and / or an amino acid substitution at a position corresponding to or located at position 200 of SEQ ID NO:67; f) an amino acid substitution at a position corresponding to or located at position 199 of SEQ ID NO:68, an amino acid substitution at a position corresponding to or located at position 200 of SEQ ID NO:68, an amino acid substitution at a position corresponding to or located at position 201 of SEQ ID NO:68, and / or an amino acid substitution at a position corresponding to or located at position 202 of SEQ ID NO:68; g) a threonine at a position corresponding to or located at position 21 of SEQ ID NO: 1, a leucine at a position corresponding to or located at position 23 of SEQ ID NO: 1, an alanine at a position corresponding to or located at position 25 of SEQ ID NO: 1, a glycine at a position corresponding to or located at position 80 of SEQ ID NO: 1, an alanine at a position corresponding to or located at position 205 of SEQ ID NO: 1, and / or a histidine at a position corresponding to or located at position 207 of SEQ ID NO: 1; h) a threonine at a position corresponding to or located at position 21 of SEQ ID NO: 3, a leucine at a position corresponding to or located at position 23 of SEQ ID NO: 3, and / or an isoleucine at a position corresponding to or located at position 24 of SEQ ID NO: 3; i) a threonine at a position corresponding to or located at position 21 of SEQ ID NO:4, a leucine at a position corresponding to or located at position 23 of SEQ ID NO:4, an alanine at a position corresponding to or located at position 25 of SEQ ID NO:4, a glycine at a position corresponding to or located at position 80 of SEQ ID NO:4, and / or a histidine at a position corresponding to or located at position 207 of SEQ ID NO:4; j) a threonine or valine at a position corresponding to or located at position 15 of SEQ ID NO: 64, and / or a tyrosine or valine at a position corresponding to or located at position 203 of SEQ ID NO: 64; k) a leucine at a position corresponding to or located at position 199 of SEQ ID NO:67, and / or a histidine at a position corresponding to or located at position 200 of SEQ ID NO:67; 1) a leucine at a position corresponding to or located at position 199 of SEQ ID NO: 68, a histidine at a position corresponding to or located at position 200 of SEQ ID NO: 68, an asparagine at a position corresponding to or located at position 201 of SEQ ID NO: 68, and / or a histidine at a position corresponding to or located at position 202 of SEQ ID NO: 68; and / or m) the amino acid sequence of SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:84, SEQ ID NO:19, SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:75 or SEQ ID NO:

76.

8. The polypeptide according to any one of the preceding claims, wherein the variant IgG Fc polypeptide comprises: a) an amino acid substitution at a position corresponding to or located at position 93 of SEQ ID NO: 2, or an amino acid substitution at a position corresponding to or located at position 93 of SEQ ID NO: 3; b) an amino acid substitution at a position corresponding to or located at position 87 of SEQ ID NO:63, an amino acid substitution at a position corresponding to or located at position 87 of SEQ ID NO:65, an amino acid substitution at a position corresponding to or located at position 87 of SEQ ID NO:66, or an amino acid substitution at a position corresponding to or located at position 87 of SEQ ID NO:69; c) an amino acid substitution at a position corresponding to or located at position 198 of SEQ ID NO:80, or an amino acid substitution at a position corresponding to or located at position 198 of SEQ ID NO:81; d) an arginine at a position corresponding to or located at position 93 of SEQ ID NO: 2, or an arginine at a position corresponding to or located at position 93 of SEQ ID NO: 3; e) a serine at a position corresponding to or located at position 87 of SEQ ID NO:63, a serine at a position corresponding to or located at position 87 of SEQ ID NO:65, a serine at a position corresponding to or located at position 87 of SEQ ID NO:66, or a serine at a position corresponding to or located at position 87 of SEQ ID NO:69; f) an alanine at a position corresponding to or located at position 198 of SEQ ID NO:80, or an alanine at a position corresponding to or located at position 198 of SEQ ID NO:81; g) the amino acid sequence of SEQ ID NO:78, SEQ ID NO:79 or SEQ ID NO:84; h) the amino acid sequence of SEQ ID NO:70, SEQ ID NO:73, SEQ ID NO:74 or SEQ ID NO:77; i) the amino acid sequence of SEQ ID NO: 82 or SEQ ID NO: 83; j) an amino acid substitution at a position corresponding to or located at position 5 of SEQ ID NO: 2, an amino acid substitution at a position corresponding to or located at position 38 of SEQ ID NO: 2, an amino acid substitution at a position corresponding to or located at position 39 of SEQ ID NO: 2, an amino acid substitution at a position corresponding to or located at position 97 of SEQ ID NO: 2, and / or an amino acid substitution at a position corresponding to or located at position 98 of SEQ ID NO: 2; k) an amino acid substitution at a position corresponding to or located at position 5 of SEQ ID NO: 3, an amino acid substitution at a position corresponding to or located at position 38 of SEQ ID NO: 3, an amino acid substitution at a position corresponding to or located at position 39 of SEQ ID NO: 3, an amino acid substitution at a position corresponding to or located at position 97 of SEQ ID NO: 3, and / or an amino acid substitution at a position corresponding to or located at position 98 of SEQ ID NO: 3; 1) a proline at a position corresponding to or located at position 5 of SEQ ID NO: 2, a glycine at a position corresponding to or located at position 38 of SEQ ID NO: 2, an arginine at a position corresponding to or located at position 39 of SEQ ID NO: 2, an isoleucine at a position corresponding to or located at position 97 of SEQ ID NO: 2, and / or a glycine at a position corresponding to or located at position 98 of SEQ ID NO: 2; m) proline at a position corresponding to or located at position 5 of SEQ ID NO:3, glycine at a position corresponding to or located at position 38 of SEQ ID NO:3, arginine at a position corresponding to or located at position 39 of SEQ ID NO:3, isoleucine at a position corresponding to or located at position 97 of SEQ ID NO:3, and / or glycine at a position corresponding to or located at position 98 of SEQ ID NO:3; or n) SEQ ID NO: 139, SEQ ID NO: 140, SEQ ID NO: 141, SEQ ID NO: 142, SEQ ID NO: 143, SEQ ID NO: 144, SEQ ID NO: 145, SEQ ID NO: 146, SEQ ID NO: 147, SEQ ID NO: 148, SEQ ID NO: 149, SEQ ID NO: 150, SEQ ID The amino acid sequence of NO:151, SEQ ID NO:152, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156 or SEQ ID NO:

157.

9. A polypeptide comprising a variant IgG Fc polypeptide, wherein the variant IgG Fc polypeptide comprises: a) a tyrosine or tryptophan at a position corresponding to or located at position 138 of SEQ ID NO: 1, a tyrosine or tryptophan at a position corresponding to or located at position 137 of SEQ ID NO: 2, a tyrosine or tryptophan at a position corresponding to or located at position 137 of SEQ ID NO: 3, or a tyrosine or tryptophan at a position corresponding to or located at position 138 of SEQ ID NO: 4; b) a tyrosine or tryptophan at a position corresponding to or located at position 154 of SEQ ID NO: 16, a tyrosine or tryptophan at a position corresponding to or located at position 154 of SEQ ID NO: 80 or SEQ ID NO: 117, or a tyrosine or tryptophan at a position corresponding to or located at position 154 of SEQ ID NO: 81 or SEQ ID NO: 118; or c) the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:109, SEQ ID NO:111, SEQ ID NO:113, SEQ ID NO:115, SEQ ID NO:119, SEQ ID NO:121 or SEQ ID NO:

123.

10. A polypeptide comprising a variant IgG Fc polypeptide, wherein the variant IgG Fc polypeptide comprises: a) a serine corresponding to or located at a position 138 of SEQ ID NO: 1, a serine corresponding to or located at a position 137 of SEQ ID NO: 2, a serine corresponding to or located at a position 137 of SEQ ID NO: 3, a serine corresponding to or located at a position 138 of SEQ ID NO: 4, a serine corresponding to or located at a position 154 of SEQ ID NO: 16, a serine corresponding to or located at a position 154 of SEQ ID NO: 80 or SEQ ID NO: 117, or a serine corresponding to or located at a position 154 of SEQ ID NO: 81 or SEQ ID NO: 118; b) an alanine at a position corresponding to or located at position 140 of SEQ ID NO: 1, an alanine at a position corresponding to or located at position 139 of SEQ ID NO: 2, an alanine at a position corresponding to or located at position 139 of SEQ ID NO: 3, an alanine at a position corresponding to or located at position 140 of SEQ ID NO: 4, an alanine at a position corresponding to or located at position 156 of SEQ ID NO: 16, an alanine at a position corresponding to or located at position 156 of SEQ ID NO: 80 or SEQ ID NO: 117, or an alanine at a position corresponding to or located at position 156 of SEQ ID NO: 81 or SEQ ID NO: 118; c) a threonine corresponding to or located at position 181 of SEQ ID NO: 1, a threonine corresponding to or located at position 180 of SEQ ID NO: 2, a threonine corresponding to or located at position 180 of SEQ ID NO: 3, a threonine corresponding to or located at position 181 of SEQ ID NO: 4, a threonine corresponding to or located at position 197 of SEQ ID NO: 16, a threonine corresponding to or located at position 197 of SEQ ID NO: 80 or SEQ ID NO: 117, or a threonine corresponding to or located at position 197 of SEQ ID NO: 81 or SEQ ID NO: 118; and / or d) the amino acid sequence of SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:110, SEQ ID NO:112, SEQ ID NO:114, SEQ ID NO:116, SEQ ID NO:120, SEQ ID NO:122 or SEQ ID NO:124.

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